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A Comprehensive Overview of Irritable Bowel Syndrome: Clinical and Basic Science Aspects [1 ed.]
 0128213248, 9780128213247

Table of contents :
Cover
A COMPREHENSIVE
OVERVIEW OF
IRRITABLE BOWEL
SYNDROME
Clinical and Basic Science
Aspects
Copyright
Contributors
Preface
Introduction to irritable bowel syndrome: General overview and epidemiology
References
Pathogenesis of irritable bowel syndrome
Fundamentals-Impaired gut motility and visceral hypersensitivity in IBS
Alteration in gut motility
Visceral hypersensitivity
Factors and mechanisms in IBS pathology
Brain-gut axis
Serotonin and its metabolism
Possible role of peptide YY
Histamine and mast cells
Gut microbiota
Genetics
Low-grade mucosal inflammation and immune activation
The role of diet in IBS
Conclusions
References
Irritable bowel syndrome and the brain-gut connection
Introduction
BGA anatomy and IBS
Hypothalamic-pituitary-adrenal axis
Enteric nervous system
Immune system
Central nervous system
The microbiota-brain-gut axis
MBGA pathways
5-HT
SCFAs
GABA
Restoring the microbiota-brain-gut axis to treat IBS
Conclusion
References
The control of the intestinal epithelium integrity in irritable bowel syndrome patients
Mechanical barrier
Intestinal microbiota
Immunological activation in irritable bowel syndrome
T cells
Mast cells
Macrophages and eosinophils
B cells
Immune system activation in IBS
Nervous system
Conclusions
Acknowledgments
References
Irritable bowel syndrome and gut microbiota
Gut microbiota
Post-infectious IBS (PI-IBS)
Microbiota-brain-gut axis
Gut microbiota alteration in IBS
Small intestine bacterial overgrowth
Prebiotics, probiotics and synbiotics
Fecal microbiota transplantation
Conclusions
Acknowledgments
References
Gender-related differences and significance of gonadal hormones in irritable bowel syndrome
Gender-related differences in irritable bowel syndrome
Gonadal hormones in irritable bowel syndrome
Estrogen and androgen receptors in irritable bowel syndrome
Gonadal hormones in the colonic motility modulation
Gonadal hormones in the visceral pain regulation
Conclusions
Acknowledgments
References
Genetic aspect (with SNPs) of irritable bowel syndrome
Introduction
Mutations within genes related to voltage-gated sodium channel
Single nucleotide polymorphisms associated with IBS pathophysiology
Serotonin genes
Serotonin transporter gene
Serotonin receptor genes
Cannabinoid receptor genes
Guanine nucleotide-binding protein
Catechol-O-methyltransferase gene
Interleukin genes
Conclusion
Acknowledgments
References
Clinical diagnosis of irritable bowel syndrome
Introduction
Rome IV criteria for IBS
Step I
Step II
Step III
Step IV
Basic laboratory tests
Additional laboratory tests
Conclusion
Further reading
Biomarkers of irritable bowel syndrome
Introduction
Markers of the inflammatory process
Microbiome-related markers
Biomarkers related to changes in intestinal permeability
Biomarkers related to intercellular interactions
Adipokines and neuropetides as biomarkers in IBS
Biomarkers related to lipid turnover
Potential biomarkers expressed in leukocytes
Immune cell-derived biomarkers
Biomarkers in panels
Other potential biomarkers
Genetic testing
Conclusions
References
Irritable bowel syndrome: Current therapies and future perspectives
Empirical treatment
Anti-spasmodics
Constipation-predominant IBS (IBS-C)
Prostaglandin derivative (lubiprostone)
Targeting guanylyl cyclase C (linaclotide)
Sodium-hydrogen exchanger inhibitor (tenapanor)
Diarrhea-predominant IBS (IBS-D)
Inhibition of serotonergic pathway (alosetron, cilansetron, ramosetron)
Targeting opioid receptors (loperamide, eluxadoline, asimadoline)
Targeting gut microbiota (probiotics, antibiotics)
Probiotics
Antibiotic (rifaximin)
Future perspectives
Adsorbent-AST-120
Tryptophan hydroxylase-1 inhibitor-LX1031
Tachykinin receptor inhibitor-Ibodutant
5-HT4 agonists-Tegaserod, prucalopride
Glucagon-like peptide 1 analog-ROSE-010
Muscarinic receptor type 3 antagonist-Solifenacin
Tyrosine derivative-Tiropramide
Bombesin receptor subtype 2 antagonist-ASP-7147
Melatonin
Conclusion
Acknowledgments
References
Pain in irritable bowel syndrome
Non-pharmacological treatment
Psycho- and hypnotherapy in IBS
Self-management
Education
Patient-doctor relationship
Dietary modifications
FODMAP-diet
Fiber
Probiotics
Red pepper-capsaicin
Peppermint oil
Herbal supplements
Pharmacological treatment
Antidepressants
TCAs
SSRIs
SNRIs
Pregabalin and gabapentin
Benzodiazepines
Antibiotics
Antispasmodics
Laxatives
Lubiprostone
Linaclotide
Tegaserod
Antidiarrheals
Alosetron
Ramosetron
Ondansetron and granisetron
Loperamide
Eluxadoline
Centrally acting opioids
Non-steroidal anti-inflammatory drugs (NSAIDs): Acetaminophen, acetylsalicylic acid
Conclusion
References
Non-pharmacological approach in irritable bowel syndrome therapy
Non-pharmacological approach
Diet
FODMAP
Medical foods
Dietary advices for IBS patients
Psychological interventions
Cognitive behavioral therapy
Gut-directed hypnosis
Psychodynamic interpersonal therapy
Physical activity
Fecal microbiota transplantation
Conclusions
Acknowledgments
References
Diet in irritable bowel syndrome
Introduction
The diet
The first line therapy
Energy and macronutrients intake
Fluid intake
Alcohol intake
Caffeine intake
Fiber intake
Milk and dairy products
Spicy food intake
Physical activity
The second line approach-Low FODMAP diet
Other possibilities
Gluten free diet
Probiotic supplementation
Fecal microbiota transplantation
Conclusions
References
Correlation of irritable bowel syndrome with psychiatric disorders
Introduction
Bipolar disorder
Depression
Anxiety disorders
Obsessive-compulsive disorder
Posttraumatic stress disorder
Schizophrenia
Sleep disorders
Use disorders
Erectile dysfunction
Dementia
Eating disorders
Summary
References
Preclinical models of irritable bowel syndrome
Introduction
Animal models of irritable bowel syndrome
IBS induction through the direct stimulation of the colonic mucosa
Chemically-induced IBS models
Parasite infection-induced animal models
Stress-induced IBS
Stress during adult life
Stress during early life
Models of IBS with constipation
In vitro methods to study irritable bowel syndrome
Studies in biopsies from IBS patients and animal models
Protein expression and immunohistochemical studies
Transmission electron microscopy studies
Ussing chambers to study mucosa permeability of IBS patients and animal models
Cell and organ cultures and organ bath studies
Cell and organoid cultures
Whole-mount preparations
Organ bath studies
Gut-on-a-chip
Conclusions
References
Index
A
B
C
D
E
F
G
H
I
L
M
N
O
P
R
S
T
U
V
W
Z
Back Cover

Citation preview

A COMPREHENSIVE OVERVIEW OF IRRITABLE BOWEL SYNDROME

A COMPREHENSIVE OVERVIEW OF IRRITABLE BOWEL SYNDROME Clinical and Basic Science Aspects

Edited by

JAKUB FICHNA

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-821324-7 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Mica Haley Acquisitions Editor: Stacy Masucci Editorial Project Manager: Mona Zahir Production Project Manager: Niranjan Bhaskaran Cover Designer: Christian J. Bilbow Credits for the cover image: Leon Pawlik Typeset by SPi Global, India

Contributors Raquel Abalo Department of Basic Health Sciences, University Rey Juan Carlos (URJC); High Performance Research Group in Physiopathology and Pharmacology of the digestive system (NeuGut), URJC, Alcorco´n; R+D+i Unit Associated to Medical Chemistry Institute (IQM, CSIC), Madrid, Spain €e s Department of Basic Health Sciences, University Rey Juan Ana Bagu Carlos (URJC); High Performance Research Group in Experimental Pharmacology (PHARMAKOM), URJC, Alcorco´n; R+D+i Unit Associated to Medical Chemistry Institute (IQM, CSIC), Madrid, Spain Agata Binienda Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Miłosz Caban Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Jakub Fichna Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Damian Jacenik Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland Laura Lo´pez-Go´mez Department of Basic Health Sciences, University Rey Juan Carlos (URJC); High Performance Research Group in Physiopathology and Pharmacology of the digestive system (NeuGut), URJC, Alcorco´n, Spain Leon Pawlik Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Maciej Salaga Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Michał Sienkiewicz Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Aleksandra Sobolewska-Włodarczyk Department of Biochemistry; Department of Gastroenterology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Mikołaj S´wierczyn´ski Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Patrycja Szałwin´ska Department of Biochemistry, Medical University of Lodz, Lodz, Poland

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Contributors

Adrian Szczepaniak Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Agata Szymaszkiewicz Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Aleksandra Tarasiuk Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland  Antonio Uranga Department of Basic Health Sciences, University Jose Rey Juan Carlos (URJC); High Performance Research Group in Physiopathology and Pharmacology of the digestive system (NeuGut), URJC, Alcorco´n, Spain Marek Waluga Department of Gastroenterology and Hepatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland Jakub Włodarczyk Department of Biochemistry, Medical University of Lodz, Lodz, Poland Marcin Włodarczyk Department of General and Colorectal Surgery; Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Anna Zielin´ska Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland Marta Zielin´ska Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Preface Rich or poor, young or old… Nearly 15% of our population suffer from irritable bowel syndrome (IBS) and only very few are taken good care of. In the era of “westernization” of our lifestyles and increasing environmental pollution, but also in the times when infections spread across the world, there will only be more IBS cases in the coming years. Proper IBS diagnosis and efficient therapy are needed, and they are needed now. This book summarizes current knowledge on IBS and points to new directions in basic and clinical studies. The book may be read in its entity, but also by single chapters, depending if one is a scientist, a clinician, or a patient. I do hope that it will become a helpful guide for all through IBS causes, symptoms, and treatment.

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Introduction to irritable bowel syndrome: General overview and epidemiology

1

Jakub Fichna Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract Irritable bowel syndrome (IBS) is a functional gastrointestinal condition characterized by the disruption of the bowel movement and abdominal pain. There is no single factor known to cause IBS, hence its diagnosis and treatment are troublesome. Yet, due to increasing incidence, IBS has become a serious global issue. In this chapter, the incidence and prevalence of IBS are discussed. Also, epidemiology in different corners of the world is compared to elucidate whether there is any association with geographical location or socioeconomical status. Finally, age and gender are briefly discussed in an attempt to draw a picture of an IBS sufferer.

Keywords Irritable bowel syndrome, Epidemiology, Incidence, Prevalence

List of abbreviations IBS IBS-C IBS-D IBS-M

irritable bowel syndrome constipation-predominant irritable bowel syndrome diarrhea-predominant irritable bowel syndrome mixed irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal condition, to which both internal and external factors contribute. There is no single (in)organic causative agent identified so far, hence several hypotheses were formed to what extent genetic, A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00001-0 # 2020 Elsevier Inc. All rights reserved.

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Chapter 1 Introduction to irritable bowel syndrome

neuronal, microbial, immunological or environmental factors promote the development of IBS. Typical symptoms: abdominal pain and changes in stool frequency or consistency, leading to constipation and/or diarrhea are debilitating to an extent where IBS is a major cause for visits in general practitioners office. Together with a significant impact on patients quality of life due to physical suffering, work absenteeism and economic nonproductivity, but also psychological co-morbidity (increased risk of depression and suicidal ideation), IBS constitutes a major socioeconomic issue worldwide [1–3]. Nellesen et al. [4] report that the direct annual cost of diagnosing and treating IBS in the United States alone is estimated between $1.7 and $10 billion, while Chatila et al. [5] evaluate that the indirect costs in terms of absenteeism, workdays lost, disability will double that figure. As there are no diagnostic or monitoring biological markers, IBS diagnosis bases on well-established criteria (currently Rome IV) in which patient’s symptom reporting is crucial [6]. However, as the guidelines are constantly being updated, studies on incidence and prevalence based on Rome I, Rome II, Rome III and Manning criteria need also to be taken into consideration. Worth mentioning, as noticed by Canavan et al. [7], the Manning criteria account for the highest reported prevalence [8, 9] whilst the Rome iterations are associated with lower estimates of prevalence [8]. Consequently, different figures regarding IBS epidemiology are obtained, which can be additionally influenced by the fact that not in all the countries criteria regarding IBS have been defined. Moreover, factors like survey methods and the study instrument could also affect the estimates. This has been best illustrated by Endo et al. [10]: the prevalence of IBS in Iranian adults based on the modified Rome III criteria was established at 21.5% [11] and only 9.0% (95% CI, 6.0–13.0) based on the Rome II criteria [12]. In terms of incidence, Canavan et al. [7] reported two US studies, of which one conducted two population cohort surveys 1 year apart [13] and the other defined cases as first diagnosis by a physician [14]. In the former, 9% of subjects had developed symptoms over the year, an incidence rate of 67 per 1000 person-years. A significantly lower estimate based on the latter, with around two per 1000 person years was provided. In 2012, based on a systematic review and meta-analysis of 260,960 subjects from 80 studies the global pooled prevalence of IBS was estimated at 11.2% [12], but later the data were questioned due to significant heterogeneity between the studies [6]. Major geographical differences have been observed: in 2012 IBS rates in the Western countries ranged from 10% to 20% [15] compared to 1% to 10% in the Asian countries [16]; the lowest reported rates were in Southeast Asia (7.0%) while the highest (21.0%) were

Chapter 1 Introduction to irritable bowel syndrome

in South America. However, these estimates change rapidly over time: a rise in IBS rates in Asian countries is observed, and more developed nations, such as Japan and Singapore, already report prevalence comparable to that in the Western countries [17]. In terms of IBS subtypes, Lovell and Ford [12] point to diarrhea-predominant IBS (IBS-D) as the most prevalent (40.0%), followed by constipation-predominant (IBS-C, 35.0%) and mixed (IBS-M, 23.0%). A small study by Kibune-Nagasako et al. [18] on Brazilian population stays in line with these statistics: the most frequent IBS subtype was IBS-D (46%), followed by IBS-C (32%) and IBS-M (22%). However, other studies cited by these authors report opposite results: for example IBS-M was the largest bowel habit subgroup in population-based studies performed in United Kingdom and the United States [19, 20], while IBS-C was the most frequent among Iranian adults [11]. It is thus hypothesized that the increased prevalence of a given IBS subtype depends primarily—but not exclusively—on the severity of symptoms in a given subtype and on who provides the epidemiological data. Consequently, IBS-D—which may demand a more complex investigation in a gastrointestinal outpatient clinic—will rather be reported by GI specialists; general practitioners may be more confident in the management of IBS-C. There are several demographic parameters that need to be mentioned in relation to IBS epidemiology, including sex, age, and socioeconomical status. Canavan et al. [7] report that in most populations the IBS rates in women are approximately 1.5- to 3-fold higher than those seen in men [21–23] and internationally, the overall prevalence of IBS in women is 67% higher than in men (odds ratio 1.67 [95% CI 1.53–1.82]). These data may also be presented as outnumbering males by females by the ratio of 2:1 in the Western countries, and by 3:2 in United States [24]. On the other hand, in South Asia, South America, and Africa, the rates of IBS in men are almost equal to those of women, and in some cases even higher [12]. For example, Pimparkar et al. report a reversed females to males IBS ratio in India compared to the Western countries, i.e. 1:3, with the prevalence of IBS in general population of India at 15% [25]. This may result from disparities in the access to health care, but also sex-related motivation to seek consulting. IBS is reported in all age groups, with no difference in the frequency of subtypes by age [7, 26]. However, the disease is more prevalent among adolescents and declines with age [12]. In line, Canavan et al. point to the fact that 50% of patients with IBS report having first symptoms before the age of 35 years, and that prevalence is 25% lower in those aged over 50 years than in those who are younger [7, 12, 27].

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Whether IBS is in relation to the socioeconomic status, it remains to be elucidated. Canavan et al. [7] reported two studies with opposing outcomes: Drossman et al. [28] suggested that IBS was associated with lower socioeconomic status (as lower income pairs with poorer health care outcomes, lower overall quality of life, and increased life stressors), while others prove that being in a higher socioeconomic group during childhood or being exposed to the higher level of stress when working in professional and managerial roles is associated with higher prevalence of IBS [29, 30]. In line with the latter, the higher income brings greater access to health care and tendency to seek help and hence receive a diagnosis [31]. Chatila et al. [5] list several lifestyle factors such as smoking, alcohol consumption [32–35] and physical activity [36, 37] being linked to IBS. However, this may differ depending on a study and population examined: for example Nagaonkar et al. [25] found no such correlation between alcohol abuse and IBS in the Urban Slum Community in Mumbai. Higher prevalence of IBS associates with psychological factors such as stress and anxiety [10, 16, 38], and is seen among psychiatric patients (up to 39.7%, which is twice the general population) [39]. Genetics factors may also play a role in IBS pathogenesis and nearly 33% of patients with IBS report a positive family history [40]. Noteworthy, there is no increase in mortality rates in IBS patients compared with healthy controls. Canavan et al. [7] proves this by citing data from a large study conducted in the United States of over 4000 patients, followed for a total of 30,000 patient-years, in which no increased mortality compared with the general population was observed (hazard rate 1.06 [95% CI 0.86–1.32]) [41]. These results were in line with a smaller study from the People’s Republic of China which followed 263 patients over 5 years [42]. In conclusion, on average IBS is first diagnosed in 30–50-year-old women; however, the symptoms may already occur in childhood and in both genders, which proves the inaccuracy of reporting techniques as well as unequal access to healthcare and/or regional gender and age-related differences in seeking professional medical aid. Nevertheless, IBS has become a major global issue that needs general attention. Consequently, as proposed by Masudur Rahman et al. [1] based on available guidelines [43, 44] a good care of the IBS patient must be introduced, which should rely on the development of a good doctor patient relationship, identification of contributing factors, and critical appraisal of the efficacies of various drugs according to the subtype of IBS.

Chapter 1 Introduction to irritable bowel syndrome

References [1] Masudur Rahman M, Mahadeva S, Ghoshal UC. Epidemiological and clinical perspectives on irritable bowel syndrome in India, Bangladesh and Malaysia: a review. World J Gastroenterol 2017;23(37):6788–801. [2] Agarwal N, Spiegel BMR. The effect of irritable bowel syndrome on healthrelated quality of life and health care expenditures. Gastroenterol Clin North Am 2011;40(1):11–9. [3] El-Serag HB, Olden K, Bjorkman D. Health-related quality of life among persons with irritable bowel syndrome: a systematic review. Aliment Pharmacol Ther 2002;16(6):1171–85. [4] Nellesen D, Yee K, Chawla A, Lewis BE, Carson RT. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm 2013;19(9):755–64. [5] Chatila R, Merhi M, Hariri E, Sabbah N, Deeb ME. Irritable bowel syndrome: prevalence, risk factors in an adult Lebanese population. BMC Gastroenterol 2017;17(1):137. [6] Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel disorders. Gastroenterology 2016;150(6):1393–407. e5. [7] Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol 2014;6:71–80. [8] Saito YA, Locke GR, Talley NJ, Zinsmeister AR, Fett SL, Melton LJ. A comparison of the Rome and Manning criteria for case identification in epidemiological investigations of irritable bowel syndrome. Am J Gastroenterol 2000; 95(10):2816–24. [9] Mearin F, Badı´a X, Balboa A, Baro´ E, Caldwell E, Cucala M, et al. Irritable bowel syndrome prevalence varies enormously depending on the employed diagnostic criteria: comparison of Rome II versus previous criteria in a general population. Scand J Gastroenterol 2001;36(11):1155–61. [10] Choung RS, Saito YA. Epidemiology of irritable bowel syndrome. In: GI epidemiology: diseases and clinical methodology. 2nd ed; John Wiley & Sons, Ltd; 2014. p. 222–34. https://doi.org/10.1002/9781118727072 ch20. [11] Keshteli AH, Dehestani B, Daghaghzadeh H, Adibi P. Epidemiological features of irritable bowel syndrome and its subtypes among Iranian adults. Ann Gastroenterol 2015;28(2):253–8. [12] Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 2012;10(7): 712–21. e4. [13] Talley NJ, Weaver AL, Zinsmeister AR, Melton LJ. Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders. Am J Epidemiol 1992;136(2):165–77. [14] Locke GR, Yawn BP, Wollan PC, Melton LJ, Lydick E, Talley NJ. Incidence of a clinical diagnosis of the irritable bowel syndrome in a United States population. Aliment Pharmacol Ther 2004;19(9):1025–31. [15] Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol 2002; 97(8):1910–5. [16] Chang F-Y, Lu C-L, Chen T-S. The current prevalence of irritable bowel syndrome in Asia. J Neurogastroenterol Motil 2010;16(4):389–400. [17] Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome. Gastroenterol Clin North Am 2011;40(1):141–62. [18] Kibune-Nagasako C, Garcia-Montes C, Silva-Lorena SL, AparecidaMesquita M. Irritable bowel syndrome subtypes: clinical and psychological features, body mass index and comorbidities. Rev Esp Enfermedades Dig 2016;108(2):59–64.

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[19] Lin S, Mooney PD, Kurien M, Aziz I, Leeds JS, Sanders DS. Prevalence, investigational pathways and diagnostic outcomes in differing irritable bowel syndrome subtypes. Eur J Gastroenterol Hepatol 2014;26(10):1176–80. [20] Su AM, Shih W, Presson AP, Chang L. Characterization of symptoms in irritable bowel syndrome with mixed bowel habit pattern. Neurogastroenterol Motil 2014;26(1):36–45. [21] Manning AP, Heaton KW, Thompson WG, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J 1978;2(6138):653–4. [22] Kennedy TM, Jones RH, Hungin APS, OFlanagan H, Kelly P. Irritable bowel syndrome, gastro-oesophageal reflux, and bronchial hyper-responsiveness in the general population. Gut 1998;43(6):770–4. [23] Drossman DA, Thompson WG, Talley NJ, Funch-Jensen P, Janssens J, Whitehead WE. Identification of subgroups of functional bowel disorders. Gastroenterol Int 1990;3:159–72. [24] Singh RK, Pandey HP, Singh RH. Irritable bowel syndrome: challenges ahead. Curr Sci 2003;84(12):1525–33. [25] Nagaonkar SN, Singh VS, Kangule DT, Sadhanala S. A study of prevalence and determinants of irritable bowel syndrome in an urban slum community in Mumbai. J Datta Meghe Inst Med Sci Univ 2018;13(2):87–90. [26] Tang YR, Yang WW, Liang ML, Xu XY, Wang MF, Lin L. Age-related symptom and life quality changes in women with irritable bowel syndrome. World J Gastroenterol 2012;18(48):7175–83. [27] Maxwell PR, Mendall MA, Kumar D. Irritable bowel syndrome. Lancet 1997;350(9092):1691–5. [28] Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Grant Thompson W, et al. U. S. householder survey of functional gastrointestinal disorders—prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38(9):1569–80. [29] Howell S, Talley NJ, Quine S, Poulton R. The irritable bowel syndrome has origins in the childhood socioeconomic environment. Am J Gastroenterol 2004;99(8):1572–8. ˚ O. Could gastrointes€ T, Bergfors E, Faresjo €A [30] Grodzinsky E, Hallert C, Faresjo tinal disorders differ in two close but divergent social environments? Int J Health Geogr 2012;11:5. [31] Cremonini F, Talley NJ. Irritable bowel syndrome: epidemiology, natural history, health care seeking and emerging risk factors. Gastroenterol Clin North Am 2005;34(2):189–204. [32] Reding KW, Cain KC, Jarrett ME, Eugenio MD, Heitkemper MM. Relationship between patterns of alcohol consumption and gastrointestinal symptoms among patients with irritable bowel syndrome. Am J Gastroenterol 2013; 108(2):270–6. [33] Locke GR, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ. Risk factors for irritable bowel syndrome: role of analgesics and food sensitivities. Am J Gastroenterol 2000;95(1):157–65. [34] Ligaarden SC, Lydersen S, Farup PG. Diet in subjects with irritable bowel syndrome: a cross-sectional study in the general population. BMC Gastroenterol 2012;12:61. [35] Masand PS, Sousou AJ, Gupta S, Kaplan DS. Irritable bowel syndrome (IBS) and alcohol abuse or dependence. Am J Drug Alcohol Abuse 1998;24(3): 513–21. [36] Costanian C, Tamim H, Assaad S. Prevalence and factors associated with irritable bowel syndrome among university students in Lebanon: findings from a cross-sectional study. World J Gastroenterol 2015;21(12):3628–35. [37] Kim YJ, Ban DJ. Prevalence of irritable bowel syndrome, influence of lifestyle factors and bowel habits in Korean college students. Int J Nurs Stud 2005; 42(3):247–54.

Chapter 1 Introduction to irritable bowel syndrome

[38] Whitehead WE, Drossman DA. Validation of symptom-based diagnostic criteria for irritable bowel syndrome: a critical review. Am J Gastroenterol 2010;105(4):814–20. [39] Dewsnap P, Gomborone J, Libby G, Farthing M. The prevalence of symptoms of irritable bowel syndrome among acute psychiatric inpatients with an affective diagnosis. Psychosomatics 1996;37(4):385–9. [40] Whorwell PJ, McCallum M, Creed FH, Roberts CT. Non-colonic features of irritable bowel syndrome. Gut 1986;27(1):37–40. [41] Chang JY, Locke GR, McNally MA, Halder SL, Schleck CD, Zinsmeister AR, et al. Impact of functional gastrointestinal disorders on survival in the community. Am J Gastroenterol 2010;105(4):822–32. [42] Tang YR, Wang P, Yin R, Ge JX, Wang GP, Lin L. Five-year follow-up of 263 cases of functional bowel disorder. World J Gastroenterol 2013;19(9):1466–71. [43] Gwee KA, Bak YT, Ghoshal UC, Gonlachanvit S, Lee OY, Fock KM, et al. Asian consensus on irritable bowel syndrome. J Gastroenterol Hepatol 2010;25(7): 1189–205. [44] Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 2002;123(6):2108–31.

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Pathogenesis of irritable bowel syndrome

2

Jakub Włodarczyk and Patrycja Szałwi nska Department of Biochemistry, Medical University of Lodz, Lodz, Poland

Abstract Irritable bowel syndrome (IBS) is a heterogenous, chronic disease with a complex and multifactorial pathogenesis. Multiple studies have provided many well explored mechanisms involved in the pathophysiology of IBS. Possible factors such as genetic predisposition, diet, changes in gut-brain axis, gut microbiota, mucosal inflammation, stress and anxiety have been identified and linked with IBS. However, pathogenesis of this condition is still not fully understood and further investigation is necessary in order to provide more useful information which could help develop specific treatment. In this chapter, the current knowledge about pathogenesis of IBS will be discussed.

Keywords Irritable bowel syndrome, Pathogenesis, Diet, Genetics, Microbiota, Serotonin, Brain-gut axis, Peptide YY, Mucosal inflammation

List of abbreviations 5HT CNS ECs ENS FODMAPs GI IBS IFN-γ MCs NCGS NPY PBMCs PI-IBS

5-hydroxy-tryptamine central nervous system enterochromaffin cells enteric nervous system fermentable oligosaccharides, disaccharides, monosaccharides and polyols gastrointestinal irritable bowel syndrome interferon-gamma mast cells non-celiac gluten sensitivity neuropeptide Y peripheral blood mononuclear cells post-infectious irritable bowel syndrome

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00002-2 # 2020 Elsevier Inc. All rights reserved.

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PYY SCFAs TPH VH

peptide YY short chain fatty acids tryptophan hydroxylase visceral hypersensitivity

Irritable bowel syndrome (IBS) has been considered a disorder without a clear pathological or biochemical explanation. At first, studies regarding IBS focused on the alteration of gastrointestinal (GI) motility and visceral sensory function. However, while these were the fundamentals of IBS, the pathogenesis remained uncertain. Further search for these abnormalities revealed many well explored mechanisms. According to current research, it is believed that IBS is a condition connected with many factors such as genetic predisposition, stress, anxiety, food intolerance, changes in gut-brain axis and GI impairments which overall make it a heterogenous disorder. The latter also involve alternation in gut microbiota (dysbiosis), changes in gut motility and permeability, low-grade mucosal inflammation and immune activation [1, 2]. Analyses confirm a striking cumulative effect of these factors on the overall IBS somatic symptoms, and also on the patients’ quality of life, indicating the importance of considering and evaluating variations of pathophysiologic factors in IBS [3].

Fundamentals—Impaired gut motility and visceral hypersensitivity in IBS Alteration in gut motility IBS, sometimes also called “spastic colon,” implies heterogenous motility disorders, with various underlying disease mechanisms and subtypes categorized by the predominant stool pattern: diarrhea in IBS-D, constipation in IBS-C or both in IBS-M [4]. Impaired motility from abnormal gut contractions results in symptoms described as abdominal pain and discomfort. Studies have shown that in IBS patients multiple stimuli like diet or stress may implicate exaggerated physiological response and therefore various gastrointestinal (GI) motor disturbances [5]. However lack of consistent motor patterns changes among IBS patients makes it difficult to interpret and understand underlying pathogenesis. Multiple studies proposed a plurality of possible disease mechanisms, acting on different levels along the braingut axis or intestines itself [6, 7].

Chapter 2 Pathogenesis of irritable bowel syndrome

Visceral hypersensitivity Altered and increased sensation (including pain) of physiological stimuli is defined as visceral hypersensitivity (VH). VH comprises of two major components, which are allodynia and hyperalgesia. Hyperalgesia refers to an intensified pain sensation in response to a certain stimulus, whereas allodynia is defined as painful sensation in response to normal stimulus, which was previously not perceived as being painful. Studies revealed that VH develops from alterations in the peripheral sensory pathway and/or central nervous system (CNS). It is suggested that VH is considered as a pivotal biological hallmark of IBS [8, 9]. According to epidemiological studies prevalence of VH in IBS patients varies from 33% to 90%. VH mainly occurs in IBS-D patients with increased intestinal permeability and affects, apart from rectum and sigmoid colon, also small bowel, stomach and esophagus indicating decreased thresholds of nociceptive sensation all over the GI tract [10]. In fact, VH as a multifactorial condition may occur both within the peripheral nervous system and at the level of CNS. Several factors, including intestinal microbiota, genetics, psychological factors, inflammation and immunological factors, brain-gut axis, diet, are involved in the VH process among IBS patients [10].

Factors and mechanisms in IBS pathology Brain-gut axis Anxiety and depression are among the most frequent IBS symptoms which do not relate to the GI tract that are commonly found in outpatient and community samples [7, 11]. Observations as such made many look at IBS as a primary disorder of gut-brain function or somatization, with the brain being responsible for the gut abnormalities and fatigue, among many others. Nevertheless, three recent studies show that in approximately half of the patients the mood disorders are preceded by symptoms of GI nature [12]. These results suggest that in a patients’ subgroup mood disorder might be caused by an initial gut disorder. Moreover, structured interviews conducted in an independent study of psychiatric disorders and IBS showed that in 40% of patients with a mood disorder and in 23% of patients suffering from anxiety those disorders were diagnosed after the development of IBS [13]. Additionally, studies regarding cytokine response, intestinal inflammation and gut microbiome provided evidence that gut precipitates brain alterations in IBS [14, 15]. If those implications

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are proved to be factual, with a reversal of GI dysfunction, alleviation of inflammation and bringing back proper microbiota balance—which happens to be feasible, as the brain is by far less accessible than the gut—there is a chance to reverse or at least improve gut and mood dysfunction.

Serotonin and its metabolism Serotonin (5-hydroxy-tryptamine, 5HT) is a monoamine neurotransmitter primarily found in the enteric nervous system (ENS) located in the GI system and the central nervous system (CNS). However, serotonin located in enterochromaffin cells (ECs) of GI system makes up the majority—almost 90%—of total 5HT stores [16]. Serotonin plays a remarkable role in regulation of GI motility and changes in this neurotransmitter levels were observed in patients with IBS: patients with IBS-D have increased serotonin levels while in IBS-C these levels are reduced [16, 17]. There is a theory that those suffering from IBS-D have decreased 5HT reuptake, while IBS-C patients have decreased 5HT release [18]. Additionally, patients with post-infectious IBS have constant increases in ECs and increased 5HT levels after meals, while IBS-C patients have decreased 5HT release [19, 20]. The fact that 5HT receptor ligands (especially 5-HT3 receptor antagonists and 5-HT4 receptor agonists) had positive effects on IBS symptoms (such as reducing perception of visceral distension and colonic hypersensitivity in women with IBS-D, improving stool pattern and abdominal pain) is yet another proof of importance of the serotonin’s role in the IBS pathogenesis [21]. Polymorphisms in 5HT receptors, 5HT transporters—SERT (especially 5HTTLPR) and in tryptophan hydroxylase (TPH), which is an enzyme responsible for restricting 5HT synthesis have been studied and described in patients with IBS but, unfortunately, the results of the studies are unconvincing [16]. However, according to a meta-analysis from 2014 the LL genotype of 5HTTLPR seemed to be a risk factor for IBS-C in East Asia [22]. Studies have also noted that microRNA expression increases in the colonic samples from IBS patients. It has been proven that microRNAs, such as miR-510 or miR-16, can promote epigenetic and genetic changes through modulating intestinal pathways such as 5HT signaling, which result in intestinal permeability and somatic hypersensitivity in IBS patients [23, 24]. According to few studies there seems to be a connection between 5HT metabolism and immune activation, inflammation of the mucosa as well as intestinal barrier function [16]. A study on colon biopsies from IBS patients versus healthy controls performed in 2011 revealed elevated numbers of EC cells rich in 5HT with the advantage in IBS-D over IBS-C [25]. Moreover, this

Chapter 2 Pathogenesis of irritable bowel syndrome

study proved that mucosal 5HT was substantially raised in patients with IBS and that it was connected with increased number of mast cells and severity of pain. Another study showed intriguing association between proinflammatory interferongamma (IFN-γ) protein and SERT expression [26]. This investigation showed that IFN-γ levels were augmented in IBS patients’ mucosa and SERT expression was decreased, what consequently affected the amount of 5HT in gut. These results are in line with knowledge that inflammation lowers SERT expression, what may be another clue to understanding the pathogenesis of IBS.

Possible role of peptide YY Peptide YY (PYY) which belongs to the neuropeptide Y (NPY) family is synthesized in endocrine cells (PYY cells) located between the epithelial cells of the human ileum, colon and rectum [27]. PYY plays an important role in proper functioning of the GI system: it regulates appetite and food intake, slows emptying of the stomach, inhibits gastric and pancreatic secretion and induces absorption of water and electrolytes [28, 29]. What is more, PYY is considered to have an impact on modulating 5HT excretion from colonic ECs through NK2/NK3 cascade system [30]. As discussed earlier, 5HT modulates visceral sensitivity and accelerates GI motility and secretion [31]. Abnormalities in PYY in IBS patients were a topic of many investigations which led to a conclusion that IBS patients and healthy subjects have the same density of PYY cells in the ileum, but suffer from a decreased density of these cells and concentration of PYY itself in the colon compared with healthy subjects [32, 33]. The same is observed in the rectum. All things considered, it is probable that low density of PYY cells and PYY concentration in the gut may lead to low release of PYY, which consequently contributes to abnormal motility observed in IBS patients. Moreover, the impact of PYY on 5HT release may contribute to visceral hypersensitivity which is crucial in the pathophysiology of IBS.

Histamine and mast cells Another molecule apart from 5HT, which may be connected with the pathogenesis of IBS is histamine [34]. Histamine is a short-acting endogenous amine involved in inflammatory response that functions as a neurotransmitter in the human body. This compound is mainly produced by mast cells (MCs) using the enzyme histidine decarboxylase, and also by basophils, gastric enterochromaffin-like cells, and histaminergic neurons but in

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lower amounts [35, 36]. However, only MCs and basophils store large amounts of histamine, while other cells synthesize it and secrete immediately without storage. Histamine can fulfill its functions by binding to four subtypes of receptors: H1R-H4R, of which each has a specific location and role. In the GI system histamine is believed to modulate motility, increase production of gastric acid and modify mucosal ion secretion [37, 38]. There are some studies in which the role of histamine in IBS patients was investigated. One such study revealed that 58% IBS patients experienced GI symptoms due to a histamine-releasing food intake (milk, wine, beer) and food rich in biogenic amines (wine, beer, cheese) [39]. In another study, high levels of histamine were found in supernatants from IBS colonic samples [40]. Moreover, there is proof of increased expression of H1R (proinflammatory signaling) and H2R (anti-inflammatory signaling) in IBS patients [41, 42]. Apart from that, H4R are believed to involve visceral sensory signaling and GI contractility [43]. Mast cells cannot be underestimated in understanding the pathophysiology of IBS. These cells store not only histamine but also tryptase and nerve growth factors, which can activate and sensitize enteric nerves and influence the integrity of the epithelial barrier [44]. A range of investigations prove that IBS patients have elevated number of MCs in almost all intestinal mucosa including rectum, rectosigmoid, descending and ascending colon, cecum, jejunum and duodenum [40, 45–48]. What is more, activation, level of degranulation and, consequently, release of modulators of these cells is also increased. It is also worth mentioning that mast cells through degranulation might also influence proteins responsible for forming cell junctions, such as zonula occludens-1, claudin-1 and other adhesional molecules, causing their lower expression in both upper and lower GI tract. This is probably connected with tryptase release after exposure to food antigens [48–50].

Gut microbiota It is commonly known that gut is the richest in microorganisms part of the human body. The intestinal microbiota is composed of 17 families, 50 genera and more than 1000 species of bacteria of which only one third have been identified so far [51]. Gut microbiota include not only bacteria but also viruses, fungi and protozoa which live in symbiosis under normal circumstances and are responsible for gut development, digestion and metabolism, proper development of humoral and cellular mucosal immune system and protection against pathogens [52, 53].

Chapter 2 Pathogenesis of irritable bowel syndrome

Gut microbiota develops from the day of birth to the adulthood and undergoes wide variety of changes during life due to genetic and environmental factors, dietary habits, stress, invasive medical procedures or use of medications, especially antibiotics [52]. Firmicutes (which form approximately 64% of gut microbes; e.g., Lactobacillus), Bacteroidetes (23%; e.g., Bacteroides fragilis), Proteobacteria (8%; e.g., Eschericha coli, Salmonella, Shigella) and Actinobacteria (3%; e.g., Bifidobacteria) are four dominating bacterial phyla in human intestines [51, 54, 55]. Methanogens and halophilic archae were also identified as highly associated with gut (e.g., Methanobrevibacter smithii) [53]. Any changes in bacterial number and composition may result in dysregulation of interactions between host and microbes. This state is called dysbiosis and might be triggered by pathogens, inflammatory mediators or any initiators that can provoke reaction of the immune system and lead to loss of beneficial influence of microbiota, affecting the intestinal environment. Hence, it is believed that disruptions in the microbiome may play an important role in pathogenesis of IBS by changing integrity of the gut and its immunological properties, and lead to dysregulation of gut-brain axis homeostasis [51, 53]. According to a study from 2015 performed in Sweden, Norway, Denmark and Spain involving patients between 17 and 76 years old, gut dysbiosis was observed in 73% of IBS patients [52]. Although many detailed investigations of bacterial composition of intestines in IBS patients were performed, the results differ between study groups and still are not univocal. Nevertheless, the majority of studies confirm that there are some changes in microbiota of IBS patients in comparison to healthy ones. Some observations show that IBS-positive patients present downregulation of Methanobacteriales, Prevotella, Bifidobacteria, Lactobacillus and Bacteroides species (the latter two are particularly perceived as beneficial bacteria) and increased number of pathogenic bacteria such as Streptococcus spp. [56–58]. A different investigation confirms lower numbers of Methanobacteriales, Lactobacilli and Bifidobacteria, but indicates that the number of Bacteroides was higher in IBS patients (even 12 times according to the 2014 study) [58–60]. Another study, however, showed higher numbers of Proteobacteria and Firmicutes (including Lactobacillus) [61]. In IBS-D subtype significant decrease of Lactobacillus and Bifidobacterium population was observed contrary to healthy controls and IBS-C patients. Microbes of the intestine generate gases (hydrogen, methane) and short chain fatty acids (SCFAs) as by-products which could affect bowel passage and permeability [62]. Studies

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revealed lower methane production among IBS-D patients and higher in IBS-C, which may explain changes in stool pattern in these patients [63]. Methane production may also have anti-inflammatory effects in the colon, so its lower amount in the state of dysbiosis can be a part of improper functioning of gut immune system. A smaller number of the archaea which convert H2 to CH4 in IBS patients may contribute to a lower rate of hydrogen removal, what can lead to abdominal distension observed in these people. Furthermore, gut microbiota affect also serotonergic regulation through stimulation of EC cells by production of SCFAs and therefore increasing 5HT levels [57]. Summarizing, disturbances in the intestinal microbiota may play a key role in IBS pathogenesis. Additional aspect is that some antibiotics and probiotics have beneficial effect on relief of IBS symptoms. However, many issues still need further investigation to examine which microbes are IBS contributors and which ones only adapt and survive in changed conditions.

Genetics It has been reported by some that IBS seemingly aggregates in families. Conducted twin studies have shown lower concordance of IBS in dizygotic twins and higher in monozygotic twins, what suggest that genetics might indeed be involved [64]. Some investigators focus on the role of specific genes in IBS predisposition, while others try broader approach by using large populationbased cohort studies for gene-hunting efforts. One of the most studied genetic aspects in IBS is its correlation with 5HT transporters—SERT. A recent meta-analysis based on a total of 27 studies including 7039 subjects concluded that the SERT insertion/deletion polymorphism was associated with IBS in both Asians and Caucasians but only for those with IBS-C [22]. Other reports mention multiple genes that might play role in pathophysiology of IBS, such as ion channel gene TRPM8, sucraseisomaltase mutations or single nucleotide polymorphisms [65–67]. Results are promising, however a wide range of studies were hindered by a small size of the sample, where genetic association of selected candidate genes in IBS had less than 2000 patients enrolled with the largest to date containing just about 7000 patients, compared to 30,000–40,000 in certain inflammatory bowel disease cohorts. In addition a lack of reproducibility in large data sets, together with the variability of the clinical

Chapter 2 Pathogenesis of irritable bowel syndrome

phenotype have engendered a cautious approach to the interpretation of these findings.

Low-grade mucosal inflammation and immune activation According to many recent studies, pathogenesis of IBS is believed to be connected with low-grade mucosal inflammation and overactivity of the immune system [1]. Abnormal function of immune responses may be a result of impaired epithelial barrier, dysbiosis and altered stress levels [68–70]. Mucosal inflammation may also be a consequence of past history or history of non-recognized GI infections caused by bacteria, parasites or viruses—this IBS subtype is called PI-IBS (post-infectious IBS) [71]. Consequently, young women with high anxiety, suffering from depression and with history of long initial infection with fever are more prone to PI-IBS [72]. Investigations of biopsies of mucosa from PI-IBS patients revealed an increased number of immune cells such as mast cells (especially near enteric nerve fibers in gut mucosa of IBS patients) and lymphocytes, and elevated cytokine production in peripheral blood mononuclear cells (PBMCs) and intestinal mucosa [60, 73]. A study from 2016 shows that 25% patients with Clostridium difficile gastroenteritis developed IBS 6 months or more after infection [74]. What is more, the microbiota of PI-IBS patients differed significantly from other IBS subtypes and healthy controls, and also a correlation between large number of CD8, CD4RA + cells and depressive mood was observed [75]. Apart from that, in some patients with dysbiosis some studies showed increased levels of C-reactive protein, IL-6, and IL-8 (inflammatory mediators and cytokines) and higher expression of TLR-4 and TLR-5 (which recognize bacterial structures) [76, 77]. Apart from that, many patients with IBS symptoms suffer from innate inflammatory diseases such as celiac disease, inflammatory bowel disease or severe acute gastroenteritis [78, 79]. This may be a proof for a connection between abnormal activity of the immune system and IBS development, however the exact pathophysiological explanation for this relationship is still not clear enough. A possible one is that gut permeability is changed due to inflammatory response that causes infiltration of immune cells which promote local edema and produce large amounts of cytokines [80].

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Currently, only a few cytokines are accurately identified to have a possible relationship with IBS. According to a study from 2007 elevated proinflammatory cytokines in PBMCs of IBS-D patients are IL-6, TNF-alfa and IL-1beta, all of which are also highly linked with depression and anxiety, suggesting the role of gut in proper brain functioning [14]. Another study emphasized the association of IL-17 and TNF-alfa with IBS symptoms and quality of life in different subtypes of IBS [81]. Yet another abnormality in patients with IBS is a decreased level of beta-endorphin from PBMCs with consequence of their reduced inhibitory effects in comparison to IBS negative controls [74].

The role of diet in IBS Dietary influence cannot be omitted in understanding the pathophysiology of IBS. Food and its components can affect proper bowel functioning in terms of gut motility and permeability, GI immune system, microbiota and the gut-brain axis [82]. Some products are more prone to cause or exacerbate IBS symptoms—especially these rich in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) such as legumes, vegetables, fatty foods, artificial sweeteners, stone fruits and lactose-containing foods [83]. Gut microbiota is responsible for FODMAPs breakdown to gases (methane and hydrogen) [84]. According to investigations weak absorption of these gases is believed to cause bloating symptoms and abdominal discomfort in about 70% of IBS patients [85, 86]. What is more, FODMAPs due to increasing osmotic pressure may be responsible for GI distension and alternation in gut motility [1]. They also have impact on the GI endocrine cells which adjust GI motility and processes of secretion and absorption due to 5HT release [87]. Gluten is another diet component which is believed to cause changes in the gut physiology. Investigations revealed that consuming products with gluten caused symptoms such as abdominal pain in IBS patients diagnosed negatively for celiac disease. This condition is called “non-celiac gluten sensitivity” (NCGS) and may be the reason for IBS-like symptoms development [88]. Another proof of association between gluten and IBS symptoms was provided by the study in which mucosal permeability occurred to be elevated in IBS-D patients on gluten containing diet, contrary to a part of group on gluten-free diet [89]. Although diet clearly seems to be connected with IBS symptoms genesis, it may also be used for managing IBS, for example through low-FODMAP content. These aspects will be discussed specifically in further chapters.

Chapter 2 Pathogenesis of irritable bowel syndrome

Conclusions All things considered, it seems clear that IBS is a condition connected with many factors such as genetic predisposition, stress, anxiety, food intolerance, changes in gut-brain axis and GI impairments which overall make it a heterogenous disorder. Pathogenesis also involves alternation in gut microbiota (dysbiosis), changes in gut motility and permeability, low-grade mucosal inflammation and immune activation. Highlighting a specific factor as a main and leading aspect in IBS pathophysiology is troublesome and questionable. Moreover, mentioned factors require further investigation in order to provide more useful information on the origin of IBS and to identify potential triggers of the disease, so that specific treatment could be designed and used to help patients dealing with this disorder.

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Irritable bowel syndrome and the brain-gut connection

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Leon Pawlik and Aleksandra Tarasiuk Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract The brain-gut axis (BGA) is a complex, bidirectional communication system between enteric nervous system and central nervous system and in healthy organism it is an essential pathway in regulating the proper functioning of the gastrointestinal tract. Main manifestations of irritable bowel syndrome (IBS) such as abdominal pain, bloating and abnormal bowel movements can be understood as a disruption in BGA. Stress, strong emotional experiences or altered intestinal microbiota can affect BGA and therefore modulate the bowel motility, secretion and visceral sensibility. In this chapter we will discuss as well as describe constituents of the BGA and their connections with IBS.

Keywords Brain-gut axis, BGA, Irritable bowel syndrome (IBS), Functional gastrointestinal disorder, Microbiota-gut-brain axis

List of abbreviations 5-HT ACC ACTH ANS BGA CNS CRH EC GABA GI GM HPA IBS

5-hydroxytryptamine; serotonin anterior cingulate cortex adrenocorticotropic hormone autonomic nervous system brain-gut axis central nervous system corticotrophin-releasing hormone enterochromaffin cells gamma aminobutyric acid gastrointestinal gut microbiota hypothalamic-pituitary-adrenal (axis) irritable bowel syndrome

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00003-4 # 2020 Elsevier Inc. All rights reserved.

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Chapter 3 Irritable bowel syndrome and the brain-gut connection

IBS-C IBS-D MC MBGA SCFAs VH

constipation-predominant irritable bowel syndrome diarrhea-predominant irritable bowel syndrome mast cells microbiota-brain-gut axis short chain fatty acids visceral hypersensitivity

Introduction Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders and among the most frequent causes of gastroenterology consultations [1]. Despite the high prevalence (about 10% of the world population), the pathogenesis of IBS is still not fully understood. Main pathophysiological mechanisms are: altered GI motility, visceral hypersensitivity, increased intestinal permeability, brain-gut axis (BGA) dysregulation and changes in the intestinal microbiota. These changes in turn contribute to the main manifestations of IBS such as abdominal pain, bloating and abnormal bowel function (diarrhea and/or constipation) [2]. Psychosocial factors can also influence digestive function, symptom perception, illness behavior and outcome. Conversely, visceral pain affects central pain perception, mood and behavior. IBS may be perceived as a disorder resulting at least in part from disruption of BGA [3]. More recently, the role of the gut microbiota in the bidirectional communication along BGA, and subsequent changes in behavior, has emerged [4]. Brain-gut axis (BGA) is a term used to describe complex, bidirectional communication between the central nervous system (CNS), the enteric nervous system (ENS), gut wall and the hypothalamicpituitary-adrenal (HPA) axis (Fig. 1) [5]. It was introduced to describe the central and peripheral effects of gut-brain peptides such as cholecystokinin and bombesin [6]. The BGA communication is functioning via neural, endocrine and immune pathways. In physiological conditions, signals from the GI tract influence the brain, which in turn can exert changes in motility, secretion and immune function of GI tract, therefore it is an important communication system for regulation of food intake, digestion, gut sensation and control of bowel movements [7]. Disruptions of the BGA cause changes in perceptual and reflexive responses of the nervous system and may lead to functional GI disorders, including IBS, which often comorbid with chronic psychiatric diseases [8, 9]. This chapter will focus on constituents of the BGA, gut microbiota and their connections with IBS.

Chapter 3 Irritable bowel syndrome and the brain-gut connection

Enteric nervous system

Central nervous system

Gut wall

Brain-gut axis Hypothalamic -pituitaryadrenal axis

Gut microbiota

Immune system

Fig. 1 Brain-gut axis (BGA) is a complex bidirectional communication path between the central nervous system (CNS) and the gut. BGA is composed of the CNS, the hypothalamic-pituitary-adrenal (HPA) axis, the enteric nervous system (ENS), the gut wall and the immune system. Gut microbiota is another element that is involved in maintaining homeostasis within the gastrointestinal (GI) tract therefore the microbiota-brain-gut axis (MBGA) concept has emerged. Disturbance of any of BGA constituents may lead to changes in perceptual and reflexive responses of the nervous system and to GI disorders, including irritable bowel syndrome (IBS).

BGA anatomy and IBS Hypothalamic-pituitary-adrenal axis HPA axis and the sympathetic nervous system are two main stress response pathways in mammals. The HPA axis consists of paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland and the adrenal gland. The HPA axis responds to a stressor by releasing corticotrophin-releasing hormone (CRH) into the hypophyseal portal circulation, which passes into the anterior pituitary gland, where it binds to the CRH1 receptor. This event leads to the release of the adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH targets the adrenal cortex to stimulate the production and secretion of a glucocorticoid— cortisol [10, 11]. Glucocorticoids are the main effector molecules of the HPA axis and, via binding to their intracellular receptors, function to regulate the physiological adaptations to stress [12].

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Stress is known as a cause of IBS and exacerbates its GI symptoms [13]. Enhanced CRH activity seems to influence gut motility, secretion and sensitivity, so the possible relevance of brain CRH pathways in the pathophysiology of IBS has been suggested [14]. Increased CRH expression in the central nucleus of amygdala (CeA) is associated with stress-induced visceral pain and oligonucleotide knockdown of CRH within the CeA reverses corticosterone- and stress-induced visceral hypersensitivity [15]. Moreover administration of a specific CRH1 receptor antagonist—CP376395—to the CeA reverses visceral hypersensitivity and administration of CRH increases this effect, therefore it has been suggested that CeA is a critical nucleus involved in CRH effects on the visceral sensitivity [16–18]. Patients with IBS have also increased response to CRH and elevated plasma cortisol blood serum level in the morning [19]. It should be mentioned that HPA axis alternations are not specific to IBS and are also present in metabolic and psychiatric disorders including depression and anxiety [20, 21].

Enteric nervous system The ENS is an important part of the autonomic nervous system (ANS) and it is responsible for maintaining the proper functioning of the GI tract. The ENS is composed of small aggregations of nerve cells, enteric ganglia (myenteric and submucosal plexuses), the neural connections between these ganglia, and nerve fibers that supply effector tissues, including the muscle of the gut wall, the epithelial lining, intrinsic blood vessels and gastroenteropancreatic endocrine cells [22]. ENS is capable of acting regardless of the CNS, however physiologically, it is not autonomous. Neuronal control of the GI function is an integrated system involving interactions between local enteric reflexes, neurons in sympathetic ganglia and CNS [22]. Main functions of the ENS are: synchronizing the movement of GI tract, regulating movement of fluid across the lining epithelium, changing local blood flow, interactions with immune and endocrine systems and maintaining the integrity of epithelial barrier [22, 23]. ENS and CNS regulate the functioning of the GI tract by monitoring and reacting to constantly changing conditions (pH, pressure, nutrients concentration) within the enteric lumen. As nerve fibers do not enter the GI tract lumen or even the epithelial lining, therefore there must be a way to convey information to nerves. Enterochromaffin cells (EC) are the best characterized signaltransducer cells that transfer information from the GI lumen to

Chapter 3 Irritable bowel syndrome and the brain-gut connection

the sensory fibers through a serotonin (5-hydroytryptamine, 5-HT)-dependent mechanism. EC release 5-HT from their basolateral surface into the lamina propria [24]. Here, 5-HT has access to the intrinsic (IPANs) and extrinsic primary afferent (sensory) neurons. 5-HT3 receptors mediate serotonergic signaling to the CNS as well as they activate myenteric IPANs and are responsible for fast serotonergic neurotransmission in the ENS. Of note, because of 5-HT3 receptor distribution, 5-HT3 receptor antagonists can be used as a treatment of IBS associated visceral hypersensitivity [25]. 5-HT3 antagonists, however, can be constipating because of their effects on serotonergic neurotransmission within the ENS and perhaps also because they stimulate myenteric IPANs, therefore their use is restricted to diarrhea-predominant irritable bowel syndrome (IBS-D) [26]. Serotonergic signaling in the gut is terminated via action of plasmalemmal serotonin transporter (SERT), which mediates the reuptake of 5-HT. Of note, expression of SERT is decreased in the mucosa of patients with IBS-D, constipation-predominant irritable bowel syndrome (IBS-C), and ulcerative colitis [27]. Concurrently, mice that lack SERT protein exhibit diarrhea, constipation or both in alternation which are all the main symptoms of IBS [28]. This may be caused by the fact that the upregulation of 5-HT receptors should lead to diarrhea and discomfort, while desensitization of 5-HT receptors (as a result of excessive amount of 5-HT in the mucosa) should cause constipation.

Immune system An important role for immunological alterations and lowgrade inflammation within the GI tract and abnormal neuroimmune interactions has been proposed in the pathophysiology of IBS. For instance, in IBS patients the number of sensory nerve fibers that express the capsaicin receptor TRPV1 is elevated. Additionally the increased colonic MC and lymphocytes infiltration and mediator release in proximity to mucosal innervation correlate with the severity of abdominal pain perception in IBS patients [29–31]. Initial evidence suggests that pharmacological control of MC activation and mediator release may thus be beneficial in functional GI disorders [32, 33]. Causes of increased MC activity and low-grade inflammation in IBS are complex and remain not fully understood, but a number of factors have been proposed, such as genetic factors, undiagnosed food allergies, previous infections of GI tract, changes in intestinal microflora and increased intestinal permeability [33].

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Central nervous system The brain is connected to the bowel through many neural pathways that collect information from the receptors in the periphery and send it to the cortical areas. The information collected by receptors is transmitted via parasympathetic and sympathetic fibers. The main pain signaling pathways in BGA are spinothalamic tracts and dorsal columns. From the hypothalamus and thalamus, the information is sent to, integrated and neuromodulated at different central cortical areas such as anterior and posterior cingulate cortexes, insular and amygdalian areas, as shown using brain imaging methods [34]. After the information is integrated and analyzed at cortical levels, a response is generated downstream, further neuromodulating the actions of ENS [34]. Brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography are useful to study visceral functions in healthy people and IBS patients. Studies using these techniques have shown abnormal brain activations in response to visceral stimulation in IBS patients. The key to understand pathological brain responses is the phenomenon of the visceral hypersensitivity (VH), which is responsible for reducing the pain threshold in the gut and trigger painful sensation even during physiological stimuli. VH is thought to be determined by central and peripheral mechanisms, as it may result from altered transmission within the gut wall, the spinal cord, or the brain, however, the specific contribution of the BGA components to hypersensitive responses in IBS remains unclear [8]. Up to 60% of IBS patients show lower pain thresholds in studies with rectal distention compared to healthy population [35, 36]. During experimental rectal distension, similar regions were found to be activated in healthy volunteers and IBS patients (areas of the visceral sensory neuromatrix). However the extent of the brain activation varied between these groups—especially in the anterior cingulate cortex (ACC) and the prefrontal cortex [35]. The results of the studies suggest that differences between brain activations in controls and IBS patients to intestinal stimulation indeed do exist, but they are not consistent [37–39]. ACC is thought to be a critical structure in coding pain suffering. It is also a part of the limbic system, which is responsible for emotional responses [40]. Abnormalities in the limbic system have been discovered in depression and anxiety [41]. The intersection of the pain signaling system and limbic system at ACC may therefore have implications for patients with IBS and other stress related pain disorders [40]. Additionally IBS patients have decreased gray matter density in widespread areas of the brain, including medial prefrontal and ventrolateral prefrontal cortex, posterior parietal cortex, ventral striatum, and thalamus [34].

Chapter 3 Irritable bowel syndrome and the brain-gut connection

The microbiota-brain-gut axis Trillions of microorganisms, collectively described as the gut microbiota (GM) live throughout mammalian GI tract and influence host digestive, metabolic, immune and neural function. GM include not only bacteria (mainly Firmicutes and Bacteroidetes phyla- about 90% of the microbial population) but also fungi (Saccharomyces, Malassezia, and Candida), archaea and viruses [42, 43]. These microbes modulate the functioning of the most important organ of the nervous system—the brain. In turn CNS regulates the gut physiology and GM composition via immune system and HPA axis [44]. Therefore, more recently, the communication model between brain and the gut has been extended by the GM and the concept of microbiota-brain-gut axis (MBGA) has been proposed. GM can influence the functioning of CNS and even contribute to neurological and neuropsychiatric diseases such as Alzheimer’s disease and Parkinson’s disease [45, 46] (Fig. 2). The fact that changes in GM composition might be the factor in IBS was first suggested by the observation of postinfectious development of IBS [47]. Further studies confirmed down-regulation of bacterial colonization including Lactobacillus, Bifidobacterium and Faecalibacterium in IBS patients, particularly in diarrheapredominant IBS [48]. The role of the gut bacteria in IBS was also observed in clinical trials relating to two interventions— probiotics and antibiotics administration. The poorly absorbed antibiotic rifaximin and probiotics (e.g., Lactobacillus plantarum DSM 9843, E. coli DSM 1752, and Streptococcus faecium) have been proven to mitigate the main symptoms of IBS [49–51].

MBGA pathways Currently, the precise pathways of communication between microbiota and the brain are not fully understood. GM exert effects on the brain not only through the nervous system (gut-brain’s neuroanatomical pathway) but also through the endocrine, immune, and metabolic system [52]. Direct neuronal communication in MBGA is executed mainly by the vagus nerve that can induce both anxiogenic and anxiolytic effects depending of the stimulus. Interestingly, the vagus might differentiate between potentially pathogenic and non-pathogenic bacteria even in the absence of inflammation [53, 54]. Within the GI tract bacteria can synthesize or regulate the synthesis of a variety of neural regulators and neurotransmitters such as brain-derived neurotrophic factor, gamma aminobutyric acid

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MBGA pathways

Metabolite synthesis

HPA axis

Dopamine

SCFAs

Gut immune system

Vagus nerve

5-HT

GABA

Fig. 2 Possible communication routes of the microbiota-brain-gut axis (MBGA). HPA axis, hypothalamic-pituitary-adrenal axis; SCFAs, short chain fatty acids; 5-HT, 5-hydroxytryptamine; GABA, gamma aminobutyric acid.

Chapter 3 Irritable bowel syndrome and the brain-gut connection

(GABA), acetylcholine, 5-HT, dopamine and short chain fatty acids (SCFAs) [55]. Neurochemicals produced by microbiota can be either taken up into the portal circulation (and then via bloodstream influence CNS and other parts of the nervous system) or directly interact with receptors found on the ENS cells. These may lead to the alternation of behavior, cognition, food preferences and appetite [56, 57].

5-HT 5-HT is a key signaling molecule in BGA, both in the ENS and CNS [58]. The GI tract is an important site for 5-HT biosynthesis, but the regulatory mechanisms underlying the metabolism of gut-derived 5-HT are not completely understood [59]. GM plays a key role in promoting levels of colon and blood 5-HT, largely by elevating synthesis by host ECs. GM within the GI lumen release metabolites such as SCFAs that increase expression of tryptophan hydroxylase 1 in EC and therefore promote 5-HT synthesis [59]. Dysfunctions of the central or peripheral serotonergic system can be involved in the pathophysiology of IBS, as suggested also by the therapeutic effects of both tricyclic antidepressants and selective serotonin reuptake inhibitors [60, 61].

SCFAs Dietary fibers are metabolized by GM into SCFAs, mainly acetate, propionate and butyrate. Beyond being an important energy source for the host, these metabolites display biological activity. SCFAs act on G protein-coupled receptors (GPR41 and GPR43) [62], can interact with neurons in the CNS and ENS, regulating heart rate, oxygen consumption and GI motility [44, 63, 64]. IBS patients express higher levels of acetic acid, propionic acid and total organic acids than healthy controls what may be related to abdominal symptoms, impaired quality of life and negative emotions [65]. Noteworthy, rectal administration of sodium butyrate induced a sustained, concentration-dependent colonic hypersensitivity particularly in female rats, but no macroscopic and histologic modifications of the colonic mucosa, as observed in patients with IBS [66, 67]. This can be a possible explanation why the consumption of wheat bran (insoluble dietary fiber) exacerbates the symptoms in IBS patients [68, 69].

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GABA GABA is the main inhibitory neurotransmitter in the mammalian cortex, the effects of which are mediated through two major classes of receptors—the ionotropic GABAA receptors and the GABAB receptors, which belong to GPCR family [70, 71]. Mice treated with Lactobacillus rhamnosus, a probiotic with antiinflammatory properties, exhibited altered GABA receptor expression in the brain accompanied by reduced anxiety and depressive-like behaviors [72]. GABA receptors are important pharmacological targets for clinically relevant antianxiety agents (e.g., benzodiazepines acting on GABAA receptors), and alterations in the GABAergic system play important role in the development of stress-related psychiatric conditions [72]. Gabapentin (GABAergic agent) reduces rectal mechanosensitivity and increases rectal compliance in patients with IBS-D, what validates a link between severity of IBS symptoms and GABA activity [73].

Restoring the microbiota-brain-gut axis to treat IBS Because IBS is associated with qualitative and quantitative changes in GM, it is reasonable to approach IBS therapy by targeting these alternations [74]. The studies have proven the efficiency of probiotics [75, 76], prebiotics [77], synbiotics [78–80] and poorly-absorbed antibiotics administration [81, 82] and fecal microbiota transplant [83, 84] in IBS treatment. The efficacy of GM-oriented therapy seems to be another proof that IBS pathogenesis is associated with altered MBGA.

Conclusion In summary, MBGA is a complex, bidirectional communication network between gut and brain. It consists of CNS, ENS, HPA axis, neuroimmune system and gut microbiota and their metabolites. The information about the state of the GI tract can be transmitted via MBGA to the brain, which in turn can exert changes in the gut functioning. Dysfunctions in the MBGA lead to the alternation of the gut motility, secretion and sensibility. Functional GI disorders such as IBS can at least in part be perceived as a result of MBGA deregulation. The decreasing costs of microbiota analyses made it possible to identify patient subgroups with specific dysbioses and assess that such subgroups

Chapter 3 Irritable bowel syndrome and the brain-gut connection

will respond to personalized therapy using e.g. pro- pre- and symbiotic interventions [85]. Current data offers a solid framework to the future understanding of the disorder and potential therapeutic targets. More largescale, highly controlled, longitudinal human studies are required to find and implement new methods of diagnostic and therapeutic interventions.

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[63]

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carboxylic acids. J Biol Chem 2003;278(13):11312–9. https://doi.org/10.1074/ jbc.M211609200. Kimura I, Inoue D, Maeda T, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A 2011;108(19):8030–5. https://doi.org/ 10.1073/pnas.1016088108.  C, et al. Short-chain fatty acids modify colonic Cherbut C, Ferrier L, Roze motility through nerves and polypeptide YY release in the rat. Am J Physiol Gastrointest Liver Physiol 1998;275(6). https://doi.org/10.1152/ajpgi.1998. 275.6.g1415. Tana C, Umesaki Y, Imaoka A, Handa T, Kanazawa M, Fukudo S. Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol Motil 2010;22(5). https://doi. org/10.1111/j.1365-2982.2009.01427.x. Bourdu S, Dapoigny M, Chapuy E, et al. Rectal instillation of butyrate provides a novel clinically relevant model of noninflammatory colonic hypersensitivity in rats. Gastroenterology 2005;128(7):1996–2008. https://doi.org/10.1053/j. gastro.2005.03.082. Xu D, Wu X, Grabauskas G, Owyang C. Butyrate-induced colonic hypersensitivity is mediated by mitogen-activated protein kinase activation in rat dorsal root ganglia. Gut 2013;62(10):1466–74. https://doi.org/10.1136/gutjnl-2012302260. Bijkerk CJ, De Wit NJ, Muris JWM, Whorwell PJ, Knottnerus JA, Hoes AW. Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ 2009;339(7721):613–5. https://doi.org/ 10.1136/bmj.b3154. Francis CY, Whorwell PJ. Bran and irritable bowel syndrome: time for reappraisal. Lancet 1994;344(8914):39–40. https://doi.org/10.1016/s0140-6736 (94)91055-3. Cryan JF, Kaupmann K. Don’t worry “B” happy!: a role for GABA B receptors in anxiety and depression. Trends Pharmacol Sci 2005;26(1):36–43. https://doi. org/10.1016/j.tips.2004.11.004. Petroff OAC. GABA and glutamate in the human brain. Neuroscientist 2002;8(6):562–73. https://doi.org/10.1177/1073858402238515. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A 2011;108(38):16050–5. https://doi.org/ 10.1073/pnas.1102999108. Lee KJ, Kim JH, Cho SW. Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2005;22(10):981–8. https://doi. org/10.1111/j.1365-2036.2005.02685.x. Dupont HL. Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Ther 2014;39(10):1033–42. https://doi.org/10.1111/apt.12728. Didari T, Mozaffari S, Nikfar S, Abdollahi M. Effectiveness of probiotics in irritable bowel syndrome: updated systematic review with meta-analysis. World J Gastroenterol 2015;21(10):3072–84. https://doi.org/10.3748/wjg.v21.i10.3072. Zhang Y, Li L, Guo C, et al. Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis. BMC Gastroenterol 2016;16(1). https://doi.org/10.1186/s12876-016-0470-z. Silk DBA, Davis A, Vulevic J, Tzortzis G, Gibson GR. Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome. Aliment Pharmacol Ther 2009;29(5):508–18. https://doi.org/10.1111/j.1365-2036.2008.03911.x.

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[78] Bas¸ turk A, Artan R, Yilmaz A. Efficacy of synbiotic, probiotic, and prebiotic treatments for irritable bowel syndrome in children: a randomized controlled trial. Turkish J Gastroenterol 2016;27(5):439–43. https://doi.org/10.5152/ tjg.2016.16301. [79] Bittner AC, Croffut RM, Stranahan MC. Prescript-assist™ probiotic-prebiotic treatment for irritable bowel syndrome: a methodologically oriented, 2-week, randomized, placebo-controlled, double-blind clinical study. Clin Ther 2005;27(6):755–61. https://doi.org/10.1016/j.clinthera.2005.06.005. [80] Colecchia A, Vestito A, La Rocca A, et al. Effect of a symbiotic preparation on the clinical manifestations of irritable bowel syndrome, constipationvariant: results of an open, uncontrolled multicenter study, Minerva Gastroenterol Dietol 2006;52(4):349–58. http://www.embase.com/search/ results?subaction¼viewrecord&from¼export&id¼L46166443. (Accessed 17 December 2019). [81] Saadi M, Mccallum RW. Rifaximin in irritable bowel syndrome: rationale, evidence and clinical use. Ther Adv Chronic Dis 2013;4(2):71–5. https://doi.org/ 10.1177/2040622312472008. [82] Lembo A, Pimentel M, Rao SS, et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology 2016;151(6):1113–21. https://doi.org/10.1053/j. gastro.2016.08.003. € nther S, Christensen AH, Petersen AM. Can fecal [83] Halkjær SI, Boolsen AW, Gu microbiota transplantation cure irritable bowel syndrome? World J Gastroenterol 2017;23(22):4112–20. https://doi.org/10.3748/wjg.v23.i22. 4112. € sch F, Cavanagh JP, et al. Faecal microbiota transplantation [84] Johnsen PH, Hilpu versus placebo for moderate-to-severe irritable bowel syndrome: a doubleblind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol 2018;3(1):17–24. https://doi.org/10.1016/ S2468-1253(17)30338-2. [85] Martin CR, Osadchiy V, Kalani A, Mayer EA. The brain-gut-microbiome axis. Cell Mol Gastroenterol Hepatol 2018;6(2):133–48. https://doi.org/10.1016/j. jcmgh.2018.04.003.

The control of the intestinal epithelium integrity in irritable bowel syndrome patients

4

Adrian Szczepaniak and Marta Zieli nska Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract Microbiome, mechanical barrier, and the immune system interact together to ensure intestinal homeostasis. Immune cells such as lymphocytes (T cells), dendritic cells, macrophages, and mast cells play an important role in maintaining homeostasis, while their overproduction can disrupt intestinal barrier integrity and also contributes to the development of irritable bowel syndrome (IBS). Molecules produced by immune cells can affect intestinal function and disrupt barrier integrity through changes in tight junctions. Immune activation raises interest in identifying biomarkers useful for clinical purposes, enabling the development of new therapeutic agents in IBS. In this chapter we describe the elements of the intestinal barrier focusing on the immune system and their role and significance under physiological conditions and in pathological states.

Keywords Immune cells, Mast cells, T cells, Intestinal barrier

List of abbreviations 5-HT CGRP CLDNs GF GI IBS IBS-C IBS-D IFN-γ

5-hydroxytryptamine calcitonin gene-related peptide claudins germ-free gastrointestinal irritable bowel syndrome irritable bowel syndrome with constipation irritable bowel syndrome with diarrhea interferon gamma

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00004-6 # 2020 Elsevier Inc. All rights reserved.

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IL MCs PI-IBS SP TJs TNF-α ZOs

interleukin mast cells post-infectious IBS substance P tight junctions tumor necrosis factor alpha zonula occludins

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder [1] characterized by chronic abdominal pain, intestinal bleeding or changes in stool form and frequency [2]. Numerous studies have found that the intestinal barrier disturbances in IBS, i.e. changes in intestinal secretion and permeability are associated with GI symptoms [3–5]. Increased intestinal secretion is observed in IBS patients with predominant diarrhea (IBS-D), whereas the opposite correlation is specific for patients with constipation-predominant IBS (IBS-C). The pivotal role of the intestinal barrier is to separate the body from the external environment and control the selective absorption of nutrients from food. The GI tract is the main line of defense in which epithelial cells form a physical barrier and cooperate with immune cells to eradicate pathogens (Fig. 1). The major role of the intestinal immune system is to distinguish which antigens should be tolerated and which should be neutralized [6, 7]. The intestinal barrier is composed of four main elements: 1. intestinal epithelial cells (a mechanical barrier) that form a continuous and polarized monolayer through intercellular connections 2. intestinal microorganisms, which are responsible for resistance to colonization of pathogenic bacteria 3. mucosal layer—the first line of physical defense 4. lamina propria which is termed an immune barrier because it contains immune cells such as T cells, B cells, macrophages or dendritic cells

Mechanical barrier The layer of the intestinal epithelial cells is the most important mechanical protective barrier for the body. Among these cells, there are enterocytes, Paneth cells, goblet cells, and microfold cells. The most critical are intestinal epithelial cells and enterocytes [8]. Paneth cells physiologically are located in small intestinal crypts where they secrete antimicrobial peptides such as defensins and

Chapter 4 The control of the intestinal epithelium integrity in irritable bowel syndrome patients

lumen

mucus

tight junction

intestinal epithelium

adherens junctions desmosome

lamina propria

B cell

T cell macrophage dendritic cell

Fig. 1 Model of intestinal mucosal barrier.

lysozyme [9, 10]. α-Defensins are the dominant antimicrobial agents that provide an effective host defense against intestinal bacterial pathogens. They play a key role in shaping the composition of intestinal microbiota and can modulate the mucosal immune response. The deficiency of α-defensin may contribute to dysbiosis of host microorganisms and increased intestinal inflammatory response [11]. Whereas, lysozyme has the ability to directly control bacteria by hydrolysis of glycosidic bond β-(1–4) in their cell wall [12]. Moreover, lysozyme can regulate the immune functions through direct or indirect modulation of the complement system [13]. Noteworthy, patients with IBS had similar levels of fecal lysozyme to healthy controls, whereas fecal lysozyme concentrations in patients with inflammatory bowel diseases were significantly increased [14]. Goblet cells produce mucus and peptides that participate in the epithelial layer repair. The main component of mucus is glycosylated mucin MUC2. The pivotal role of mucus in the small

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intestine is to limit the number of bacteria that can get into the epithelial cells. In contrast, the large intestine has two layers of mucus: the outer, which is a natural environment for commensal bacteria, and the inner, separating the commensal bacteria from the epithelium [15]. Bacteria do not pass through inner layer due to the presence of antibacterial molecules in the mucus, such as defensins and IgA [16]. The highest concentration of IgA is found in the duodenum and the ileum [17]. Of note, probiotics used in IBS regulate mucins by increasing their production to prevent adhesion of pathogenic strains of bacteria [18]. Goblet cells can also form tight junction (TJ) with lymphatic cells, creating an epithelial barrier for microorganisms. Microfold cells secrete IgA helping to present bacterial antigens to dendritic cells and play a key role in initiating resistance of the mucous membrane against pathogens [19, 20]. The cells forming the barrier are connected by special protein complexes. The most important are TJs, which are formed by adjacent epithelial cells in their apical part, preventing the migration of microorganisms or antigens through the intestinal epithelium [21]. These connections are built up of the integral transmembrane proteins such as occludins, claudins (CLDNs), adhesion molecule links (JAM), which are directly linked to the scaffold protein zonula occludins (ZOs). ZOs are membrane proteins expressed on the epithelial and endothelial cells, which include peripheral membrane adaptor proteins ZO-1, ZO-2, ZO-3 and combine integral connections with actin cytoskeleton [22]. Other intracellular connections in the intestinal epithelium are adherens junctions (AJs) and desmosomes. AJs regulate the adhesion between adjacent cells via transmembrane adhesion receptors by binding to actin and joining the cytoskeletons of two cells. The components of these combinations are cadherins and catenins, and associated protein complexes which connect the cytoskeleton [23]. However, desmosomes are dynamic structures whose adhesion changes in various processes such as embryo development or wound healing. They consist of desmoglein, desmocollin and desmoplakin, and ensure strong adhesion between cells, as well as mechanical strength of tissues and maintain cell morphology [24]. Several studies suggest that dysregulated protein degradation through proteasomes may contribute to the induction of intestinal inflammation, increase in intestinal permeability and IBS. Consequently, proteasome changes have been shown to occur in the intestinal mucosa of patients with IBS and contribute to an increase in the degradation of the occludins [25]. The expression of ZO-1 and occludins is significantly lower in colonic mucosa in patients

Chapter 4 The control of the intestinal epithelium integrity in irritable bowel syndrome patients

with IBS. Interestingly, no difference in ZO-1 expression was detected between IBS subtypes, whereas the expression of occludin and claudine-1 was reduced in IBS-D compared to IBS-C. Moreover, the distribution of proteins in the cell was changed in the course of IBS. In patients with IBS the location of proteins was disrupted and the proteins were distributed irregularly and did not form a characteristic reticular pattern in the upper part of the cell. Additionally, it was found that expression of claudine-1 was correlated with abdominal pain in patients with IBS-D [26].

Intestinal microbiota Gut microbiota is a population of microorganisms, bacteria or fungi that colonizes the intestines [27]. Most of these bacteria are non-pathogenic and have a positive effect on intestinal function. Eckburg et al. [28] found that 90% of commensal bacteria in the intestines of healthy subjects belong to the Firmicutes and Bacteroidetes types. In addition, it was shown that the same types of bacteria are the most common in human distal gut [29]. Commensal bacteria live in symbiosis with the host. They provide essential nutrients, defense against the colonization of pathogenic microorganisms and stimulate the immune system to maturation which will recognize and distinguish between commensal and pathogenic bacteria. Moreover, bacteria regulate the intestinal motility, produce vitamins or destroy toxins and mutagens [30]. Short-chain fatty acids (SCFA), namely propionate, butyrate and acetate are bacterial metabolites resulting from fermentation of dietary oligosaccharides which play a particular role in maintaining colon homeostasis. Butyrate can weaken bacterial translocation and strengthen the intestinal barrier. SCFAs also participate in the regulation of the immune system and inflammatory reaction [31]. Moreover, SCFAs stimulate the production of IL-18, which is involved in the maintenance and repair of the epithelial integrity [32]. It is now known that concentration of SCFAs in feces is different in IBS patients compared to healthy individuals: in patients with IBS-C propionate and butyrate were reduced, while butyrate was increased in patients with IBS-D. Recently, it was hypothesized that these SCFAs can be used as biomarkers for diagnosis of IBS [33]. Commensal bacteria strains prevent colonization by pathogenic microorganisms and support the proper functioning of the gut barrier [34] by maintaining connections between enterocytes [35, 36]. A report by Martin et al. showed that Bifidobacteria isolated from infants and cultured on human milk oligosaccharides led to higher

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expression of ZO-1 and occludin in HT-29 cells. Bifidobacterium animalis reduced the intestinal permeability in the mouse model of inflammation by normalizing TJ protein expression levels [37].

Immunological activation in irritable bowel syndrome Most of the cells involved in immunological reactions are found in the lamina propria. This layer contains basic structural elements (fibroblasts, fibrocytes, vascular endothelial cells and smooth muscle cells), blood cells (granulocytes, mast cells, macrophages, Tand B lymphocytes) and nerve fibers. The number and distribution of immune cells may change in pathological states [38]. This also holds true in IBS: the cells of the immune system are activated and can release mediators (Table 1).

Table 1 Cells activated in IBS and their mediators. Cell type

Mediators/molecules

T lymphocytes

– – – – – – – – – – – – – – – – – –

Mast cells

Macrophages

Eosinophils

B lymphocytes

TNF-a IFN-g Il-1b Il-4 Il-13 Histamine Serotonin Proteases Chymase Prostaglandin D2 Tryptase TNF-a Il-1b Il-6 Basic protein Eosinophil-derived neurotoxin Eosinophil peroxidase Antibodies

Chapter 4 The control of the intestinal epithelium integrity in irritable bowel syndrome patients

T cells Patients with IBS have an increased number of CD4+ T lymphocytes and CD8+ intraepithelial T cells along the intestinal mucosa. Intraepithelial lymphocytes are located on a critical interface between intestinal lumen which is chronically exposed to food and microorganisms [39]. T cells produce proinflammatory interleukins (IL) and cytokines which are involved in the intestinal epithelial barrier disorders, i.e. tumor necrosis factor alpha (TNF-α) and interferon gamma (IFNγ), which disrupt TJs and impair absorption of Na+ and co-transport Na+-glucose [40]. Additionally, IL-4 and IL-13 induce apoptosis of the epithelial cells, increasing intestinal permeability [41, 42]. In order to maintain homeostasis and eliminate potential inflammation caused by microorganisms, immune cells migrate to the intestinal lumen. However, prolonged antigen stimulation and excessive release of inflammatory mediators can lead to the breaking of TJs. This is a result of the phosphorylation of the light chain of myosin, followed by changes in the expression and location of the TJs proteins.

Mast cells Mast cells (MCs) are located near the blood vessels or on intestine surface. MCs are a key element of the innate immune system, which upon activation release the substances contained in their granules, including histamine, serotonin (5-HT) and proteases or cytokines, prostaglandins and leukotrienes [43]. These molecules regulate permeability, secretion, peristalsis and mechanisms of congenital and acquired immunity. MCs are the principal cells involved in the pathophysiology of IBS and their activity increases in the intestinal mucosa of IBS patients. There, they release even more mediators such as tryptase and histamine [44]. An increased release of histamine nearby the colonic nerves leads to an increased incidence of abdominal pain, abnormal intestinal secretion and permeability [45]. MCs also release other mediators such as chymase and prostaglandin D2 that stimulate the secretion of water and chlorine in the intestinal epithelium. Moreover, they contribute to the reduction of the expression of TJs proteins, causing increased permeability and exacerbation of IBS symptoms [44].

Macrophages and eosinophils The intestinal barrier disorders can be caused by other immune cells, such as antigen-presenting cells, which include macrophages

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and dendritic cells; however, these are poorly studied in IBS. Macrophages induce acute inflammatory response and release proinflammatory cytokines, including TNF-α, IL-1β and IL-6, which recruit other inflammatory cells and cause intestinal barrier disruption [46, 47]. Macrophages are involved in GI phagocytosis but are also capable of antigen presentation [48]. Eosinophils are located in the GI tract, where they synthesize and release severe immunological mediators (i.e., basic protein, eosinophil-derived neurotoxin and eosinophil peroxidase). Eosinophils are usually associated with allergic reactions, but IBS patients show no changes in the levels of these cells in intestinal biopsies. Furuta et al. reported that basic protein is the main mediator that induces epithelial barrier dysfunction associated with the down-regulation of occludin [49]. Moreover, an increased eosinophils counts has been identified in IBS patients [50]. However, little is known about the effect of eosinophilic mediators on GI nerves.

B cells There are not many results showing the involvement of B cells in IBS pathogenesis. So far, elevated IgG specific antibodies have been confirmed in the serum of the patients with IBS [51, 52]. € However, Ohman et al. [53] indicated that B cells isolated from the blood of IBS patients showed a higher level of activation. This has been further confirmed by the identification of increased IgG expression on these cell surface. Moreover, the expression of the CD80 costimulating molecule induced by the bacterial component is impaired in IBS patients.

Immune system activation in IBS The precise mechanisms of the intestinal immune cells activation in IBS patients have not been described so far. It is considered that stress, previous GI infections, colonization by pathogenic bacteria or increased intestinal permeability are the factors that may influence this process [54, 55]. The key mediator of stress response in IBS is corticotropin releasing factor (CRF), which takes part in changes in the GI function, including inflammatory processes, defecation pattern or secretory function. It is known that CRF and its receptors can be a key part in the immune and motor function through the brain-gut axis in IBS [56]. Concurrently, increased intestinal permeability in patients with IBS is associated with activation of immune cells, which mediate the formation of intestinal motor disorders and visceral pain [45, 57]. As regards the intestinal

Chapter 4 The control of the intestinal epithelium integrity in irritable bowel syndrome patients

mucosa, an increased number of immune cells, mainly MCs and T cells, can be found in the epithelium and in the lamina propria [58]. In addition, higher amounts of various mediators are produced there, including proteases, histamine and prostaglandins [45, 59]. Gastrointestinal infections lead to the development of postinfectious IBS. Excessive activation of the immune system causes inflammation and mucous membrane damage. In patients with PI-IBS, increased levels of IL-6, IL-1β in rectal samples or macrophages and T-cells in intestinal biopsies are observed, which indicates the pathophysiological role of inflammation in the development of PI-IBS [60–63]. It is worth mentioning that the activation of immune cells in IBS is dependent on several factors. It was found that the growth of MCs was gender dependent. Women with IBS showed a higher number of MCs, but a lower number of T cells CD3 + and CD8 + than men. In some cases, a similar degree of MC infiltration was found in patients with predominant diarrhea or constipation [64, 65] but other studies showed that the immune cell count was higher in patients with diarrhea [57].

Nervous system Interactions between microbiota, epithelial cells, the immune system and the nervous systems participate in the control of the intestinal permeability. MCs can activate and sensitize the intestinal nerves and modulate the integrity of the epithelial barrier [66]. There is evidence of a link between the central nervous system and the activation of the mucosal immune system and the sensation of symptoms. The mechanisms by which the brain affects intestinal physiology are not fully understood, but include interactions in the brain-gut axis through changes in the release of neurotransmitters [67]. The immune system modulates the sensory and motor functions of the intestines, also in pathological conditions. In IBS patients, mediators released from the intestinal mucosa contribute to increased activation of pain signaling [44]. Further studies showed that supernatants obtained from colon biopsies of IBS patients caused overactivation of submucosal neurons which has been confirmed with the use of voltage-sensitive dyeing imaging [68]. Pain sensation may also be enhanced by MCs or intestinal bacteria secreting serine proteases, which are significantly increased in IBS mucosa and which activate receptors located

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on the intestinal nerves. In addition, proteases stimulate sensory neurons and induce sensitivity to pain by activating PAR2 [69]. The central nervous system regulates the intestinal barrier by monitoring ion secretion, immune function and peristalsis through release of neuropeptides and neurotransmitters that stimulate the secretion of mediators by MCs [21]. Nerves can release various substances, including 5-HT, a calcitonin gene-related peptide (CGRP) and substance P (SP). 5-HT is associated with secretion, motility and sensation in the intestines and the 5-HT dysfunction in IBS has been confirmed [70]. On the other hand, SP and nerve growth factor released from the nerves induce the release of vasoactive mediators from MCs, thus contributing to chloride secretion, barrier dysfunction, pain sensitization, diarrhea, inflammation and motility changes [71].

Conclusions The intestinal barrier, bacteria and immune system interact to ensure intestinal homeostasis. However, changes in their equilibrium lead to pathological states of the GI tract. IBS is a result of the intestinal barrier dysregulation, changes in TJs protein expression, bacterial translocation and hyperactivation of the immune system. Activated immune cells release inflammatory mediators causing disturbance of intestinal mucosa. Future research in experimental models is needed to better understand the relationship between all these elements. If specific measures are identified to prevent intestinal barrier disruption and reduce intestinal permeability, they may serve as new future therapeutic or diagnostic approaches to IBS treatment.

Acknowledgments This study supported by grant from the Medical University of Lodz, Lodz, Poland (No. 503/1-156-04/503-11-001) and the Ministry of Science and Higher Education “Mobility Plus 5” (No. 1658/1/MOB/V/17/2018/0 to MZ).

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[25] Coe¨ffier M, Gloro R, Boukhettala N, Aziz M, Lecleire S, Vandaele N, et al. Increased proteasome-mediated degradation of occludin in irritable bowel syndrome. Am J Gastroenterol 2010;105(5):1181–8. [26] Bertiaux-Vandae¨le N, Youmba SB, Belmonte L, Lecleire S, Antonietti M, Gourcerol G, et al. The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype. Am J Gastroenterol 2011;106 (12):2165–73. [27] Sekirov I, Russell SL, Antunes LCM, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010;90(3):859–904. [28] Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science 2005;308(5728): 1635–8. [29] Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature 2011;473(7346):174–80. [30] Macfarlane S, Steed H, Macfarlane GT. Intestinal bacteria and inflammatory bowel disease. Crit Rev Clin Lab Sci 2009;46(1):25–54. [31] Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 2016;7(3):189–200. [32] Corr^ea-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MAR. Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunol 2016;5(4). [33] Sun Q, Jia Q, Song L, Duan L. Alterations in fecal short-chain fatty acids in patients with irritable bowel syndrome: a systematic review and metaanalysis. Medicine (Baltimore) 2019;98(7). [34] Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol 2015;21(29): 8787–803. [35] Ahrne S, Johansson Hagslatt M-L. Effect of lactobacilli on paracellular permeability in the gut. Nutrients 2011;3(1):104–17. [36] Khailova L, Dvorak K, Arganbright KM, Halpern MD, Kinouchi T, Yajima M, et al. Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Liver Physiol 2009;297(5):G940–9. [37] Martı´n R, Laval L, Chain F, Miquel S, Natividad J, Cherbuy C, et al. Bifidobacterium animalis ssp. lactis CNCM-I2494 restores gut barrier permeability in chronically low-grade inflamed mice. Front Microbiol 2016;7:608. [38] Hunyady B, Mezey E, Palkovits M. Gastrointestinal immunology: cell types in the lamina propria—a morphological review. Acta Physiol Hung 2000;87 (4):305–28. [39] Hoytema van Konijnenburg DP, Reis BS, Pedicord VA, Farache J, Victora GD, Mucida D. Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection. Cell 2017;171(4):783–94. e13. [40] Musch MW, Clarke LL, Mamah D, Gawenis LR, Zhang Z, Ellsworth W, et al. T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na +/K+-ATPase. J Clin Invest 2002;110(11):1739–47. [41] Wisner DM, Harris LR, Green CL, Poritz LS. Opposing regulation of the tight junction protein claudin-2 by interferon-γ and interleukin-4. J Surg Res 2008;144(1):1–7. [42] Weber CR, Raleigh DR, Su L, Shen L, Sullivan EA, Wang Y, et al. Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity. J Biol Chem 2010;285(16):12037–46. [43] Barbara G, Stanghellini V, De Giorgio R, Corinaldesi R. Functional gastrointestinal disorders and mast cells: implications for therapy. Neurogastroenterol Motil 2006;18(1):6–17.

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[44] Lee KN, Lee OY. The role of mast cells in irritable bowel syndrome. Gastroenterol Res Pract 2016;2016:1–11. [45] Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126(3):693–702. [46] Al-Sadi R, Ye D, Said HM, Ma TY. Cellular and molecular mechanism of interleukin-1β modulation of Caco-2 intestinal epithelial tight junction barrier. J Cell Mol Med 2011;15(4):970–82. [47] Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem 2011;286(36):31263–71. [48] Hughes PA, Zola H, Penttila IA, Blackshaw AL, Andrews JM, Krumbiegel D. Immune activation in irritable bowel syndrome: can neuroimmune interactions explain symptoms? Am J Gastroenterol 2013;108(7):1066–74. [49] Furuta GT, Nieuwenhuis EES, Karhausen J, Gleich G, Blumberg RS, Lee JJ, et al. Eosinophils alter colonic epithelial barrier function: role for major basic protein. Am J Physiol Liver Physiol 2005;289(5):G890–7. [50] Park KS, Ahn SH, Hwang JS, Cho KB, Chung WJ, Jang BK, et al. A survey about irritable bowel syndrome in South Korea. Dig Dis Sci 2008;53(3):704–11. [51] Zar S, Mincher L, Benson MJ, Kumar D. Food-specific IgG4 antibody-guided exclusion diet improves symptoms and rectal compliance in irritable bowel syndrome. Scand J Gastroenterol 2005;40(7):800–7. [52] Zuo XL, Li YQ, Li WJ, Guo YT, Lu XF, Li JM, et al. Alterations of food antigenspecific serum immunoglobulins G and E antibodies in patients with irritable bowel syndrome and functional dyspepsia. Clin Exp Allergy 2007;37(6):823–30. € € vall H, et al. B-cell [53] Ohman L, Lindmark A-C, Isaksson S, Posserud I, Strid H, Sjo activation in patients with irritable bowel syndrome (IBS). Neurogastroenterol Motil 2009;21(6):644–e27. [54] Gao X, Cao Q, Cheng Y, Zhao D, Wang Z, Yang H, et al. Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response. Proc Natl Acad Sci U S A 2018;115(13):E2960–9. [55] Wang C, Li Q, Ren J. Microbiota-immune interaction in the pathogenesis of gut-derived infection. Front Immunol 2019;10:1873. [56] Chatoo M, Li Y, Ma Z, Coote J, Du J, Chen X. Involvement of corticotropinreleasing factor and receptors in immune cells in irritable bowel syndrome. Front Endocrinol 2018;9:21. [57] Guilarte M, Santos J, De Torres I, Alonso C, Vicario M, Ramos L, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007;56(2):203–9. €hlmann HWH, Van den [58] Aerssens J, Camilleri M, Talloen W, Thielemans L, Go Wyngaert I, et al. Alterations in mucosal immunity identified in the colon of patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2008; 6(2):194–205. [59] Macsharry J, O’Mahony L, Fanning A, Bairead E, Sherlock G, Tiesman J, et al. Mucosal cytokine imbalance in irritable bowel syndrome. Scand J Gastroenterol 2008;43(12):1467–76. [60] Bashashati M, Moradi M, Sarosiek I. Interleukin-6 in irritable bowel syndrome: a systematic review and meta-analysis of IL-6 (-G174C) and circulating IL-6 levels. Cytokine 2017;99:132–8. [61] Schwille-Kiuntke J, Mazurak N, Enck P. Systematic review with meta-analysis: post-infectious irritable bowel syndrome after travellers’ diarrhoea. Aliment Pharmacol Ther 2015;41(11):1029–37. [62] Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased

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Irritable bowel syndrome and gut microbiota

5

Damian Jacenika and Marta Zieli nskab a

Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland. bDepartment of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract The intestinal microbiota consist of numerous different bacterial species taxonomically classified by genus, family, order, and phyla. Microbiota consist one of the pillars of the microbiota-brain-gut axis, which is a bidirectional link between the central nervous system and the enteric nervous system. This axis participates in the maintenance of homeostasis in the gastrointestinal (GI) system through prevention of the pathogen colonization of the GI tract and through control of the GI motor function as well as fluid and ion secretion. The intestinal microbiota also play a role in food digestion, nutrition and vitamin production. The changes in the composition of the intestinal microbiota are combined with many diseases, i.e. allergy, asthma and irritable bowel syndrome (IBS). The modulation of the intestinal microbiota using pre-, pro-, syn- or antibiotics may become a novel strategy in IBS therapy.

Keywords Antibiotics, Gut microbiota, Microbiota, Prebiotics, Synbiotics

Abbreviations CNS ENS FMT GI HPA IBS IBS-A IBS-C

central nervous system enteric nervous system microbiota transplantation gastrointestinal hypothalamic-pituitary-adrenal axis irritable bowel syndrome altered irritable bowel syndrome constipation-predominant irritable bowel syndrome

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00005-8 # 2020 Elsevier Inc. All rights reserved.

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IBS-D PI-IBS SCFA SIBO

diarrhea-predominant irritable bowel syndrome postinfectious irritable bowel syndrome short chain fatty acid small intestine bacterial overgrowth

Gut microbiota The intestinal epithelium is the frontline of host defense, which is termed as “all that separates us and them”, because the intestinal lumen is home to a wide range of microbes, including bacteria, archaea, fungi, viruses, and phages. The most important for our body are bacteria on which we will focus in this chapter. The gastrointestinal (GI) system contains more than 1000 different bacterial species and 7000 strains [1]. The microbiota composition is changing throughout the GI tract, i.e. the density of microbiota per gram of luminal content can reach 103 bacteria/g in the duodenum, 104 bacteria/g in the jejunum, 107 bacteria/g in the ileum, and 1014 bacteria/g in the colon, which makes the colon one of the most densely populated microbial habitats known on Earth [2]. The most predominant bacterial phyla in the GI tract, i.e. Firmicutes (most common genus: Lactobacillus, Bacillus, Clostridium, Enterococcus and Ruminicoccus), Actinobacteria (mainly Bifidobacterium), Proteobacteria and Bacteroidetes (Bacteroides and Prevotella), represent more than 90% of the microbial population [3]. Each individual possesses a unique gut microbiota profile, which is shaped in the early life, affected by i.e. gestational age, type of delivery, method of milk feeding, weaning period or antibiotics therapy in first months after delivery. Moreover, the composition of the microbiota is strongly influenced by genetics (that explains 5–10% of the bacterial variability between individuals) and environmental factors (i.e. geographical location, diet, antibiotics, non-antibiotic drugs, surgery, smoking, and depression) [4]. The intestinal microbiota protect against ingested pathogens as our microbiota are able to change nutrient metabolism, modify pH and secrete anti-microbial peptides and thus they prevent pathogens colonization [5]. Moreover, the microbiota affect function of innate, and adaptive immune cells, as well as they maintain the intestinal epithelial barrier integrity. The intestinal microbiota participate in nutrient and mineral absorption (calcium, magnesium, and iron), digestion of food that was not digested in the stomach, and small intestine, as well as in

Chapter 5 Irritable bowel syndrome and gut microbiota

vitamin production (for instance vitamin B, and K). They are involved in the metabolism of xenobiotics and food toxicants [6]. Microbiota produce short chain fatty acids (SCFAs) through non-digestible carbohydrates fermentation in the colon, which are important for the communication between cells located in the enteric or central nervous system (CNS) [3]. It was proved that disturbances in the composition of the intestinal microbiota are combined with the course of numerous diseases, i.e. irritable bowel syndrome (IBS), obesity, allergy, diabetes, asthma, liver diseases and neuropsychiatric disorders (i.e. depression, and anxiety), however it is still not known if changes in the microbiota composition are a result of disease or its cause [7]. Therefore, detailed studies on the role of microbiota in the whole GI tract are urgently needed. Most of the studies are carried out on the colonic bacteria, which are the most important, and also easy to study. Interestingly, there are even differences in the composition of the intestinal microbiota in the mucosal layer, and in the stool [8]. A useful mouse model to study microbiota constitutes germfree animals, which lack microbiota, and can be colonized with selected bacterial strains and thus we are able to deepen the knowledge on the selected bacterial strain on the body function [9]. Furthermore, it was proved that germ-free mice possess a completely immature immune system, alterations in the structure and function of the GI tract and changed stress and anxiety response, as well as cognition disturbances, so it emphasizes how important are microbiota.

Post-infectious IBS (PI-IBS) Beside sporadic IBS, which can be divided into subtypes related to changes in the GI motility, namely diarrheapredominant IBS (IBS-D), constipation-predominant IBS (IBSC), and IBS with altered bowel habits (IBS-A), a disease combined with a history of GI infection termed post-infectious IBS (PI-IBS) needs to be mentioned. PI-IBS is diagnosed in 6–17% of IBS patients [10]. Salmonella, Shigella and Campylobacter are most common agents responsible for the gastroenterocolitis, which then leads to PI-IBS development. Beside gastritis, female gender, old age, antibiotic treatment and concomitant psychiatric disorder are risk factors for PI-IBS development. Interestingly, in the case of PI-IBS: patients will develop IBS-D subtype (63%), IBS-A (24%) and IBS-C (13%).

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Microbiota-brain-gut axis IBS used to be called a disorder of the brain-gut axis, as beside symptoms from the GI system stress, bad sleeping, fatigue, mental confusion, impaired judgment, and trouble concentrating were listed as its psychological aspects [11]. Few years ago the term brain-gut axis changed to the microbiota-brain-gut axis. The latter includes the CNS, the neuroendocrine (hypothalamic-pituitary-adrenal axis, known as HPA axis) and neuroimmune systems (cytokines, and chemokines), the autonomic nervous system, the enteric nervous system (ENS), the vagus nerve and the intestinal microbiota [12]. The bidirectional communication between CNS and viscera can occur through multiple molecular mechanisms, including epithelial cells, receptor-mediated signaling or direct stimulation of host immune cells in the lamina propria. All these are secured by several chemical signaling molecules: acetylcholine, catecholamines, γ-aminobutyric acid, histamine, melatonin, and serotonin, which all have an impact on the motor, sensory and secretory modalities of the GI system by affecting immune, epithelial and smooth muscle cells and enteric neurons [13]. The alterations in the composition of the intestinal microbiota correlate with changes in the levels of circulating cytokines, which may modulate cell signaling pathways in the CNS [14]. The low microbial diversity, called dysbiosis, activates the immune cells and causes a low-grade inflammation in the intestines, disrupts the gut-brain axis interactions and may lead to depression or mood disturbances [15]. On the other hand, the HPA axis is activated during chronic or acute stressful situations and causes changes in the intestinal microbiota and intestinal epithelium permeability [16]. It can thus be stated that it is difficult to determine if microbiota affect the brain function or the CNS affects microbiota composition. It was also proved that even up to 60% of IBS patients suffer from psychiatric disorders including anxiety, panic, mood disorders, depression and post-traumatic stress disorder, what confirms that disturbances in the function of the microbiotagut-brain axis may be present in IBS patients [17]. Moreover, all these symptoms related to the CNS let doctors use antidepressants as one of the forms of IBS therapy, however currently available data on their efficacy are conflicting.

Gut microbiota alteration in IBS An accumulating body of evidence highlighted alteration of microbiota diversity and composition in IBS patients [18]. For example, an increased growth of Prevotella copri, Eubacterium

Chapter 5 Irritable bowel syndrome and gut microbiota

dolichum, Veillonella dispar, and Haemophilus parainfluenzae as well as a reduction of Anaerostipes was reported by Presti et al. [19] in the mucosa of IBS patients. Dysbiosis may be associated with IBS subtype: a comparison of total bacterial counting in the intestines of IBS-D revealed up-regulation of Escherichia coli, Clostridium, Bacteroides, and down-regulation of Bifidobacteria when compared to healthy controls. Interestingly, Zhong et al. [20] proved that specific mucosa-associated microbiota are related to IBS symptoms. Negative correlation between the severity of abdominal pain and the count of Escherichia coli, the defecation frequency and the count of Lactobacillus and defecation satisfaction and the count of Bifidobacteria in IBS-D patients was found. Dysbiosis in IBS patients is observed not only in the intestinal mucosa but also in feces of IBS patients. Zhu et al. [21] using fecal samples obtained from healthy controls and IBS patients documented 19 up-regulated and 12 down-regulated microbial populations. Among them altered level of Lachnoclostridium, Clostridium, Lachnospiraceae, Lactobacillus, Tyzerella, Ruminiclostridium, Ruminiclostridium, Parabacteroides, Hungatella, Lachnospira, Romboutsiam and Granulicatella in feces of IBS patients was observed as compared to healthy controls. In another study, Presti et al. [19] demonstrated higher level of Parabacteroides distasonis and lower level of Lactococcus and Pseudomonas in the feces of IBS compared to healthy control. In a meta-analysis of case-control studies, Wang et al. [18] confirmed that IBS is manifested by dysbiosis and feces of IBS are characterized by a higher level of Escherichia coli and Enterobacter and lower level of Lactobacillus and Bifidobacterium. Beyond clinical findings concerning the significance of microbiota in IBS, there is also evidence from animal models of IBS. Liu et al. [22] reported, using water avoidance stress as IBS model, that intestine metabolites in rats with IBS are different from control animals. However, a lower level of gut microbial diversity was found in IBS rats as compared to control group.

Small intestine bacterial overgrowth Small intestine bacterial overgrowth (SIBO) is defined as the presence of excessive bacteria in the small intestine. SIBO is frequently associated with chronic diarrhea and malabsorption. It was demonstrated that patients with SIBO suffer from unintentional weight loss and nutritional deficiencies. In a meta-analysis, Ghoshal et al. [23] assessed that IBS patients had higher prevalence of SIBO than the control group. It is also worth to note that

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higher prevalence of SIBO in IBS patients is observed irrespective from diagnostic test used for SIBO evaluation, i.e. lactulose or glucose hydrogen breath tests. In another study, Chen et al. [24] evaluated that odds of SIBO is 4.7-fold higher in patients with IBS than in control group. Additionally, it was estimated that there is a difference in the prevalence of SIBO between IBS subtypes. In fact, SIBO is more common in IBS-D patients as compared to other subtypes of IBS [24]. Moreover, IBS-D patients with SIBO suffer from more severe GI symptoms and worse quality of life as compared to IBS-D patients without SIBO [25]. Wu et al. [25] using 16S rRNA sequencing technique were able to identify differences in the composition of fecal microbiota in IBS-D patients with and without SIBO. Prevotella was the most abundant genera in feces of IBS-D patients with SIBO and it was documented that Prevotella increased while Bacteroides decreased in feces of IBS-D patients with SIBO in relation to IBS-D patients without SIBO. Further analysis revealed that Prevotella but not Bacteroides positively correlated with severity of GI symptoms in IBS-D patients with SIBO [25]. Noteworthy, the differences in microbiota diversity and composition were also observed in the duodenal and rectal mucosa of IBS-D patients with SIBO in relation to IBS-D patients without SIBO [26].

Prebiotics, probiotics and synbiotics Any therapy affecting composition, and function of the intestinal microbiota may be a useful approach in the treatment of functional gastrointestinal disorders including IBS. Prebiotics are food compounds such as oligosaccharides and polysaccharides which support the growth and/or activity of beneficial microbiota in the GI tract. Accumulating body of evidence demonstrated that prebiotic treatment is associated with reduction of IBS symptoms. Additionally, treatment with prebiotic, i.e. short-chain fructooligosaccharides improved quality of life in IBS patients as compared to placebo [27]. In another study, Silk et al. [28] proved that trans-galactooligosaccharide prebiotic treatment enhanced the level of fecal Bifidobacteria and was responsible for a change of stool consistency, improved flatulence, and bloating scores in IBS-C and IBS-D patients in comparison to IBS-C and IBS-D patients treated with placebo. Probiotics are live or attenuated microorganisms that are able to alter gut microbiota communities bringing health benefit to the host. Probiotics can help maintain the homeostasis through

Chapter 5 Irritable bowel syndrome and gut microbiota

modulation of the luminal acidity, inhibition of bacterial adherence, and producing antibacterial molecules [29]. Abincol, a probiotic mixture of Lactobacillus plantarum, Lactobacillus lactis subspecies cremoris and Lactobacillus delbrueckii was showed to affect the severity of the most relevant IBS symptoms: supplementation led to the improvement of abdominal pain and bloating, flatulence, borborygmi and eructation in patients with IBS after 4 weeks treatment [30]. A positive impact of some other microbiota like Lactobacillus reuteri on visceral pain was also observed in animal models of IBS. In line, Kamiya et al. [31] noted that oral administration of live or killed Lactobacillus reuteri inhibited the constitutive cardio-autonomic response to colorectal distension in rats through effects on the enteric nerves. Probiotics have also been suggested to exert immunoregulatory effects. For example, O’Mahony et al. [32] using peripheral blood mononuclear cells obtained from IBS patients and healthy controls estimated that Bifidobacterium infantis but not Lactobacillus salivarius affects production of interleukin 10 and 12 in vitro (cytokines important in inflammatory response). Finally, accumulating evidence indicates that synbiotics may be helpful in the treatment of IBS patients. Synbiotics are described as a mixture of prebiotics and probiotics which selectively improve the growth, and activate the metabolism of a limited number of health-promoting bacteria in the GI tract. Moser et al. [33] documented positive effect of short-term oral synbiotic treatment in the case of IBS-D patients. Currently, there is a commercially available synbiotic mixture containing multiple species of probiotic strains such as Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus salivarius, Lactobacillus plantarum, Lactococcu slactis, Bifidobacterium lactis, Bifidobacterium bifidum and prebiotics including corn starch, maltodextrin, inulin, fructooligosaccharides, potassium chloride, magnesium sulfate, manganese sulfate, and enzymes. Treatment with the above mentioned synbiotic for 4 weeks resulted in the reduction of the mucosal CD4+ T cells in IBS-D patients in relation to the same patients before the experiment [33]. Beyond immunerelated action, synbiotic treatment seems to be associated with disturbances of SCFAs in the feces of IBS-D patients. Additionally, significant differences in the case of phylogenetic diversity and microbial abundances in IBS-D patients before and after synbiotic treatment were observed. Bacterial community profiling has shown higher abundance of Halomonas, Neisseriaceae, Propionibacterium acnes and Clostridiaceae while Actinobacteria was reduced in gastric corpus of IBS-D patients after synbiotic

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treatment compared to gastric corpus of IBS-D patients before. In line, synbiotic treatment affected abundance of Schwartzia, Catonella and Lactobacillus in duodenal specimens and Lactobacillaceae, Moraxella and Moryella in fecal samples of IBS-D patients [33].

Fecal microbiota transplantation Fecal microbiota transplantation (FMT) is defined as the transfer of the intestinal microbiota from healthy donor into the GI tract of a patients with dysbiosis. FMT is a promising therapeutic approach in some GI diseases like Clostridium difficile infection and may be beneficial in encephalopathy or ulcerative colitis [34]. From the clinical point of view there are two sources of fecal microbiota obtained for transplantation: patient-directed donors and universal donors through stool banks [35]. Fecal microbiota may be taken from healthy donors who are rigorously screened based on history and serological tests. On the other hand, healthy donors have to meet several demographical criteria regarding for instance age and body mass index [36]. After donation, feces are subject to a number of laboratory tests which exclude parasitic, virologic, and bacterial pathogens. Because the microbiota used have to be thoroughly tested, those for FMT obtained from universal donors are more often employed than microbiota taken from patient-directed donors. To the best of our knowledge, FMT seems to be ineffective in the treatment of IBS as proven by a number of experimental studies and clinical trials [37]. Important evidence were provided in a double-blind, randomized, placebo-controlled trial where Aroniadis et al. [38] observed that FMT seems to be safe but did not improve symptoms in IBS-D patients compared to placebo recipients. In line, in a systemic review and meta-analysis, Myneedu et al. [39] based on single-arm trials and randomized controlled trials conclude that FMT is not a successful strategy in IBS. On the other hand, there is evidence supporting hypothesis about positive impact of FMT in IBS patients. Huang et al. [40] using several score systems estimated that FMT positively affects the development of IBS but only at the beginning of therapy and not as a long-term strategy. IBS patients treated with microbiota reported improvement of quality of life and severity scoring after 1 and 3 months of FMT therapy. In line, short-term FMT was related with reduction of general GI symptoms and improved anxiety and depression in IBS patients compared to IBS patients

Chapter 5 Irritable bowel syndrome and gut microbiota

before FMT. In another clinical trial, Holvoet et al. [41] observed that 75% of IBS patients experienced relief from IBS symptoms and abdominal bloating 12 weeks after FMT. El-Salhy et al. [42] suggest that higher dose of microbiota or additional FMT are associated with improvement of abdominal pain, and fatigue, as well as quality of life in IBS patients who did not respond to lower dose of microbiota. It has to be noted that studies about FMT provide conflicting results and further experiments are needed to conclude effect of FMT treatment in IBS.

Conclusions There are numerous intestinal microbiota living in the GI tract; their presence is valuable for our body, as they are involved in many physiological processes, including nutrition, vitamin production, digestion and protection against other microorganisms. Microbiota seem to be crucial in both physiology and pathophysiology of colon including IBS development, and symptomatology. It was proven that intestinal microbiota interact not only with colon per se but also with CNS affecting microbiota-brain-gut axis. In IBS patients the microbiota composition is changed, and also dependent on the IBS subtype, but it is already known that modulation of the intestinal microbiota with prebiotics, probiotics, synbiotics or even antibiotics may be helpful in disease symptoms alleviation. However, due to geographical discrepancies as well as dietary differences there is no standardization of IBS therapy with drugs acting on the intestinal microbiota.

Acknowledgments Supported by grant from Medical University of Lodz, Lodz, Poland (#503/1-156-04/503-11-001) and Ministry of Science and Higher Education “Mobility Plus 5” (#1658/1/MOB/V/17/2018/0 to MZ).

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[5] Dinan TG, Stilling RM, Stanton C, Cryan JF. Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res 2015;63:1–9. https://doi.org/ 10.1016/j.jpsychires.2015.02.021. [6] Guarner F, Malagelada J-R. Gut flora in health and disease. Lancet 2003; 361(9356):512–9. [7] Herndon CC, Wang YP, Lu CL. Targeting the gut microbiota for the treatment of irritable bowel syndrome. Kaohsiung J Med Sci 2019;36:160–70. [8] Gu Y, Zhou G, Qin X, Huang S, Wang B, Cao H. The potential role of gut mycobiome in irritable bowel syndrome. Front Microbiol 2019;10:1894. [9] Jung J, Surh CD, Lee YJ. Microbial colonization at early life promotes the development of diet-induced CD8αβ intraepithelial T cells. Mol Cells 2019; 42(4):313–20. [10] Vich Vila A, Imhann F, Collij V, Jankipersadsing SA, Gurry T, Mujagic Z, et al. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome. Sci Transl Med 2018;10(472) eaap8914. [11] Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC. Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther 2015;37(5):984–95. https://doi. org/10.1016/j.clinthera.2015.04.002. [12] Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 2009; 6(5):306–14. [13] Osadchiy V, Martin CR, Mayer EA. The gut–brain axis and the microbiome: mechanisms and clinical implications. Clin Gastroenterol Hepatol 2019;17:322–32. [14] Sherwin E, Rea K, Dinan TG, Cryan JF. A gut (microbiome) feeling about the brain. Curr Opin Gastroenterol 2016;32(2):96–102. [15] Fond G, Boukouaci W, Chevalier G, Regnault A, Eberl G, Hamdani N, et al. The “psychomicrobiotic”: targeting microbiota in major psychiatric disorders: a systematic review. Pathol Biol 2015;63(1):35–42. https://doi.org/10.1016/j. patbio.2014.10.003. [16] Hyland NP, Quigley EMM, Brint E. Microbiota-host interactions in irritable bowel syndrome: epithelial barrier, immune regulation and brain-gut interactions. World J Gastroenterol 2014;20(27):8859–66. [17] Dinan TG, Cryan JF. Melancholic microbes: a link between gut microbiota and depression? Neurogastroenterol Motil 2013;25(9):713–9. [18] Wang L, Alammar N, Singh R, Nanavati J, Song Y, Chaudhary R, et al. Gut microbial dysbiosis in the irritable bowel syndrome: a systematic review and meta-analysis of case-control studies. J Acad Nutr Diet 2019; [in press]. [19] Lo Presti A, Zorzi F, Del Chierico F, Altomare A, Cocca S, Avola A, et al. Fecal and mucosal microbiota profiling in irritable bowel syndrome and inflammatory bowel disease. Front Microbiol 2019;10:1655. [20] Zhong W, Lu X, Shi H, Zhao G, Song Y, Wang Y, et al. Distinct microbial populations exist in the mucosa-associated microbiota of diarrhea predominant irritable bowel syndrome and ulcerative colitis. J Clin Gastroenterol 2019; 53(9):660–72. [21] Zhu S, Liu S, Li H, Zhang Z, Zhang Q, Chen L, et al. Identification of gut microbiota and metabolites signature in patients with irritable bowel syndrome. Front Cell Infect Microbiol 2019;9:346. [22] Liu S, Si C, Yu Y, Zhao G, Chen L, Zhao Y, et al. Multi-omics analysis of gut microbiota and metabolites in rats with irritable bowel syndrome. Front Cell Infect Microbiol 2019;9:178. [23] Ghoshal UC, Nehra A, Mathur A, Rai S. A meta-analysis on small intestinal bacterial overgrowth in patients with different subtypes of irritable bowel syndrome. J Gastroenterol Hepatol 2019; [in press].

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[24] Chen B, Kim JJ-W, Zhang Y, Du L, Dai N. Prevalence and predictors of small intestinal bacterial overgrowth in irritable bowel syndrome: a systematic review and meta-analysis. J Gastroenterol 2018;53(7):807–18. [25] Wu K-Q, Sun W-J, Li N, Chen Y-Q, Wei Y-L, Chen D-F. Small intestinal bacterial overgrowth is associated with Diarrhea-predominant irritable bowel syndrome by increasing mainly Prevotella abundance. Scand J Gastroenterol 2019;54(12):1419–25. [26] Yang M, Zhang L, Hong G, Li Y, Li G, Qian W, et al. Duodenal and rectal mucosal microbiota related to small intestinal bacterial overgrowth in diarrhea-predominant irritable bowel syndrome. J Gastroenterol Hepatol 2019; [in press]. [27] Paineau D, Payen F, Panserieu S, Coulombier G, Sobaszek A, Lartigau I, et al. The effects of regular consumption of short-chain fructo-oligosaccharides on digestive comfort of subjects with minor functional bowel disorders. Br J Nutr 2008;99(2):311–8. [28] Silk DBA, Davis A, Vulevic J, Tzortzis G, Gibson GR. Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome. Aliment Pharmacol Ther 2009;29(5):508–18. [29] Lee BJ, Bak Y-T. Irritable bowel syndrome, gut microbiota and probiotics. J Neurogastroenterol Motil 2011;17(3):252–66. [30] Bonavina L, Arini A, Ficano L, Iannuzziello D, Pasquale L, Aragona SE, et al. Abincol® (Lactobacillus plantarum LP01, Lactobacillus lactis subspecies cremoris LLC02, Lactobacillus delbrueckii LDD01), an oral nutraceutical, pragmatic use in patients with chronic intestinal disorders. Acta Biomed 2019;90(7–S):8–12. [31] Kamiya T, Wang L, Forsythe P, Goettsche G, Mao Y, Wang Y, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut 2006;55(2):191–6. [32] O’Mahony L, Mccarthy J, Kelly P, Hurley G, Luo F, Chen K, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005;128(3):541–51. [33] Moser AM, Spindelboeck W, Halwachs B, Strohmaier H, Kump P, Gorkiewicz G, et al. Effects of an oral synbiotic on the gastrointestinal immune system and microbiota in patients with diarrhea-predominant irritable bowel syndrome. Eur J Nutr 2019;58(7):2767–78. [34] Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 2017;66(6):1727–38. [35] Allegretti JR, Kassam Z, Osman M, Budree S, Fischer M, Kelly CR. The 5D framework: a clinical primer for fecal microbiota transplantation to treat Clostridium difficile infection. Gastrointest Endosc 2018;87:18–29. [36] Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, et al. Fecal microbiota transplant for treatment of clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014;109(7):1065–71. [37] Ianiro G, Eusebi LH, Black CJ, Gasbarrini A, Cammarota G, Ford AC. Systematic review with meta-analysis: efficacy of faecal microbiota transplantation for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2019;50:240–8. [38] Aroniadis OC, Brandt LJ, Oneto C, Feuerstadt P, Sherman A, Wolkoff AW, et al. Faecal microbiota transplantation for diarrhoea-predominant irritable bowel syndrome: a double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol Hepatol 2019;4(9):675–85. [39] Myneedu K, Deoker A, Schmulson MJ, Bashashati M. Fecal microbiota transplantation in irritable bowel syndrome: a systematic review and metaanalysis. United European Gastroenterol J 2019;7:1033–41.

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[40] Huang HL, Chen HT, Luo QL, Xu HM, He J, Li YQ, et al. Relief of irritable bowel syndrome by fecal microbiota transplantation is associated with changes in diversity and composition of the gut microbiota. J Dig Dis 2019;20(8):401–8. [41] Holvoet T, Joossens M, Wang J, Boelens J, Verhasselt B, Laukens D, et al. Assessment of faecal microbial transfer in irritable bowel syndrome with severe bloating. Gut 2017;66(5):980–2. [42] El-Salhy M, Hausken T, Hatlebakk JG. Increasing the dose and/or repeating faecal microbiota transplantation (fmt) increases the response in patients with irritable bowel syndrome (IBS). Nutrients 2019;11(6):1415.

Gender-related differences and significance of gonadal hormones in irritable bowel syndrome

6

Damian Jacenik Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland

Abstract Clinical and experimental observations indicate that there is a sexual dimorphism in the incidence and prevalence as well as symptomology of irritable bowel syndrome (IBS), which strongly suggests that gonadal hormones may participate in the pathophysiology of the disease. Both estrogens and androgens affect several phenomena in the colon such as colonic motility and visceral pain which are the main hallmarks of IBS. Additionally, it has been proven that estrogen signaling pathways involving cognate receptors participate in the regulation of several events related with functional gastrointestinal disorders. Accumulating evidences highlighted that gonadal hormones may also be crucial in the therapy of IBS.

Keywords Irritable bowel syndrome, Constipation, Diarrhea, Colonic motility, Visceral pain, Gender, Estrogen, Androgen, Estrogen receptor, Androgen receptor

List of abbreviations 5-HT 5-HT3R AR CCA ER GABA GABAA GPER HRT

5-hydroxytryptamine 5-hydroxytryptamine 3 receptor androgen receptor colonic contractile activity estrogen receptor gamma-aminobutyric acid gamma-aminobutyric acid receptor G protein-coupled estrogen receptor hormone replacement therapy

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00006-X # 2020 Elsevier Inc. All rights reserved.

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IBS IBS-C or IBS subtype C IBS-D or IBS subtype D OC OR OT OVX SNP TRH

irritable bowel syndrome constipation predominant irritable bowel syndrome diarrhea predominant irritable bowel syndrome oral contraceptives odds ratio oxytocin ovariectomized single-nucleotide polymorphisms thyrotropin-releasing hormone

Gender-related differences in irritable bowel syndrome Most of clinical and epidemiological studies indicate that there is a difference in IBS incidence and prevalence taking into consideration gender of IBS patients [1]. IBS has been reported to be predominantly diagnosed in women than men by a ratio 2–2.5:1 or by a ratio 3–4:1 [2–4]. Consequently, it was estimated that IBS incidence rate is 196 per 100,000 person/year in the United States population and is higher for women (238 per 100,000 person/year) than men (141 per 100,000 person/year) [5]. According to Locke et al., the difference between gender, in the case of IBS incidence, is not only observed in certain lifetime point but in each age group, i.e. it was documented in the age of 20–34 and 35–54 as well as 55–94 [5]. One of the biggest meta-analyses performed by Lovell and Ford which analyzed 56 studies containing over 180,000 patients revealed that pooled prevalence of IBS is higher in women than in men with pooled odds ratio (OR) 1.67 (95% confidence interval ¼ 1.53–1.82) [6]. Similar imbalance was highlighted in the study conducted by Perveen et al. where authors were able to show 1.36 times higher prevalence of IBS in the case of women in relation to men but this difference was not statistically significant [7]. It also has to be noted that the higher prevalence of IBS in women than in men is observed independently from criteria, i.e. Rome or Manning, used to define IBS presence [6]. On the other hand, there is some conflicting evidence demonstrating men “domination” in the case of IBS prevalence. Nagaonkas et al. were able to show higher prevalence of IBS in men than women [8]. However, their demographic analysis was performed using questionnaire obtained only from over 500 patients. Gender seems to be related not only to the incidence and prevalence of IBS but also with IBS subtypes presence. In-depth analysis documented that subtype C is significantly more common and subtype D significantly less common in women compared to men [6]. In line, Herman et al., in a questionnaire-based study,

Chapter 6 Gender-related differences in IBS

demonstrated that subtype C is more common in women with IBS than in men with IBS (OR ¼ 2.03; 95 confidence interval ¼ 1.24–3.30) as well as subtype D is more often diagnosed in men with IBS than women with IBS (OR ¼ 2.39; 95% confidence interval ¼ 1.53–3.75) [9]. Interestingly, these observations were confirmed by another analysis using severity score of constipation and diarrhea, which proved that women were more likely to have constipation than men [9]. It was estimated that post-menopausal women, especially women between 40 and 49 years report several bowel dysfunction symptoms such as gaseousness, bloating, heartburn and acid regurgitation more often than women before menopause further suggesting the link between gonadal hormones and IBS [10]. In fact, some results proved that bloating symptoms are more common in women with IBS and patients with IBS subtype C than in men with IBS or patients with IBS subtype D [11]. Significance of genetic variations in IBS, especially in the context of sexual dimorphism observed in patients with IBS, is poorly studied. However, crucial evidences were provided by Bonfiglio et al. who investigated DNA variants associated with IBS risk in a genome-wide association study with a large cohort including almost 500,000 participants [12]. Bonfiglio et al. found that one of single-nucleotide polymorphisms (SNP), i.e. rs10512344 on chromosome 9q31.2 is associated with IBS presence only in the case of women [12]. Additionally, it was estimated that the above mentioned SNP is related to subtype C of IBS in women and the occurrence of “harder” stool again only in women but not in men with IBS. Finally it was estimated that eight genes such as ELP1, FAM206A, ORF13C8, RAD23B, TAL2, TMEM245, TMEM38B and ZNF462 within risk locus on chromosome 9 are present.

Gonadal hormones in irritable bowel syndrome The differences in gastrointestinal symptomology during menstrual cycle is observed. It is documented that women in the luteal phase have had a worse score for nausea and early satiety when compared to women in the follicular phase [13]. Another piece of evidence suggests that exogenous gonadal hormones supplementation such as oral contraceptives (OC) or hormone replacement therapy (HRT) are associated with IBS incidence, prevalence and symptomology. In a retrospective study, Bird et al. using database containing almost 940,000 women documented some differences between the type of OC used and the risk of IBS [14]. Increased risk for development of

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IBS described as a 1.63 (95% confidence interval ¼ 1.46–1.82) in the case of women taking OC containing drospirenone compared to OC containing levonorgestrel users as a reference was documented [14]. Of note, drospirenone is a synthetic progestin which exhibits anti-androgen activity and a positive association between OC and IBS diagnosis was observed only in the case of OC containing this molecule. It also needs to be noted that other investigated types of OC, i.e. OC containing ethynodiol diacetate, norethindrone acetate, norethindrone, norgestimate or norgestrel seem not to be associated to the risk of IBS in women. In another study, Verrengia et al. documented that women using OC report little day-to-day variation of gastrointestinal symptoms in contrast to women who did not use OC in which much greater fluctuation of gastrointestinal symptoms is observed [13]. Nevertheless, there is still not enough evidence to conclude the potential impact of OC supplementation to the development of IBS in women. Concurrently, it was indicated that HRT increased the risk of IBS in relation to women who never used HRT. Ruigo´mez et al. evaluated the incidence of IBS at 1.7 (95% confidence interval ¼ 1.5–2.0) per 1000 person/years for women who never used HRT and 3.8 (95% confidence interval ¼ 3.4–4.2) per 1000 person/years for women using HRT [15]. Further analysis demonstrated that the relative risk of IBS diagnosis in women who ever used HRT is decreased with age [15]. For instance, woman between the age of 50–59 who ever used HRT had a relative risk of 2.3 (95% confidence interval ¼ 1.9–2.7) while women aged 60–69 years who ever used HRT were manifested by relative risk of 1.9 (95% confidence interval ¼ 1.4–2.7) of having a diagnosis of IBS in relation to age-matched women who never used HRT. Apart from estrogens, also testosterone seems to be associated with some clinical factors in IBS. Kim et al. found that young men at the age 19–25 years with IBS had a slightly higher testosterone level compared to gender- and age-matched control group [16]. Comparison of IBS subtypes revealed that there was no significant difference in the testosterone level between subtype C and subtype D in men with IBS. On the other hand, Houghton et al. investigated male gonadal hormones in IBS and observed that both testosterone and testosterone not associated with sex hormonebinding globulin described as “free” testosterone are not disturbed in serum of IBS patients compared to control group [17]. However, an inverse relationship between testosterone level and sensory threshold for urgency and discomfort as well as between “free” testosterone level and sensory threshold for stool, urgency and discomfort in IBS patients was found [17].

Chapter 6 Gender-related differences in IBS

An interesting yet somewhat anecdotal observation was noted in the study performed by Grape et al. who revealed testosterone disturbances in IBS patients singing in a choir [18]. Up-regulation of blood testosterone was showed after 6 months of this activity in relation to the same IBS patients before the start of singing and the difference in testosterone level in blood was observed only in IBS patients singing in the choir but not in the IBS patients group participating in discussion meetings. Without a doubt, it has been shown that some activities may have an impact on gonadal hormone levels which can affect many processes in IBS, but the particular mechanism and direct relation between singing, testosterone and IBS are unknown and should be analyzed in the future.

Estrogen and androgen receptors in irritable bowel syndrome Estrogens and androgens exert their function by cognate receptors which trigger estrogen- and androgen-dependent signaling pathways [19, 20]. Nuclear estrogen receptors (ERs), i.e. ERα and ERβ as well as androgen receptor (AR) are involved in the genomic action of estrogens and androgens, respectively. It means that nuclear ER and AR activated by ligand undergo conformational changes, heat shock protein disconnection and dimerization before being translocated into the cell nucleus. Within nucleus, they interact with specific response elements directly or indirectly by transcription factors leading to the regulation of target genes expression. It is worth to note that there is also evidence that nuclear ER and AR are able to participate in non-genomic action of estrogens and androgens [20]. In the estrogen signaling, beyond nuclear ER, the membrane-bound estrogen receptor, i.e. G proteincoupled estrogen receptor (GPER, previously known as GPR30) is responsible for non-genomic action of estrogens. The GPER initiates several “rapid,” non-genomic actions of estrogens affecting a number of secondary messengers in turn leading to gene expression modulation [21–23]. Characteristics of estrogen and androgen receptor ligands are summarized in Table 1. Nowadays, there is some evidence documented that estrogens and estrogen receptors, i.e. ERα and ERβ as well as GPER expression are altered in the colon obtained from IBS patients which suggest that estrogen signaling may be a crucial network in the IBS pathophysiology. Moreover, despite the lack of differences in the level of 17β-estradiol, the most active form of estrogens, in IBS patients compared to control group, it was estimated

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Table 1 Estrogen and androgen receptor ligands. Signaling type

Ligand

Receptor

Type

Estrogenic

17b-estradiol

GPER, ERa, ERb GPER GPER GPER, ERa, ERb AR

Natural agonist for all

G-1 G15 ICI 182.780 (fulvestrant) Androgenic

Testosterone

Synthetic agonist Synthetic antagonist Synthetic agonist for GPER and down-regulator for nuclear ER Natural agonist

AR, androgen receptor; ERa, estrogen receptor a; ERb, estrogen receptor b; GPER, G protein-coupled estrogen receptor.

that there is a difference in the level of 17β-estradiol in the serum between both IBS subtypes [24]. In the serum obtained from men and women over the age of 50 with IBS subtype D, a higher level of 17β-estradiol in relation to gender- and age-matched IBS subtype C patients was observed. Further analysis demonstrated that both ERα and GPER are up-regulated at the mRNA and protein levels in IBS subtype C and D without division into gender and age. When both gender and age of women were included, overexpression of ERα and GPER at the mRNA level in women below the age of 50 and men with IBS subtype D were documented, respectively. It should also be noted that ERβ was tended to be down-regulated in IBS patients with subtype C in relation to control group and up-regulated in IBS patients with subtypes D when compared to IBS patients with subtypes C regardless of gender and age of women, nevertheless statistical significance was observed only in the case of women [24]. Additionally, Qin et al. observed different distribution of estrogen receptors, i.e. ERα and ERβ as well as GPER in mucosa of the human colon [25]. Furthermore, it was proved that there is a correlation between ERα and ERβ, GPER and ERα, as well as GPER and ERβ which is stronger in the colon of IBS patients than in the normal epithelium [24]. Concurrently it was documented that there is a link between estrogen signaling and IBS but further studies are needed to explain the impact of certain estrogen receptors in the pathogenesis of IBS. For example, clinical evidence presented by Qin et al. revealed an increased number of GPER+ cells in the colon obtained from IBS-D patients in relation to IBS-C patients as well as control group [25]. Further analysis have

Chapter 6 Gender-related differences in IBS

shown that the number of GPER+ cells in the colon is positively correlated with severity of abdominal pain but not with symptom duration in the IBS-D patients. Mast cells participate in the regulation of visceral sensitivity, gastrointestinal motility, epithelial secretion and immune response modulation in the colon [26]. It is worth to note that some reports demonstrated a higher number of mast cells in the colon of IBS patients [27–30]. For instance, Guilarte et al. using immunohistochemistry and immunoassays observed up-regulation of mast cells number as well as higher concentration of tryptase in the jejunum of IBS-D patients in relation to control group [29]. In another study, Barbara et al. found a positive correlation between severity and frequency of abdominal pain and the number of mast cells in the colon of IBS patients [30]. Immunohistochemistry analysis conducted by Qin et al. documented that GPER is present in the cytoplasm of tryptase+ mast cells suggesting that non-genomic estrogen signaling induced by GPER in these cells may be crucial in the pathophysiology of IBS-D [25]. Taken into consideration both GPER expression and function of mast cells in the colon, membrane-bound estrogen receptor may be an important link in several phenomena in IBS but further research is needed.

Gonadal hormones in the colonic motility modulation In vitro and in vivo experiments conducted by several independent groups demonstrated that estrogens as well as androgens are capable of modulating colonic motility suggesting that gonadal hormones seem to be essential in the development of IBS [31]. Baumgartner et al. using rat distal colon and ex vivo analysis observed significantly higher spontaneous colonic contractile activity (CCA) in females than in males [32]. To further explore the effect of gonadal hormones, they used acetylcholine (as an enhancer of CCA), norepinephrine (as an inhibitor of CCA) and 17β-estradiol as well as progesterone. 17β-estradiol led to a significant decrease of spontaneous CCA in distal colon taken from both female and male rats while progesterone affected only distal colon obtained from female rats in relation to control groups [32]. In another behavioral and electrophysiological studies, Ji et al. demonstrated that 17β-estradiol affects visceral sensitivity [33]. It was proved that ovariectomized (OVX) rats are characterized by lower sensitivity and exogenous supplementation of these rats with 17β-estradiol caused sensitivity recovery to the level observed in cycling rats. Additionally, Ji et al. noted that

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increase in the response of dorsal horn neurons implicates higher processing in the spinal cord sensory system [33]. Colonic motility was also examined by Bond et al. who used thyrotropin-releasing hormone (TRH)-induced and restraint stress OVX rat models to investigate the effect of estrogens treatment on colonic motility [34]. It was documented that exogenous estrogen treatment is related with a significant down-regulation of motility index in both OVX rat models in relation to untreated rats [34]. Mechanism by which gonadal hormones may regulate colonic motility seems to be associated with 5-hydroxytryptamine (5-HT) 3 receptor (5-HT3R). Li et al. using rats with restraint stress-induced bowel dysfunction demonstrated that the decline of gonadal hormones is associated with an increased number of fecal pellets and decreased time of vitreous pellets output [35]. Moreover, in the colon of OVX rats exposed to stress, Li et al. observed overexpression of 5-HT3R at the mRNA level compared to the colon taken from sham-operated rats [35]. Further experiments proved that OVX rats with restraint stress-induced bowel dysfunction treated with a combination of 17β-estradiol and progesterone restored fecal pallet parameters to value observed in control stressed rats. Additionally, down-regulation of relative expression of 5-HT3R in the colon taken from 17β-estradiol and progesterone-treated OVX rats with restraint stress-induced bowel dysfunction in relation to in the colon obtained from OVX rats exposed to stress was demonstrated [35]. The significance of 5-HT signaling was further confirmed by Houghton et al. who observed disturbances of platelet-depleted plasma 5-HT in patients with IBS subtype D [36]. It was estimated that platelet-depleted plasma 5-HT concentration is higher in women with high progesterone/estrogen levels in contrast to women with low progesterone/estrogen levels suggesting a link between 5-HT and estrogens in IBS subtype D patients. On the other hand, estrogens seem to participate in the oxytocin (OT)-mediated colonic motility regulation [37]. It was demonstrated that stomach irritation with cold physiological saline decreased time of colonic transit and is related to an increased plasma concentration of OT and OT receptor level in the colonic myenteric plexus of stressed rats in relation to control animals. The link between OT signaling and colonic motility was confirmed by using OT receptor inhibitors which were able to inhibit the effect of OT on colonic motility. Yang et al. using OVX rats and OT treatments were able to prove that the loss of estrogens is associated with OT-induced inhibition of colonic contractility in OVX stressed rats compared to rats irritated with cold physiological saline [37]. Finally, it was noted that 17β-estradiol treatment

Chapter 6 Gender-related differences in IBS

increased plasma OT concentration and led to reduction of colonic muscle strip response to OT suggesting that there is a functional cross-talk between OT and estrogen signaling in colonic motility regulation. Unusually, there is only weak evidence concerning the role of estrogen receptors in the modulation of colonic motility.  ska et al. using in vitro organ bath studies and human Zielin as well as mouse colon revealed that the GPER specific agonist, G-1 as well as 17β-estradiol inhibit electric field stimulationinduced smooth muscle contractility, which was reversed by the GPER specific antagonist, i.e. G15 but not ERα or ERβ inhibitors [38]. It was also confirmed, in further experiments where excitatory junction potentials were evaluated in the murine colon that G-1 treatment is associated to the reduction of excitatory junction potential [38]. The results of the ex vivo studies were confirmed in vivo using colonic bead expulsion test in female and male mice. In animals treated with G-1 and 17β-estradiol a significantly longer time to bead expulsion was observed. Interestingly, the effect of G-1 on colonic motility was inhibited by all estrogen receptor antagonists. In contrast, GPER and ERα antagonists but not ERβ antagonist were able to reverse the action of 17β-estradiol in mice. Taken together,  ska et al. suggests that the action evidence provided by Zielin of estrogens seems to be crucial in the regulation of colonic motility and estrogen receptors may be a useful targets in the pathogenesis of functional gastrointestinal disorders including IBS [38]. A recent study conducted by D’Errico et al. concerning the role of ERβ in the enteric nervous system of the colon revealed some crucial aspects of estrogen signaling induced by ERβ which seems to be crucial in the gastrointestinal disorders, including IBS [39]. It was demonstrated that the activation of ERβ affects proliferation and differentiation of enteric neuronal stem/progenitor cells, enhancing their capacity to generate enteric glial cells and neurons. This in vitro study was also confirmed using murine models of enteric neuronal damage and loss. Namely, D’Errico et al. showed that ERβ activation seems to be associated to neurogenesis promotion after enteric nervous system damage in the colon [39]. In above mentioned study, Baumgartner et al. proved that beyond 17β-estradiol and progesterone also testosterone treatment is related to lower spontaneous CCA in distal colon of male rats compared to control tissues [32]. Further analysis revealed that testosterone pre-treatment of distal colon taken from male rats is manifested by enhanced acetylcholine-induced CCA.

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Gonadal hormones in the visceral pain regulation One of the first pieces of evidence suggesting a link between gonadal hormones and visceral pain comes from clinical observation of pain modulation during different phases of the menstrual cycle. In a retrospective study, Kene et al. revealed that women with IBS during premenstrual phase and menses are more prone to report diarrhea and nausea than control group during the same menstrual phase [40]. It was also found that women with IBS are more likely to report a cyclic pattern in abdominal pain than the control group [40]. Additionally, Houghton et al. were able to document some differences related with abdominal pain during menstrual cycle and they noted that menses are associated with a worsening of abdominal pain and bloating in relation to other menstrual phases [41]. Women with IBS at the menses were characterized by more frequent bowel habits compared to women with IBS during other menstrual phases [41]. Modulatory effect of menstrual cycle on visceral sensitivity was also documented in rats: Moussa et al. noted that rats in the follicular phase are more prone to occurrence of abdominal contractions that rats in the luteal phase [42]. Apart from estrogens, also androgens seem to play an important role in the regulation of visceral pain. A recent study conducted by Nozu et al. highlighted the ability of dehydroepiandrosterone sulfate, a precursor of estrogens and androgens, to modulate visceral allodynia and colonic permeability in rat models induced by lipopolysaccharide and repeated water avoidance stress [43]. Moreover, it was evidenced that gamma-aminobutyric acid (GABA) signaling involving GABAA receptor, dopamine signaling affecting dopamine D2 receptor, nitric oxide and opioid signaling as well as corticotropin-releasing factor signaling pathways seem to be involved in this phenomenon. It was also noted that treatment with 17β-estradiol enhanced while testosterone abolished visceral sensitivity following stress induction in the case of male and female rats, respectively [44]. Ji et al. suggest that gonadal hormones may be responsible for regulation of visceral hypersensitivity affecting spinal excitatory and inhibitory glutamatergic receptor expression [44]. GPER seems to be one of crucial mediators of visceral pain.  ska et al. using in vivo approach revealed that 17β-estradiol Zielin and G-1 are responsible for reduction of pain-induced behaviors in female mice [38]. Additionally, a potent antinociceptive effect of G-1 administration was also observed in male mice. On the other hand, Cao et al. observed that modulation of ERβ activity is

Chapter 6 Gender-related differences in IBS

associated to visceromotor response [45]. In fact, it was estimated that ERβ agonists attenuate visceromotor response while pretreatment with ICI 182.780 (known also as fulvestrant), which acts as a nuclear ERs down-regulator and GPER agonist, did not affect visceromotor response in OVX rats corresponding to untreated rats [45]. It has to be highlighted that also ERα seems to be an important regulator of visceral pain and mitogen-activated protein kinase signaling pathway seems to be crucial in this regulation [44]. Interesting results have been published by Jalili et al. who performed a randomized clinical trial (NCT02026518) concerning effects of soy isoflavones and vitamin D application on IBS symptomology [46]. IBS patients after 6 weeks of treatment with isoflavones or vitamin D reported lower pain duration and severity score in relation to the same group of IBS patients before treatment. Improvement of bowel habits and life disruption were also noted. It was suggested that the potential mechanisms involved in the modulation of IBS symptomology induced by isoflavones or vitamin D may be mediated by estrogen receptors. In fact, Moussa et al. were able to prove that soy germ treatment promotes the same effects as a estrogens what supports the hypothesis about the role of estrogen receptors in the modulation of visceral pain by gonadal hormones [42]. Namely, it was observed that soy germ or 17β-estradiol treatments decreased the stress-induced hypersensitivity to colorectal distension compared to untreated rats. It should also be noted that the combination of soy germ or 17β-estradiol with ICI 182.780 reversed the inhibitory action of soy germ and 17β-estradiol. Reports by Moussa et al. and  ska et al. present some conflicting results which suggest that Zielin in the study about estrogen signaling all estrogen receptors should be taken into consideration [38, 42].

Conclusions Gender-related disparity in the case of incidence, prevalence and symptomology of IBS as well as IBS subtype predominance are noted in several clinical studies. These observations are supported by studies showing disturbances of gonadal hormone levels and retrospective studies where impact of hormonal supplementation is documented. Differences between both genders are also observed at the molecular level and include for instance gonadal hormone receptors as well as genetic variations. On the other hand, accumulating evidence highlighted that estrogens and androgens are able to modulate gastrointestinal symptoms, colonic motility

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Fig. 1 Scheme representing clinical observations (red circle) and experimental evidence (green circle) supporting hypothesis about the impact of gonadal hormones in irritable bowel syndrome.

and visceral pain which raised a presumption that gonadal hormone manipulation may be an effective approach in the treatment of functional gastrointestinal disorders. Taken together, gender and gonadal hormones appear to be crucial aspects in IBS pathophysiology (summarized in Fig. 1) and should be taken into consideration not only in the design of novel therapeutic strategies.

Acknowledgments This work was supported by grants (2017/24/T/NZ5/00045 and 2015/17/N/ NZ5/00336 to DJ) from the National Science Centre, Poland.

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7

Agata Binienda and Maciej Salaga Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) diseases with unknown etiology. Genetic, environmental and physiological factors can contribute to IBS pathophysiology. Genetic predisposition to IBS was suggested by several familial and twin studies. Mutations within genes encoding Voltage-Gated Sodium Channel NaV1.5 and NaV1.9 have also been found in IBS sufferers. In addition, many studies proved association between single nucleotide polymorphisms (SNPs) and IBS etiology. SNPs located on serotonin transporter (SERT), serotonin receptors (HTR3A, HTR3E, HTR2A, HTR4), tumor necrosis factor superfamily member 15 (TNFSF15) and interleukin 10 (IL-10) genes are the best characterized genetic variations in the context of IBS. In this chapter, we focused on genetic aspect of IBS as well as we briefly described the most common SNPs, which may have an association with this disease.

Keywords Irritable bowel syndrome, Genetic predisposition, Single nucleotide polymorphism, Serotonin reuptake gene, Voltage-gated sodium channel

List of abbreviations 5-HT 5-HTTLPR A C COMT FAAD G

5-hydroxytryptomine serotonin transporter linked polymorphic region adenosine cytosine catechol-O-methyltransferase fatty acid amide hydrolase guanine

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00007-1 # 2020 Elsevier Inc. All rights reserved.

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GI GNβ3 HTR2A HTR3A HTR3E HTR4 IBD IBS IBS-C IBS-D IBS-M IL-10 PI-IBS RAP SCN5A SERT SERT-P SLC6A4 SNP T TNFSF15 UTR

gastrointestinal guanine nucleotide-binding protein subunit β-3 serotonin receptor type 2A serotonin receptor type 3A serotonin receptor type 3E serotonin receptor type 4 inflammatory bowel disease irritable bowel syndrome irritable bowel syndrome with predominant constipation irritable bowel syndrome with predominant diarrhea irritable bowel syndrome with both constipation and diarrhea interleukin 10 post-infectious irritable bowel syndrome recurrent abdominal pain sodium voltage-gated channel alpha subunit 5 serotonin reuptake serotonin reuptake promotor solute carrier family 6 member 4 single nucleotide polymorphism thymine tumor necrosis factor superfamily member 15 untranslated region

Introduction There are several factors contributing to the pathomechanism of irritable bowel syndrome (IBS). Amongst them is genetic predisposition suggested as a potential cause of this disease. Although until now a clear hereditary link has not been found [1], several studies suggest familial aggregation of IBS. In the late 1980s, Whorwell et al. [2] showed that 33% of patients suffering from this disorder had a family history of IBS compared to 2% in the control group (P < 0.0001) [2]. Moreover, children with pediatric recurrent abdominal pain (RAP) are almost three times more likely to present IBS-like symptoms (40%) compared to patients without RAP history (16%) (P < 0.05) [3]. A large family casecontrol study consisting of 477 cases with IBS, 287 controls, 1492 case-relatives, and 936 control-relatives demonstrated a strong connection between family medical history and bowel symptoms. The results showed that 50% of cases with IBS will have at least one other family member with IBS. However, the overall proportion of first-degree relatives with IBS was 25%, whereas case-relatives were two to three times more likely to have IBS than control-relatives. In addition, no gender effect on familial aggregation was observed [4]. The difference between concordance rates is used to evaluate the genetic liability of disease. There are evidences that

Chapter 7 Genetic aspect (with SNPs) of irritable bowel syndrome

concordance rates of monozygotic twins were higher than dizygotic twins suggesting genetic etiology of IBS. Based on five twin studies with IBS or other functional bowel disorder, the genetic liability is estimated to range from 0% to 20% and heritability ranging between 0% and 57% [5–9]. Interestingly, the proportion of dizygotic twins with IBS who have mother with IBS was higher than co-twins with IBS. Mother with IBS and father with IBS are thus independent predictors of this disorder [6, 10].

Mutations within genes related to voltage-gated sodium channel Beyder et al. [11] demonstrated that patients suffering from IBS have a genetic defect in SCN5A gene which codes for the VoltageGated Sodium Channel NaV1.5. It was demonstrated that even 2% of IBS patients have SCN5A mutation in Caucasian population [11]. This missense mutation causes loss-of-function of the Voltage-Gated Sodium Channel NaV1.5 in the gastrointestinal (GI) smooth and pacemaker cells and in consequence disruption of gut function. Moreover, SCN5A mutation occurs more often in patients with constipation-predominant IBS (IBS-C) (31%) than in patients with diarrhea-predominant IBS (IBS-D) (10%) [11]. Subsequently, frequency of SCN5A channelopathies which lead to decreased NaV1.5 activity were investigated by Strege et al. [12]. A racially and ethnically diverse cohort of IBS patients (n ¼ 252) and control group without IBS (n ¼ 377) were recruited for this study. Results showed that five IBS patients (2%) had six rare SCN5A mutations and each of them caused voltagedependent gating abnormalities and altered voltage dependence and four of those mutations changed NaV1.5 mechanosensitivity, compared to control group [12]. These results provide a potential, genetic mechanism for IBS. Moreover, recent report points out the role of the NaV1.9, encoded by SCN11A gene in the development of visceral inflammatory pain [13]. The NaV1.9 channels take part in modulation of the abdominal pain and are considered as regulators of primary visceral nociception and as contributors to sodium current conductance in neurons of the enteric nervous system. Mutations within gene encoding NaV1.9, including Ala808Gly and Arg225Cys contribute to painful phenotype and may occur in GI disorders, like IBS and inflammatory bowel disease (IBD) [13, 14].

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Single nucleotide polymorphisms associated with IBS pathophysiology Single nucleotide polymorphism (SNP) is a variation of a single base pair (A—adenosine, T—thymine, G—guanine, C—cytosine) that occurs in more than 1% of a population. Very often SNPs may give new information about disease’s pathophysiology. There are many SNPs that have been linked to IBS. Meta-analysis by Popa et al. [15] demonstrates a connection between SNPs in serotonin transporter (SERT) gene, guanine nucleotide-binding protein subunit β-3 gene—Gnβ3, serotonin type 3 receptor genes—HTR3A, HTR3E, tumor necrosis factor superfamily member 15 gene—TNFSF15 and IBS [15]. In another metaanalysis an association between SNPs in genes encoding antiinflammatory cytokines, like interleukin—IL-10 and IL-6 and IBS was found [16]. These point mutations could be linked to increased or decreased risk of IBS morbidity as well as might serve as diagnostic tool.

Serotonin genes Serotonin transporter gene Many studies confirm an important role of serotonin (5-hydroxytryptomine, 5-HT) in IBS pathophysiology. 5-HT is a neurotransmitter regulating bowel motility, fluid balance as well as glucose absorption and sensation [17]. Up to 95% of 5-HT is produced by enterochromaffin cells located in the GI tract, particularly in the intestinal mucosa, from which it is secreted in response to a number of various stimuli [18]. Bioavailability of 5-HT is regulated by the ubiquitous SERT, which removes it from the interstitial space following the release by EC cells hence modulating the amplitude and duration of 5-HT signaling. SERT is encoded by the solute carrier family 6 member 4 (SLC6A4, also known as SERT) gene. Decreased expression of SERT may be associated with increase in mucosal 5-HT availability and in consequence with the IBS development [19, 20]. A meta-analysis consisting of 27 studies and including 7039 participants demonstrated that SERT ins/del polymorphism is associated with Asian and Caucasian populations. Moreover, this mutation significantly correlated with IBS-C risk compared to other types of IBS [21]. Several well-known polymorphisms are located in the promotor region of SERT gene, called serotonin transporter linked polymorphic region (5-HTTLPR) or so-called SERT-promotor (SERT-P) region. Homozygous wild or long alleles (L/L) in the 5-HTTLPR

Chapter 7 Genetic aspect (with SNPs) of irritable bowel syndrome

indicate physiological function, whereas homozygous short variants (S/S) result in lover transcript level, decreased protein expression and reduced reuptake of 5-HT. The frequency of the L/L genotype in the 5-HTTLPR was significantly greater in patients with IBS-C (25%) than in healthy control (7%) in Chinese population [22]. Additionally, the response to tegaserod, which is a common medication used in IBS-C, was significantly higher in patients with S/S and L/S genotypes than in patients with L/L genotype [22]. The study performed in Korea confirmed significance of L/L genotype in IBS-C patients as well as with patients suffering from both of diarrhea and constipation IBS (IBS-M) [23]. Furthermore, a meta-analysis performed by Zhang et al. [24] consisting of 25 studies and over 3000 cases per group demonstrates that alteration in 5-HTTLPR gene involving L/L genotype is related with IBS-C development in East Asian population, but not in Central Asian populations [24]. Moreover, Areeshi et al. [25] showed that SERT (ins/del) polymorphism, S/S or L/S is related to significantly reduced risk of IBS in Asian population, while SERT-P (del/del) genotype was observed in North American Caucasian women with IBS-D [26]. In conclusion, many evidences confirm that SERT gene and its polymorphic region, 5-HTTLPR are firmly associated with IBS.

Serotonin receptor genes 5-HT receptors type 3 (5-HTR3) are involved in stimulation of the release of several neurotransmitters such as acetylcholine, which directly affects colon transit and regulates water transport, resulting in excessive defecation. Many 5-HTR3 ligands are used in the treatment of IBS, e.g. 5-HTR3 antagonists inhibit the gut-brain signaling by decreasing the excitability of neurons and subsequently reducing visceral pain and discomfort [18, 27]. The 50 untranslated region (UTR) variant C42T of HTR3A gene and 50 UTR variant G76A of HTR3E gene are associated with IBS-D. Firstly, this relation was showed by a pilot study on a sample from United Kingdom (UK) population, next this result was confirmed by a replication study on German cohort [28]. In addition, Chinese population also demonstrates association between polymorphism in HTR3A/HTR3E genes and IBS-D. Moreover, Gu et al. [29] discovered a significant difference between IBS patients and healthy controls in the GA genotype and A allele in female [29]. 5-HT receptor type 2A (HTR2A) gene is also involved in etiology of IBS. Polymorphisms within HTR2A gene were observed in patients with anorexia nervosa, obsessive compulsive disorder and seasonal affective disorder [30, 31]. Recent reports show that

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polymorphisms of HTR2A T102C and G1438A are also associated with IBS risk [32, 33]. A high incidence of homozygote C allele and increased frequency of homozygote A allele were found in patients with IBS. Additionally, T/T genotype of HTR2A T102C polymorphism may be associated with severe pain in IBS patients [32]. Markoutsaki et al. [33] replicated the results of association between G1438A polymorphism and high frequency of A allele and high risk of IBS, but association between T102C was not found in this study. Finally, 5-HT receptor type 4 (HTR4) gene was also showed to contain SNPs associated with IBS. In fact, six isoforms of human HTR4 exist and they vary in the mRNA sequence in the 30 UTR region. These regions can interact with the microRNA (miRNA, miR) and are prone to post-transcriptional regulation [34]. Wohlfarth et al. [34] demonstrated that patients with IBS-D have higher frequency of allele T in T61C polymorphism within HTR4 gene. Furthermore, the authors observed that miR-16 and miR-103 are downregulated in the jejunum of IBS-D patients and it correlates with IBS symptoms. These observations suggest that HTR4 gene expression may be affected by decreased level of miR-16 and miR-103 what can be related with T61C polymorphism [34].

Cannabinoid receptor genes Cannabinoid receptors (CNR) encoded by a CNR gene are involved in intestinal function, including motility, secretion and pain sensation [35]. Currently, many CBR ligands are regarded as promising candidates in IBS therapy [36, 37]. Importance of CNR was demonstrated by a study showing that genetic knockout of CB receptor type 1 (CNR1) leads to gut inflammation [38]. CNR1 gene contains a given number of polymorphic AAT triplets; a greater number of AAT triplets may induce a Z-shape conformation in the DNA and thus influence the gene transcription [39, 40]. Park et al. [41] showed that IBS patients have different distribution of allele frequencies of AAT triplet repeats in the CNR1 gene compared to control. They divided these alleles into two groups comprising shorter alleles (10 of AAT triplet) and longer alleles (>10 of AAT triplet). Next, they distinguished three genotypes: 10/10, heterozygote, and >10/>10. Korean population exhibits a significant association between CNR1 having >10/>10 AAT triplet repeats genotype and IBS as well as with severity of abdominal pain in IBS [41]. The endocannabinoid (ECB) system contains another element that may be engaged in the genetic predisposition to IBS: fatty acid amide hydrolase (FAAH), an enzyme responsible for

Chapter 7 Genetic aspect (with SNPs) of irritable bowel syndrome

metabolism and inactivation of ECB ligands. The C385A SNP found in the FAAH gene is strongly associated with all IBS subtypes [42]. To conclude, genetic modulation of ECB system may be associated with IBS pathophysiology affecting colonic smooth muscle contraction, tone as well as colonic transit [43, 44]. However further studies are needed to fully validate this hypothesis and introduce novel medications targeting the activity of ECB system in IBS.

Guanine nucleotide-binding protein GNβ3 gene encodes guanine nucleotide-binding protein subunit beta-3 (GNβ3), which takes part in intracellular signal transduction as well as regulates functions of ion channels and protein kinases. Changes in GNβ3 gene sequence lead to disruption in sensory function of the gut and intestinal motility playing an important role in functional GI disorder (FD), including IBS [45]. The literature data show contradictory relationship between this gene and IBS pathophysiology [46–48]. Andresen et al. [46] demonstrated no link between genotype and allele frequency of GNβ3 C825T polymorphism and IBS [46]. The same conclusion was presented by Saito et al. [49]. On the other hand, Korean group of researchers showed that the CC genotype of GNβ3 C825T may be associated with IBS-D and functional dyspepsia, whereas the TT genotype is more common in IBS-C [50]. Meta-analysis based on 11 case-control studies summed up information about C825T polymorphism in GNβ3 gene. This report demonstrates no significant association between GNβ3 C825T polymorphism and IBS risk in all populations studied. However, the authors observed that the C allele of GNβ3 C825T is linked to increased risk of IBS-C, while the CC genotype increases IBS-D risk. In fact, authors of this meta-analysis emphasize that these studies had many limitations and confirmation of above data is required [48].

Catechol-O-methyltransferase gene Catechol-O-methyltransferase (COMT) is an enzyme responsible for inactivation of catecholamines, such as dopamine, noradrenaline and adrenaline. The highest COMT activity occurs in the liver, kidneys and GI tract. IBS and IBS-like symptoms are associated with dysregulation of COMT activity [51, 52]. Val156Met substitution in COMT gene was investigated as potential mutation involved in IBS pathogenesis. The results showed that Chinese patients with Val158Met mutation were more likely to develop IBS symptoms, especially IBS-D compared to control

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group [53]. Another study demonstrated that the val/val genotype of the Val158Met COMT is more common in patients suffering from IBS compared to healthy individuals. In addition, val/val genotype was related with significantly increased bowel frequency and a smaller proportion of stools with incomplete defecation. The val/val genotype causes a three to four-fold higher enzymatic activity of COMT than the met/met genotype [54].

Interleukin genes Cytokines, such as interleukin 10 (IL-10) and transforming growth factor (TGF) have proven anti-inflammatory properties. Mutations within genes encoding these cytokines may downregulate their production resulting in development of IBS-like symptoms and low-grade inflammation. The frequency of IL-10 G1082A polymorphism was investigated in UK population. It was showed that IL-10 G1082A polymorphism was significantly reduced in patients with IBS compared to control [31, 55]. However, a study performed in the Netherlands did not confirm this finding. Both patients with IBS and healthy controls had similarly distributed IL-10 genotype [56]. However, also in this study, changes in TNF-α gene sequence were observed. The TNF-α G308A polymorphism occurred more frequently in patients suffering from IBS than in control. Furthermore, IBS patients were positive for A allele compared to healthy controls [56]. Some patients with the mentioned genotype variation may produce decreased amount of the anti-inflammatory cytokines, like IL-10 resulting in potential development of mild inflammation. Tumor necrosis factor superfamily member 15 (TNFSF15) is also a commonly occurring cytokine involved in inflammation. The main role of TNFSF15 is activation of T cell and production of Th1 cells. Post-infectious IBS (PI-IBS) points out that immunemediated mechanism can be engaged in IBS etiology. Several case-control studies proved that TNFSF15 gene polymorphism is associated with IBS, especially with PI-IBS and IBS-D [57–59].

Conclusion To summarize, genetic factors contribute to IBS etiology. Family as well as twin studies demonstrate that IBS symptoms are more common in relatives of patients with IBS. One family case-control study demonstrated strong evidence on genetic effect of IBS. A family member with IBS are at two- to threefold higher risk for IBS than control patient relatives. On the other

Chapter 7 Genetic aspect (with SNPs) of irritable bowel syndrome

93

Table 1 Summary of single nucleotide polymorphisms associated with irritable bowel syndrome. Gene symbol HTR3A HTR3E HTR2A HTR2A HTR4 FAAH GNb3 IL-10 TNF-a TNFSF15

Gene name

Mutation

Rs

Phenotype

References

5-HT receptor 3A 5-HT receptor 3E 5-HT receptor 2A 5-HT receptor 2A 5-HT receptor 4 Fatty acid amide hydrolase Guanine nucleotide-binding protein subunit beta-3 Interleukin 10 Tumor necrosis factor Tumor necrosis factor superfamily member 15

C42T

rs1062613

IBS-D

[28, 29]

G76A

rs56109847

IBS-D

[28, 29]

G1438A T102C T61C C385A C825T

rs6311 rs6313 rs201253747 rs324420 rs5443

IBS-D IBS-D IBS-D IBS IBS-C

[32, 33] [32] [34] [42] [46, 48, 49]

G1082A G308A A/G

rs1800870 rs3764147 rs4263839

IBS-D IBS-D IBS-C

[56] [56] [57–59]

IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with predominant constipation; IBS-D, irritable bowel syndrome with predominant diarrhea.

hand, there are many SNPs which may contribute to IBS pathophysiology and underlying genetic predisposition for this disease. Particular attention should be paid to genetic variations in SCN5A and SERT genes. Table 1 summarizes the information on SNPs associated with IBS. To date, no genetic tests have been developed for the IBS detection. The reason may be multifactorial pathogenesis of this disorder which requires thorough examination of the patient and elimination of other diseases, such as IBD.

Acknowledgments This work was supported by the Diamentowy Grant program of the Polish Ministry of Science and Higher Education [0229/DIA/2019/48 to AB] and Polish National Agency for Academic Exchange Bekker Programme to MS.

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Chapter 7 Genetic aspect (with SNPs) of irritable bowel syndrome

[21] Zhu Y, Zheng G, Hu Z. Association between SERT insertion/deletion polymorphism and the risk of irritable bowel syndrome: a meta-analysis based on 7039 subjects. Gene 2018;679:133–7. [22] Li Y, Nie Y, Xie J, Tang W, Liang P, Sha W, et al. The association of serotonin transporter genetic polymorphisms and irritable bowel syndrome and its influence on tegaserod treatment in Chinese patients. Dig Dis Sci 2007; 52(11):2942–9. [23] Choi YJ, Hwang SW, Kim N, Park JH, Oh JC, Lee DH. Association between SLC6A4 serotonin transporter gene linked polymorphic region and ADRA2A-1291C>G and irritable bowel syndrome in Korea. J Neurogastroenterol Motil 2014;20(3):388–99. [24] Zhang ZF, Duan ZJ, Wang LX, Yang D, Zhao G, Zhang L. The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies. BMC Gastroenterol 2014;14(1):1–12. [25] Areeshi MY, Haque S, Panda AK, Mandal RK. A serotonin transporter gene (SLC6A4) polymorphism is associated with reduced risk of irritable bowel syndrome in American and Asian population: a meta-analysis. PLoS One 2013;8(9):2–11. [26] Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut 2004;53(10):1452–8. [27] Zheng Y, Yu T, Tang Y, Xiong W, Shen X, Jiang L, et al. Efficacy and safety of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2017;12(3). € nnikes H, Walstab J, Mo € ller D, Bo € nisch H, et al. [28] Kapeller J, Houghton LA, Mo First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum Mol Genet 2008;17(19):2967–77. [29] Gu QY, Zhang J, Feng YC, Dai GR, Du WP. Association of genetic polymorphisms in HTR3A and HTR3E with diarrhea predominant irritable bowel syndrome. Int J Clin Exp Med 2015;8(3):4581–5. [30] Enoch MA, Goldman D, Barnett R, Sher L, Mazzanti CM, Rosenthal NE. Association between seasonal affective disorder and the 5-HT2A promoter polymorphism, -1438G/A. Mol Psychiatry 1999;4(1):89–92. [31] Camilleri M, Katzka DA. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome. AJP Gastrointest Liver Physiol 2012;302(10): G1075–84. [32] Pata C, Erdal E, Yazc K, Camdeviren H, Ozkaya M, Ulu O. Association of the -1438 G/A and 102 T/C polymorphism of the 5-Ht2A receptor gene with irritable bowel syndrome. J Clin Gastroenterol 2004;38(7):561–6. [33] Markoutsaki T, Karantanos T, Gazouli M, Anagnou NP, Karamanolis DG. 5-HT2A receptor gene polymorphisms and irritable bowel syndrome. J Clin Gastroenterol 2011;45(6):514–7. €rtle JD, Houghton LA, Dweep H, Fortea M, [34] Wohlfarth C, Schmitteckert S, Ha et al. MiR-16 and miR-103 impact 5-HT4receptor signalling and correlate with symptom profile in irritable bowel syndrome. Sci Rep 2017;7(1):1–14. [35] Taschler U, Hasenoehrl C, Storr M, Schicho R. Cannabinoid receptors in regulating the GI tract: experimental evidence and therapeutic relevance. Handb Exp Pharmacol 2017;239(January):343–62. [36] Fichna J, Wood JAT, Papanastasiou M, Vadivel SK, Oprocha P, Sałaga M, et al. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with

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[52] Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, et al. COMT val158 genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 2003;299(5610):1240–3. [53] Wang Y, Wu Z, Qiao H, Zhang Y. A genetic association study of single nucleotide polymorphisms in GNβ3 and COMT in elderly patients with irritable bowel syndrome. Med Sci Monit 2014;20:1246–54. ˚ , Wikgren M, So € derstro € m I, Del-Favero J, Adolfsson R, [54] Karling P, Danielsson A et al. The relationship between the Val158Met catechol-O-methyltransferase (COMT) polymorphism and irritable bowel syndrome. PLoS One 2011; 6(3):1–5. [55] Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut 2003;52(1):91–3. [56] Van Der Veek PPJ, Van Den Berg M, De Kroon YE, Verspaget HW, Masclee AAM. Role of tumor necrosis factor-α and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol 2005;100(11): 2510–6. [57] Franks I. IBS: a polymorphism in TNFSF15 is associated with susceptibility to IBS. Nat Rev Gastroenterol Hepatol 2011;8(8):419. [58] Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, et al. Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα. Gut 2013; 62(7):985–94. [59] Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, et al. Association of TNFSF15 polymorphism with irritable bowel syndrome. Gut 2011;60(12):1671–7.

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Clinical diagnosis of irritable bowel syndrome

8

Marcin Włodarczyka,b and Aleksandra Sobolewska-Włodarczykb,c a

Department of General and Colorectal Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. bDepartment of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland. cDepartment of Gastroenterology, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder with a symptom-based diagnosis without inclusion of any objective parameter measurable by known diagnostic methods. Heterogeneity of patient’s symptoms and overlapping with more serious organic diseases increase uncertainty for the physician’s work and enhance the cost of the final diagnosis. In 2016 Rome IV criteria of functional bowel disorders (FBD) were updated. Currently, these criteria are the basis for IBS diagnosis in the clinical practice, especially in daily work of general practitioners and gastroenterologists. In this chapter current diagnosis criteria of IBS are discussed.

Keywords Irritable bowel syndrome, Functional bowel disorders, Diagnosis, Symptoms

List of abbreviations CRP EMA ESR FBC FBD IBS IBS-C IBS-D IBS-M IBS-U TTG

C-reactive protein endomysial antibodies erythrocyte sedimentation rate full blood count functional bowel disorders irritable bowel syndrome IBS with predominant constipation IBS with predominant diarrhea IBS with mixed bowel habits IBS unclassified tissue transglutaminase

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00008-3 # 2020 Elsevier Inc. All rights reserved.

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Introduction Irritable bowel syndrome (IBS) belongs to the group of functional bowel disorders (FBD) in which main symptoms are related to recurrent abdominal pain with associated defecation impairment or change in bowel habits. FBD are highly prevalent disorders found worldwide and have the potential to affect all members of society, regardless of age, sex, race, creed, color, or socioeconomic status. Research in the basic and clinical sciences during the past two decades has produced new information on the epidemiology, etiology, pathophysiology, diagnosis, and treatment of FBDs. These important findings created a need to revise current Rome III criteria and develop new Rome IV criteria for FBDs. FBD are a group of chronic bowel diseases that, according to the definition of the Rome IV criteria, result from abnormal brain-gut axis interactions. The new definition of FBD indicates the key importance of brain-gut axis dysregulation in their pathogenesis, taking into account the interaction of factors such as motor disorders, visceral hypersensitivity, immune function abnormalities, intestinal dysbiosis and disorders at the level of the central nervous system. FBD can be distinguished from other gastrointestinal disorders based on chronicity (over 6 months of symptoms at the time of diagnosis), current activity (symptoms occur within the last 3 months before diagnosis), frequency (symptoms occur on average at least once a week) and no clear anatomical or physiological abnormalities identified in routine diagnostic tests considered clinically relevant. IBS is a chronic, recurrent FBD associated with altered motility and gastrointestinal secretion. It is the most commonly diagnosed FBD, with the highest prevalence in Western countries. North America and Europe remain the leading regions for the occurrence of IBS, with a prevalence of up to 25% of the population, with women to men ratio 2:1.

Rome IV criteria for IBS The “Rome process” is an international effort to create scientific data to help in the diagnosis and treatment of FBD such as IBS, functional dyspepsia and others. The Rome Diagnostic Criteria are set forth by the Rome Foundation, a non-profit organization, under the professional management of Hilliard Associates based in Raleigh, North Carolina. The Rome criteria have been evolving from the first set, issued in 1989 through the Rome Classification System for FBDs (1990),

Chapter 8 Clinical diagnosis of irritable bowel syndrome

the Rome I Criteria for IBS (1992) and the FBDs (1994), the Rome II Criteria for IBS (1999) and the FBDs (1999), the Rome III Criteria (2006), to the most recent Rome IV Criteria (2016). Currently the Rome IV Diagnostic Criteria for FBDs is currently the “Gold Standard” for the diagnosis of IBS. According to Rome IV Criteria for IBS Recurrent abdominal pain on average at least 1 day per weeka in the last 3 months associated with two or more of the following: • Related to defecation • Onset associated with a change in frequency of stool • Onset associated with a change in form (appearance) of stool According to Rome IV Criteria IBS patients should be divided into four subgroups based on their predominant symptoms: (a) IBS with predominant diarrhea (IBS-D), (b) IBS with predominant constipation (IBS-C), (c) IBS with mixed bowel habits (IBS-M), (d) IBS unclassified (IBS-U). To facilitate the proper assessment of patients according to Rome IV Criteria, the IBS adapted diagnostic questionnaire has been proposed (Table 1). The IBS questionnaire contains 10 questions and all answers are on an ordinal scale with individual frequency thresholds. The qualification of the patient to an appropriate subgroup is performed based on the answers to questions regarding bowel movements habits, frequency and consistency of stools. Despite the exact diagnostic criteria for IBS prepared by the Rome Foundation, the final diagnosis of the disease remains a big challenge in everyday clinical practice. Because there are usually no physical signs to definitively diagnose IBS, diagnosis is often a process of ruling out other conditions. To facilitate proper final IBS diagnosis in clinical practice by a general practitioner or gastroenterologist we proposed the following diagnostic steps.

Step I Healthcare professionals should consider assessment for IBS if the patient reports having any of the following symptoms for at least 6 months before diagnosis and these symptoms should be present during the last 3 months: • Abdominal pain (the term discomfort has been eliminated from the current definition and diagnostic criteria) • Abdominal bloating/distention a

Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

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Table 1 Irritable bowel syndrome questionnaire based on ROME IV criteria.

1. In the last 3 months, how often did you have pain anywhere in your abdomen?

2. For women: Did this pain occur only during your menstrual bleeding and not at other times?

3. Have you had this pain 6 months or longer? 4. How often did this pain get better or stop after you had a bowel movement?

5. When this pain started, did you have more frequent bowel movements?

6. When this pain started, did you have less frequent bowel movements?

7. When this pain started, were your stools (bowel movements) looser?

8. When this pain started, how often did you have harder stools?

0 Never 1 Less than 1 day a month 2 One day a month 3 Two to three days a month 4 One day a week 5 More than one day a week 6 Every day 0 No 1 Yes 2 Does not apply because I have had the change in life (menopause) or I am a male 0 No 1 Yes 0 Never or rarely 1 Sometimes 2 Often 3 Most of the time 4 Always 0 Never or rarely 1 Sometimes 2 Often 3 Most of the time 4 Always 0 Never or rarely 1 Sometimes 2 Often 3 Most of the time 4 Always 0 Never or rarely 1 Sometimes 2 Often 3 Most of the time 4 Always 0 Never or rarely 1 Sometimes 2 Often 3 Most of the time 4 Always

Skip remaining questions

Chapter 8 Clinical diagnosis of irritable bowel syndrome

9. In the last 3 months, how often did you have hard or lumpy stools?

0 Never or rarely 1 Sometimes 2 Often 3 Most of the time 4 Always

10. In the last 3 months, how often did you have loose, mushy or watery stools?

0 Never or rarely 1 Sometimes 2 Often 3 Most of the time 4 Always

Criteria for IBS-C: (question 9 > 0) and (question 10 ¼ 0). Criteria for IBS-D: (question 9 ¼ 0) and (question 10 > 0). Criteria for IBS-M: (question 9 > 0) and (question 10 > 0). Criteria for IBS-U: (question 9 ¼ 0) and (question 10 ¼ 0).

• Change in bowel habit Bloating means fullness or swelling in the abdomen that often occurs after meals. During the medical interview, the occurrence of diarrhea, constipation or both should be considered. It is very important to ask the patient about the frequency of symptoms (how many times per week) and how many times per day they have bowel movements related with a visit in the bathroom and about their stool consistency. Sometimes doctors can use the Bristol Scale of stool.

Step II All the patients with suspected IBS should be asked if they have any of the following “red flag” indicators and should be referred to secondary care for further investigation if any are present. “Red flag” symptoms: • Unintentional and unexplained weight loss • Rectal bleeding • A family history of bowel or ovarian cancer • A change in bowel habit to looser and/or more frequent stools persisting for more than 6 weeks in a person aged over 50 years • Anemia • Palpable abdominal masses • Rectal masses • Inflammatory markers for inflammatory bowel disease “Red flag” symptoms may be connected to colorectal cancer or ovarian cancer and they are considered as alarming signs. Each

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Alternative scale: 0 Never or rarely 1 About 25% of the time 2 About 50% of the time 3 About 75% of the time 4 Always, 100% time Alternative scale: 0 Never or rarely 1 About 25% of the time 2 About 50% of the time 3 About 75% of the time 4 Always, 100% time

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time the patient reports even only one of the above symptoms, an in-depth physical examination and further imaging studies should be performed. If there is a significant concern that symptoms may suggest ovarian cancer, gynecologist’s consultation and pelvic examination should also be considered. If a patient reports no “red flag” symptoms, diagnostic steps III and IV are necessary to confirm the IBS diagnosis.

Step III The diagnosis of IBS should be accepted in patients with abdominal pain that is either relieved by defecation or associated with altered bowel frequency or form of stool. This should be accompanied by at least two of the following four symptoms: • Changed stool passage • Abdominal bloating, distension, tension or hardness • Symptoms related with eating • Passage of mucus Other symptoms such as fatigue, nausea, backache and urinary bladder symptoms are common in IBS patients and may support the final diagnosis.

Step IV Basic laboratory tests In people who meet the diagnostic criteria from Steps I to III, the following laboratory tests are mandatory to exclude other diagnoses and confirm IBS: • Full blood count (FBC) • Erythrocyte sedimentation rate (ESR) or plasma viscosity • C-reactive protein (CRP) • Antibody testing for coeliac disease (endomysial antibodies (EMA) or tissue transglutaminase (TTG)) To perform all the above listed laboratory tests the venous blood from the patient’s peripheral vessels should be drawn.

Additional laboratory tests Additional diagnostic laboratory tests in patients who meet the IBS diagnostic criteria may be warranted in some of the patients to exclude other diseases like celiac disease. However, the extensive diagnostic testing may be unnecessary for patients without alarm symptoms. In some patients, addressing disease-related concerns, discussing reasonable treatment goals and patient’s expectations, educating and empowering patients, and

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addressing somatization issues with patients may provide greater benefit than extensive in-depth examination. However, even if the above-mentioned diagnostic steps are performed, many of IBS patients need additional clinical examinations to exclude infectious, inflammatory or neoplastic diseases. Additional tests may include: • Abdominal ultrasound • Rigid/flexible sigmoidoscopy • Colonoscopy; barium enema • Thyroid function test • Fecal ova and parasite test • Fecal occult blood • Hydrogen breath test (for lactose intolerance and bacterial overgrowth) After all the above steps (I–IV) are completed, the clinical diagnosis of IBS may be finally recognized.

Conclusion IBS is a symptom-based diagnosis FBD that significantly reduces patients’ quality of life and which imposes a significant economic burden to the healthcare system. Clinical management of IBS is characterized by significant changes in diagnostic strategies and therapeutic options over the last two decades. Currently, the diagnosis of IBS requires a thoughtful approach, limited diagnostic tests, and careful follow-up. The goal of Rome IV diagnostic criteria for IBS is to provide a readily useable framework that can be easily applied in clinical practice. However, it is worth remembering that no single test and no single definition of IBS are perfect and a combined approach is advisable.

Further reading National Institute for Health and Clinical Excellence (NICE). Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care UK: National Collaborating Centre for Nursing and Supportive Care, 2008. tude prospective et monocentrique de « l’introAmarenco G. Bristol stool chart: e cale » chez des sujets volontaires [Bristol stool chart: prospective and spection fe monocentric study of ‘stools introspection’ in healthy subjects]. Progre`s en Urologie (in French) 2014;24(11):708–13. Longstreth GL, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006;130:1480–91. http://www.romecriteria.org/. El-Salhy M. Irritable bowel syndrome: diagnosis and pathogenesis. World J Gastroenterol 2012;18(37):5151–63.

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Spiller R, Aziz Q, Creed F, et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007;56:1770–98. Rome IV. Functional gastrointestinal disorders. Disorders of gut-brain interaction. Douglas A. Drossman, senior editor; 2016. Palsson OS, Whitehead WE, van Tilburg MA, et al. Development and validation of the Rome IV diagnostic questionnaire for adults. Gastroenterology 2016;150:1481–91. Heitkemper MM, Cain KC, Jarrett ME, et al. Symptoms across the menstrual cycle in women with irritable bowel syndrome. Am J Gastroenterol 2003;98:420–30. Hyams JS, Di Lorenzo C, Saps M, et al. Childhood functional gastrointestinal disorders: children and adolescents. Gastroenterology 2016;150:1456–68. Keefer L, Drossman DA, Guthrie E, et al. Centrally mediated disorders of gastrointestinal pain. Gastroenterology 2016;150:1408–19. Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology 2016;150:1393–407. Mulak A, Smerek A, Paradowski L. Nowosci i modyfikacje w Kryteriach Rzymskich IV. Gastroenterologia Kliniczna 2016;8(2):52–61. Palsson OS, Tilburg MA, Simren M, et al. Population prevalence of Rome IV and Rome III irritable bowel syndrome (IBS) in the United States (US), Canada and the United Kingdom (UK). Gastroenterology 2016;150(Suppl 1):S739–40.

Biomarkers of irritable bowel syndrome

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Marek Waluga Department of Gastroenterology and Hepatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

Abstract The diagnosis of IBS based only on Rome IV criteria seems unsatisfactory and new diagnostic tools are necessary. Several factors could serve as potential biomarkers of IBS, both in serum and stool, and in intestinal mucosa, but their current value is debatable. In this chapter, the sensitivity and specificity of individual biomarkers and their panels is discussed.

Keywords Irritable bowel syndrome, Biomarker, Microbiome, Metabolome, Metabolic profile, Intestinal permeability, Zonulin, Calprotectin, Inflammation, Genetic testing

List of abbreviations Akt ANCA Anti-CBir1 ASCA IgA BAM syndrome BCLAF1 BDNF C4–4 CdtB Cg CgA EN-RAGE FD FGF19 FGID FUS

serine/threonine kinase antineutrophil cytoplasmic antibody antibody against CBir1 anti-saccharomyces cerevisiae IgA antibody bile acid malabsorption syndrome beclin cell lymphoma associated transcription factor 1 brain-derived neurotrophic factor cholesten cytoskeletal distending toxin B chromogranin chromogranin A extracellular newly identified receptor for advanced glycation end-products functional dyspepsia fibroblast growth factor 19 functional gastrointestinal diseases fused in sarcoma

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00009-5 # 2020 Elsevier Inc. All rights reserved.

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GA GI GRO-a HBD-2 IBD IBS IBS-C IBS-D ICC IGE IP LPS M2-PK MC MAMP MCL MDA MMP MRP NF-kappa B NGAL PAR-2 PHQ PI3K/Akt PMN SCFAs Sg T1DM TAC TNF TREM sTREM tTG TIMP-1 TJ TWEAK UC UNC5CL VOMs WAS

genetic analysis gastrointestinal growth-related oncogene-a human b-defensin-2 inflammatory bowel diseases irritable bowel syndrome constipation predominant irritable bowel syndrome diarrhea predominant irritable bowel syndrome interstitial cells of Cajal infectious gastroenteritis intestinal permeability lipopolysaccharide M2-pyruvate kinase mast cells Microbe-Associated Molecular Pattern Markov clustering malondialdehyde matrix-metalloproteinase myeloid-related protein nuclear factor kappa B neutrophil gelatinase-associated lipocalin proteinase-activated receptor 2 patient health questionnaire phosphatidylinositol 3-kinase polymorphonuclear neutrophil short chain fatty acids secretogranin type 1 diabetes mellitus total antioxidant capacity tumor necrosis factor triggering receptor expressed on myeloid cells soluble form of triggering receptor expressed on myeloid cells tissue transglutaminase tissue inhibitor of metalloproteinase 1 tight junctions tumor necrosis factor-like weak inducer of apoptosis ulcerative colitis unc-5 family C-terminal like volatile organic metabolites water avoidance stress

Introduction Irritable bowel syndrome (IBS) is a common disease of heterogenous etiology and complex pathophysiology. The diagnosis and determination of IBS subtypes are based on symptoms, since 2016—on Rome IV criteria. In many cases, the diagnostic efficiency of these criteria seems unsatisfactory. Therefore, new diagnostic tools for IBS are necessary. Several factors are considered as markers of IBS; however, their value has not been fully confirmed. Moreover, it is crucial in clinical practice to distinguish between functional gastrointestinal

Chapter 9 Biomarkers of irritable bowel syndrome

diseases (FGID) and inflammatory, malignant or infectious conditions. Differentiation between them involves the use of clinical, endoscopic, radiological, histological and laboratory technics, which are invasive, expensive, sometimes dangerous, patientcharged and also time-consuming. Thus, the growing interest for biomarkers is observed, and many studies in this field were published. Most of these biomarkers can be delivered from sera, however some fecal markers which have the potential to differentiate between functional and organic diseases, particularly between IBS and IBD have also been explored.

Markers of the inflammatory process Many studies indicate the role of inflammation, mainly subclinical, in the pathogenesis of IBS [1]. Some basic serological markers (e.g. C-reactive protein, erythrocyte sedimentation rate) reflect the presence and intensity of the inflammatory process, yet are not specific enough for intestinal inflammatory disease or IBS. Concurrently, an elevated number of immunocytes: CD4 + and CD8 + lymphocytes might be found higher in IBS comparing to controls [2, 3]. Mediators delivered from mast cells (MC) have been shown to act on the enteric nervous system, what might contribute to IBS symptoms [4–6]. MC infiltration of the gut wall is a part of this phenomenon. Moreover, MCs infiltration is the result of disturbances of the brain-gut axis, whereby MCs may be attracted to the bowel via neuropeptides [7]. This shows the potential of MCs and their secretions as possible biomarkers in IBS. A meta-analysis by Bashashati et al. [8] evaluating potential inflammation-related biomarkers for IBS from sera or colonic biopsies in IBS patients and some studies analyzing colonic biopsies in IBS patients [8] or feces [9] showed an imbalance of the two investigated cytokines—proinflammatory tumor necrosis factor α (TNF-α) and anti-inflammatory IL-10 [8]. Fecal markers are inexpensive, easily measured and suitable for extensive use, hence their likely employment in IBS surveillance.

Microbiome-related markers Interaction of the microbiome with diet as well as antibiotics and enteric infections are taken into account as the factors involved in the pathophysiology of IBS. There is also the concept of the brain-gut axis dysregulation by the gut microbiome which may play an important role in the onset or exacerbation of symptoms and which is considered as a suitable model for IBS. Together, these raise the question if microbiome alterations could

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activate or perpetuate pathophysiological mechanisms in IBS, but also if microbiota composition could be a diagnostic tool for IBS. Many changes in the microbiome composition in IBS patients were proved and correlated with IBS symptoms. One of the more consistent findings are enrichment of Firmicutes and reduced abundance of Bacteroides [10]. Also, lower abundance of mucosaassociated Bifidobacteria in diarrhea predominant IBS (IBS-D) comparing to constipation predominant IBS (IBS-C) patients was observed [11]. Other studies showed increase in the Lactobacillus genus or Lactobacillales order in IBS-D [12, 13]. An increase in Veillonella, Ruminococcus and decrease in Faecalibacterium genus have been also described [14, 15]. Finally, short chain fatty acids (SCFAs) producers—Bifidobacterium genus, Clostridiales order, Ruminococcaceae and Erysipelotrichaceae families have been found in lower proportion in patients suffering from IBS [16–18]. Some data are controversial. For example, both a higher or lower ratio of Firmicutes/Bacteroides has been described [15, 17]. Studies which have examined the association between specific symptoms and microbiota alterations have reported relationships between stool frequency and mucosa-associated Bifidobacteria and Lactobacilli [11], a correlation between symptoms scores and Proteobacteria/Firmicutes ratio [18], and between Ruminococcus-torques-like phylotype and symptom scores [19]. In terms of potential biomarkers it also needs to be highlighted that there is a distinct difference between the composition of microbiota in stool and intestinal mucosa. In line, when looking at mucosal microbial composition, V. dispar, P. copri and H. parainfluenzae were significantly represented only in IBS mucosal microbiota [20]. From this point of view these strains could serve as a diagnostic tool for IBS detection. Another group of potential biomarkers derived from the gut microbiome are its metabolites. It has to be underlined that not only human but also preclinical experimental studies indicated the differences in microbiota and metabolite profiles in IBS. Liu et al. using gas chromatography coupled to time-of-flight mass spectrometry and 16S RNA gene sequencing, and measuring fecal microbiota as well as its metabolites in water avoidance stress (WAS)—induced IBS rats, found a significantly differential metabolite profile between the IBS and control groups [21]. Methane production and its changes is one of the important features in IBS: methane has been related to slower intestinal transit and was showed to have anti-inflammatory effects [22, 23]. Some studies found lower levels of methane production in IBS-D and higher levels in IBS-C [24, 25] what encourages the assessment of methane production in breath tests as the diagnostic tool for IBS and its subtypes. However, currently this method is not widely used.

Chapter 9 Biomarkers of irritable bowel syndrome

Recently, there are attempts to analyze potential microbiomederived biomarkers in clusters or panels. In the study performed on the groups of IBS patients and healthy volunteers in China, the differences in microbiota composition and their metabolites were presented between these groups [26]. The authors found that 4 clusters with 31 metabolites, including a group of amino-acids and fatty acids were up-regulated in IBS patients. Moreover, 19 microbes were up-regulated and 12 were down-regulated in IBS patients. Among them mostly upregulated were: Lachnoclostridium, Clostriudium sensu stricto 1, Lachnospiracae UCG-004, ND3007 and FCS020, as well as Ruminiclostridium, Lachnospira, Romboutsia, Granulicatella, Lactobacillus, Tyzerella 4, whereas Ruminoclostridium 5, Parabacteroides and Hungatella were mostly down-regulated. The major differentially abundant fecal metabolites in IBS patients were: eicosatrienoic, capric, gammaaminobutyric, and oxoadipic acids as well as homoserine, leucine, methionine, norleucine, phenylalanine, tryptophan, valine, acetyl tryptophan, putrescine, and ornithine. Importantly, some clusters of fecal metabolites or microorganisms were significantly correlated with the severity of IBS symptoms—the number of bowel movements and frequency of abdominal pain/discomfort [26]. These bacilli, as well as metabolites could serve as biomarkers of IBS, at least in the population explored by the authors. Based on a big meta-analysis in which 834 citations were obtained initially, Sun et al. stated that the pathogenesis of IBS can be partly reflected by fecal SCFAs generated from gut microbiota [27]. Based on this meta-analysis, it was concluded that propionate and butyrate were reduced in IBS-C patients, whereas only butyrate was increased in IBS-D patients comparing to healthy subjects. Some studies indicated that Clostridium OTUs were enriched in IBS-C patients and negatively correlated with fecal SCFAs—propionate and butyrate [28, 29]. The Roseburia-E.rectale group is a predominant butyrate producing bacterial group in the human gut and it was detected at significantly lower levels in IBS-C [30, 31]. Patients with IBS-D had increased colonic fermentation [32], leading to higher fecal levels of SCFAs, which stimulate intestinal motility and reduce transit time, and which can shift bacteria composition in the colon [28, 33]. Consequently, propionate and butyrate could be used as biomarkers for IBS diagnosis [27]. Collectively, the microbiome as well as fecal and urine metabolome could offer objective biomarkers for diagnosis of IBS [34]. Moreover, fecal metabolomic profile can distinguish IBS-D from bile acid malabsorption syndrome (BAM syndrome). Unfortunately, as of yet the differences in microbiota do not allow to

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distinguish unequivocally between different forms of IBS according to Rome IV criteria. Attention should also be focused on the role of the diet in shaping the composition of the microbiome and in disorders of the diet-microbiome-metabolome axis [34]. For example, high protein diets are associated with abundance of Firmicutes and Ruminococcaceae and depletion of Bacteroides [35]. Similar alterations of microbiota composition are observed in IBS, even though the development of this syndrome is not associated with a high protein diet [35]. The value of few commercially available tests for fecal dysbiosis is controversial. For example, a test for fecal dysbiosis based upon 54 DNA probes (GA-mapTM Dysbiosis Test -Genetic Analysis AS, Oslo, Norway) that target gut bacteria, marketed in Europe, according to one study [32] has the sensitivity and specificity for the diagnosis of IBS at 73 and 84%, respectively. However, other authors [36] showed that this test was unsuitable as a diagnostic tool for IBS. They showed that dysbiosis evidenced by the GA-mapTM Dysbiosis Test was statistically significantly associated with morbid obesity, but not with IBS [37].

Biomarkers related to changes in intestinal permeability Many studies indicated increased intestinal permeability (IP) in IBS. The hyper-permeable gut mucosa of inflamed bowel is associated with increased cytokine levels and presence of markers of neutrophil activation in fecal samples. Zonulin is the complex protein encountered in tight junctions (TJ) and it is also considered as the marker of increased IP. Some studies indicate that zonulin has been shown to regulate IP and elevated levels of zonulin have been well documented in several disorders associated with alteration in IP including celiac diseases, type 1 diabetes mellitus (T1DM) and rheumatoid arthritis [38–40]. Zonulin alters small intestinal intercellular TJ integrity by activating epidermal growth factor receptor through proteinase-activated receptor 2 (PAR-2) [38]. Zonulin can also increase colonic permeability in response to exposure to enteric bacteria [41]. Alteration in gut microbiome and mucosal inflammation probably contribute to TJ dysfunction in IBS. It has been demonstrated that patients with IBS-C and IBS-D had higher zonulin levels compared with healthy subjects [42]. Although zonulin levels did not correlate with the overall IBS symptom severity scale, they positively correlated with stool frequency per week, as well as severity and dissatisfaction with bowel habits in IBS-D [42]. Because both of these symptoms are

Chapter 9 Biomarkers of irritable bowel syndrome

surrogates of diarrhea severity, it can be hypothesized that zonulin is the marker of severity of the disease or at least some of its symptoms [42]. Noteworthy, the authors observed that the levels of zonulin in IBS are comparable to those in celiac disease, what may hamper its use as a valuable biomarker [42]. Other studies have shown that IBS-D patients with altered IP have higher stool frequency, visceral hypersensitivity and more severe IBS symptoms [43–45]. In this point of view zonulin has the importance, and its plasma level reflects the pathophysiological changes and severity of IBS. However, the value of zonulin is controversial [36]. The study performed by Linsalata et al. assessed gastrointestinal (GI) permeability in IBS-D, celiac disease patients and healthy controls. The IP was assayed by high-performance liquid chromatography determination of sucrose and lactulose/mannitol ratio in the urine. The authors used ELISA kits to assay circulating concentrations of zonulin, intestinal fatty acid binding protein—IFABP and diamine oxidase—DAO, as well as IL-6, IL-8, LPS and TLR-4. It was stated that IL-8 levels were significantly higher in both IBS-D and celiac disease than in healthy subjects but markers of bacterial translocation—IL-6 and LPS were significantly higher only in IBS-D comparing to non-IBS participants. Moreover, the authors stated that two distinct IBS-D subtypes could be identified by this method and concluded that these factors should serve as biomarkers [46].

Biomarkers related to intercellular interactions Antibodies to cytoskeletal distending toxin B (CdtB) and vinculin are considered as biomarkers that could differentiate IBS-D from other causes of diarrhea and healthy controls. Cdt toxins are commonly produced by bacilli such as Campylobacter jejuni, Salmonella, Escherichia coli and Schigella that cause infectious gastroenteritis (IGE), which, together with alterations in the gut microbiome (dysbiosis) play integral role in the development and persistence of IBS symptoms [47]. Vinculin is an actin-binding protein and is involved in cell adhesion, neuronal cell motility, contractility, and epithelial barrier formation [48–51]. It is present in the myenteric ganglia and in the interstitial cells of Cajal (ICC) [52]. It was proved that the number of ICC in the small intestine is significantly reduced in animals infected by C. jejuni. This phenomenon potentially contributes to dysmotility, bacterial overgrowth, as well as the development of IBS-like symptoms [53, 54]. A study by Rezaie et al. evidenced that plasma levels of anti-CdtB and anti-vinculin antibodies were highest in IBS-D and lowest in IBS-C and healthy controls, and in IBS-C patients these values were not statistically different from controls [52].

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The authors concluded that anti-CdtB and anti-vinculin titers and positivity rate differ in IBS subtypes. Since higher antibody levels were found in IBS-D and IBS-M, and the levels in IBS-C were similar as in healthy subjects, these antibodies appear useful in the diagnosis of IBS-D and IBS-M, but not IBS-C. Moreover, this study suggests that that pathophysiology of IBS-C is distinct from subtypes with diarrhea [52]. Respecting this knowledge, CdtB and vinculin or antibodies against them could be considered as biomarkers of indicated subtypes of IBS. Noteworthy, other authors [53] did not find significant differences in anti-CdtB in IBS and functional dyspepsia (FD) outpatients or a subgroup with overlapping IBS/FD compared with patients with organic GI disease. There were also no significant differences in anti-vinculin levels between IBS, FD and healthy controls or between IBS or FD and organic GI diseases patients. Summarizing, these authors did not confirm that anti-CdtB or anti-vinculin could discriminate IBS-D from organic disease in Australian subjects [53]. In conclusion, it is not clear whether anti-CdtB and anti-vinculin antibodies are good biomarkers for diagnosis IBS or its subtypes.

Adipokines and neuropetides as biomarkers in IBS Liu et al. proved colocalization of leptin and leptin receptors on MCs and PGP9,5-positive nerve fibers in the intestinal mucosa. Statistically important increased levels of mucosal leptin as well its expression in IBS-D patients were showed. Moreover, leptin expression was positively correlated with anxiety, depression and MC activation rate, but negatively correlated with the defecation sensation threshold and the maximum tolerance threshold [55]. In consequence, leptin could not only be one of the factors involved in the pathogenesis of IBS-D, but also might partly serve as a marker of this disease in some cases. IBS-D patients had increased adipokines (leptin, adiponectin) serum levels in comparison to control [56]. IL-6 levels correlated with lipopolysaccharide (LPS) in this study. Brain-derived neurotrophic factor (BDNF) was significantly higher, but neurotensin serum levels was significantly lower in IBS-D than in controls. These factors could serve as biomarkers of IBS-D. Moreover, the authors indicated a potential impact of the molecules secreted by the visceral adipose tissue on barrier function [56].

Chapter 9 Biomarkers of irritable bowel syndrome

Biomarkers related to lipid turnover Bile acid secretion and colonic transit could serve as biomarkers of IBS subtypes. The case-control study has been performed in the model consisting of total fecal bile acid excretion measurement and colonic transit time assessment to differentiate between IBS-D and IBS-C patients, and healthy volunteers. In this 2-item model the differentiation between IBS and healthy subjects was possible with positive LR of 2.78 (95% CI: 1.55–5.58) and a negative LR of 0.46 (95% CI: 0.33–0.65) [57]. Other authors showed that patients with IBS-C had a significant increase in proportion of fecal lithocholic acid but a decrease in deoxycholic acid comparing with controls. Moreover, IBS-C patients had inverse relationship between serum levels of 7αhydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19); the positive correlation was observed among the levels of 48-h fecal bile acids, colonic transit and serum C4 as well as FGF19 [58]. The authors stated that total and primary fecal bile acids and fecal fat were significant predictors of increased stool weight, its free test and < $500 categorize biomarkers as costeffective, the authors concluded that fecal bile acids and fecal fat are cost-effective, and accurate biomarkers, associated with significant bowel dysfunction among IBS-C and IBS-D patients [59].

Potential biomarkers expressed in leukocytes Calprotectin—S100A8 [known also as calgranulin A and myeloid-related protein 8 (MRP8)] and S100A9 (cangranulin B, MRP14) are members of the S100 calcium-binding protein family. Both proteins are expressed in granulocytes, monocytes/ macrophages and epithelial cells. These two proteins exist in many forms. The most abundant is the S100A8/S100A9 heterodimer—calprotectin, which constitutes 60% of cytosolic protein in neutrophils [55]. It is one of the most studied fecal biomarkers for intestinal inflammation and for the differentiation between IBD and IBS, but not for the diagnosis of IBS [60]. The molecule S100A12, known as calgranulin C (or EN-RAGE extracellular newly identified receptor for advanced glycation end-products) is also the member of the S100 calcium binding protein family. It is expressed almost exclusively by neutrophils. S100A12 was reported to function as a pro-inflammatory molecule: its binding to RAGE on endothelial cells, mononuclear phagocytes and lymphocytes leads to upregulation of proinflammatory cytokines [61]. Sensitivity of 86% and specificity

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of 96% (cutoff 0.8 mg/kg) were demonstrated when differentiating active IBD from IBS [54], but similarly as calprotectin cannot serve as a diagnostic tool for IBS. Lactoferrin is a multifunctional iron binding glycoprotein that is found in the secretions of most mucosal surfaces. It has been shown to exert bactericidal activity and is a major component of secondary granules released during the degranulation of polymorphonuclear neutrophils (PMNs) in response to inflammation [62, 63]. Lactoferrin is considered as a distinguishing marker between IBS and IBD. The diagnostic accuracy of fecal lactoferrin in the differentiation of IBD vs. IBS had sensitivities 56–100% and specificities 61–100% [64]. M2-pyruvate kinase (M2-PK) is a multifunctional protein, important in several non-glycolytic pathways including immunological responses, cellular growth and apoptosis [65]. Fecal M2-PK can be used to differentiate organic disease from FGID (cut-off 4 U/mL) with a sensitivity of 67% and specificity of 88% [66]. Polymorphonuclear neutrophil elastase is a neutral serine protease, released from leucocyte granules by activation of neutrophils, as a mediator of inflammation. It was proved, that fecal PMN elastase levels in patients with IBS were statistically similar as in healthy persons [67]; however, these levels correlated with the activity of IBD assessed endoscopically [68]. Consequently, PMN elastase can thus be used only for differential diagnosis between IBS and IBD. The specificity and overall diagnostic accuracy of PMN elastase in patients with IBS were 82%—slightly lower than that for fecal lactoferrin (83%), fecal calprotectin (87%), and serum CRP (91%) [54].

Immune cell-derived biomarkers By employing biomarkers from this class, several goals in IBS diagnosis could be achieved. Granins are proteins expressed by cells of the enteric, endocrine, and immune systems. Chromogranins (Cg) and secretogranins (Sg) as the precursors of several bioactive peptides regulate a number of cellular functions. It was demonstrated that IBS patients had higher levels of CgA, Sg II and Sg III, but lower levels of CgB, what makes them useful indicators to discriminate between IBS patients and healthy individuals [69]. Human β-defensin-2 (HBD-2) is a member of defensins, which belong to the class of protective antimicrobial peptides and have an important role in the host innate defense at the mucosal surface of the GI tract. It is interesting to note that elevated fecal levels of HBD-2 indicate activation of innate immunity not only in IBD,

Chapter 9 Biomarkers of irritable bowel syndrome

but also in IBS [70, 71]. Moreover, fecal HBD-2 levels in patients with IBS were significantly elevated compared with healthy subjects and similar to those in patients with active ulcerative colitis (UC) [71]. In contrast, some immune cell-derived biomarkers could be used to discriminate between IBS and IBD. Matrix-metalloproteinase 9 (MMP-9) are a family of zinc-dependent endopeptidases capable of degradation of extracellular matrix proteins. They are secreted by tumor cells, various immune cells and several other cell types [54]. MMP-9 were shown as potentially useful tools to differentiate IBS from inflammatory diseases. Namely, patients with UC have much higher level of MMP-9 compared to healthy subjects and patients with IBS-D. The sensitivity of fecal MMP-9 in distinguishing between UC and IBS-D was 85% and specificity—100% (cutoff 0.245ng/mL) [54]. Finally, immune cell-derived biomarkers could be employed to identify the IBS subtype. For example, in some attempts there was a strong focus on triggering receptor expressed on myeloid cells 1 (TREM-1) which is a member of the immunoglobulin superfamily. It is expressed on a variety of innate immune cells—neutrophils, monocytes, dendritic cells, macrophage subsets, microglia and many other [72–74]. This receptor is produced also in a soluble form (sTREM-1). It was showed that sTREM-1 level was significantly higher in IBS-D patients and positively correlated with abdominal pain. Consequently, it was suggested that abdominal pain in IBS may be initiated by TREM-1-associated macrophage activation, indicating the existence of subclinical inflammation in IBS-D. The authors also suggested that sTREM-1 is a potential marker of subclinical inflammation in IBS-D [75]. There is a hypothesis associating the pathogenesis of IBS with micro-inflammation which is regulated by the parasympathetic nervous system. Concurrently it was proved that increased serum cholinesterase activity induces pro-inflammatory action. Hod et al. proved that IBS-D patients had increased serum cholinesterase, as well as acetylocholinesterase activity and acetylocholinesterase/butyrylcholinesterase ratios, compared to healthy subjects. This study not only emphasized the possible role of the autonomic nervous system in IBS, but also indicated these components of the parasympathetic nervous system as potential biomarkers of IBS-D [76].

Biomarkers in panels Since single biomarkers have limited value and their level or concentration depends on many factors like region of the world, population, diet and many others, a combination or a panel of biomarkers taking into account multiple pathophysiologic

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pathways seems to be the most exploitable. Moreover, a panel of markers has potentially higher selectivity and specificity than a single biomarker. Initially, Lembo et al. selected about 150 factors as potential biomarkers of IBS, of which a combination of 10 were chosen to assess their value in diagnosing IBS, namely: IL-1b, growth-related oncogene-a (GRO-a), brain-derived neutrophic factor (BDNF), anti-saccharomyces cerevisiae IgA antibody (ASCA IgA), antibody against CBir1 (Anti-CBir1), antihuman tissue transglutaminase (tTG), TNF-like weak inducer of apoptosis (TWEAK), antineutrophil cytoplasmic antibody (ANCA), tissue inhibitor of metalloproteinase—1 (TIMP-1), and neutrophil gelatinase-associated lipocalin (NGAL) [77]. The authors of the study found a positive predictive value of 81%, 64% negative predictive value, and 50% IBS prevalence in the validation cohort [77]. Five years later, in 2014 [78] the usefulness of 10 other markers was tested, i.e.: histamine, prostaglandin E2, tryptase, serotonin, P substance, IL-12, IL-6, IL-8, IL-10, and TNF-α, as well as the expression of 14 genes. The result of this study showed that the proposed combination might differentiate IBS patients from healthy subjects with a selectivity of 83% and a specificity of 86%. By adding to all these selected 34 markers four non-gastric somatic symptoms (depression, anxiety, stress and non-GI somatic symptoms), the AUC raised from 0.93 to 0.94 [78]. Yet another study evaluated immune responses (humoral and cellular) in FGID, and especially in IBS patients in comparison to healthy subjects [79]. In it, IL-5, IL-10, IL-13, TNF-α, IFN-γ, IL-10 and IL-12 were determined in FGID patients and in healthy volunteers. It was concluded that stimulated lymphocyte expression of IL-5 and IL-13 were higher in IBS compared to healthy subjects, but stimulated monocytic IL-12 and lymphocytic IL-10 expression were reduced in IBS [79]. In contrast, a study by Buckley et al. [80] showed that IL-6 serum concentrations were similar in IBS patients, Crohn’s disease patients and healthy subjects. In a study by Darkoh et al. [9], MIP-1b, MCP-1, TNF-α, IFN-γ, IL1b, IL-4, IL-10, IL-13, and CXCL16 were significantly higher in IBS patients than in healthy volunteers [9]. This study also showed that MCP-1 and MIP had higher values not only in sera but also in feces of IBS patients. Rana with colleagues evidenced that IL-6 and TNF-α values were higher in IBS-D patients than in healthy subjects [81]. Finally, a panel of markers: IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, and IFN-γ was assessed in a study by McKernan et al. which evidenced that all of them were higher in IBS patients [82].

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In another cohort, it was showed that TNF-α, IL-17 and malondialdehyde (MDA) were significantly higher in IBS patients, and IL-10, as well as total antioxidant capacity (TAC) were significantly lower than in healthy subjects. Comparing IBS subtypes, TNF-α and IL-17 were significantly higher and IL-10 was significantly lower in IBS-D compared to healthy controls [83]. One of the most important features of IBS is visceral hypersensitivity, it is therefore of interest if there are biomarkers with relation to hypersensitivity. However, there was only one study conducted to explore the issue further. Mujagic et al. measured calprotectin, HBD2, CgA and SCFAs in feces, citrulline in plasma, and serotonin as well as its main metabolite—5-hydroxyindoloacetic acid (5-HIAA) in platelet-poor plasma in IBS patients and healthy controls. They did not find any statistically significant differences in concentrations of biomarkers between groups what suggests that these particular compounds cannot be used as biomarkers in visceral hypersensitivity in IBS [84].

Other potential biomarkers Volatile organic metabolites (VOMs) belong to fecal biomarkers, which accompany organic diseases or changes in microbiota composition. Ahmed et al. showed that VOMs may serve for differential diagnosis between IBS patients and healthy controls [85]. Concurrently, sigmoid muscularis propria thickness can serve as a biomarker. A diagnosis of IBS was made using a cut-off for abdominal muscularis mucosae thickness of 3 mm. Positive and negative LRs were 14.9 (95% CI: 7.07–31.5) and 0.31 (95% CI: 0.17–0.51) respectively [86]. Finally, some authors indicate the importance of psychological markers in differentiating IBS patients from healthy subjects. Using the patient health questionnaire 12 (PHQ-12) and cut-of score of >6, the positive LR in differentiating IBS from healthy controls was 12.5 (95% CI: 6.55–246) and the negative LR was 0.35 (95% CI: 0.30–0.41) [67].

Genetic testing Genetic testing has an important place among laboratory tests in the diagnosis of IBS and its differentiation. The estimated protein-protein network in IBS consists of 68,822 interactions from 3595 proteins, which includes growth factors, receptors, cell adhesion molecules, enzymes and chemokines, as well as many biological functions such as signaling cascades,

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neuro-endocrine-immune pathways, inflammation, nuclear receptor transcription and serotoninergic pathways, bile acids synthesis, neuropeptide activity, visceral hypersensitivity, toll like receptors activity, intestinal motility, lipid metabolism [87]. In a study by Calva et al. the IBS interactome was mapped with colon tissue, which resulted in a sub-network containing 153 genes. Thereafter authors applied a special algorithm— MCL (Markov clustering algorithm) to sub-network to identify six major clusters, which are associated with several pathways such as MAMP, PI3K/Akt, and NF-kappa B. Since FUS, UNC5CL and BCLAF1 were found in the clusters among the expressed genes, it was suggested that the identified clusters might play a potential role in the regulation of IBS. Then, the authors performed gene prioritization studies and identified top 10 genes that can be used as candidate biomarkers for early diagnosis of IBS. PRPF31 was expressed in this study in all biofluids— serum, saliva and urine, out of top ten genes [88]. Concurrently, DNA microarray analyses were performed by Dussic et al. using colonic RNA derived from IBS and asymptomatic sample populations [88]. Subsequent analysis of the raw microarray data based on a series of 858 genes/biomarkers that display differential expression was performed. As a result, the authors made a list of top 200 biomarkers exhibiting differential expression between IBS patients and healthy controls [88].

Conclusions A differential diagnosis of IBS based only on Roman IV criteria seems insufficient. Both, physicians—practitioners and researchers—need efficient, sensitive and specific markers that allow putting a more precise diagnosis of IBS, as well as defining its subtypes. There are many potential biomarkers, both in serum and stool and in the intestinal mucosa. Unfortunately, the diagnostic value of most of them is far from sufficient. Therefore, the research is directed, on the one hand, to the exploration for new biomarkers, and, on the other hand, to the identification of optimal panels consisting of multiple biomarkers. Further studies are needed to find more sensitive and specific tests of IBS.

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[71] Langhorst J, Wieder A, Michalsen A, Musial F, Dobos GJ, Rueffer A. Activated innate immune system in irritable bowel syndrome? Gut 2007;56:1325–6. PMID: 17429012, https://doi.org/10.1136/gut.2007.12500517429012. [72] Ford JW, Mcvicar DW. TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 2009;21:38–46. [73] Klesney-Tait J, Keck K, Li X, Gilfillan S, Otero K, Baruah S, Meyerholz DK, Varga SM, Knudson CJ, Moninger TO, Moreland J, Zabner J, Colonna M. Transepithelial migration of neutrophils into the lung requires TREM-1. J Clin Invest 2013;123:138–49. [74] Arts RJ, Joosten LA, Van Der Meer JW, Netea MG. TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukoc Biol 2013;93:209–15. [75] Du C, Peng L, Kou G, Wang P, Lu L, Li Y. Assessment of serum sTREM-1 as a marker of subclinical inflammation in diarrhea-predominant patients with irritable bowel syndrome. Dig Dis Sci 2018;63(5):1182–91. https://doi.org/ 10.1007/s10620-018-5002-y [Epub 2018 Mar 7]. [76] Hod K, Sperber AD, Maharshak N, Ron Y, Shapira I, David Z, Rogowski O, Berliner S, Shenhar-Tsarfaty S, Dekel R. Serum cholinesterase activity is elevated in female diarrhea-predominant irritable bowel syndrome patients compared to matched controls. Neurogastroenterol Motil 2018;30(12). https://doi.org/10.1111/nmo.13464 [Epub 2018 Sep 21]. [77] Lembo AJ, Neri B, Tolley J, Barken D, Carroll S, Pan H. Use of serum biomarkers in a diagnostic test for irritable bowel syndrome. Aliment Pharmacol Ther 2009;29(8):834–42. [78] Jones MP, Chey WD, Singh S, Gong H, Shringarpure R, Hoe N, Chuang E, Talley NJ. A biomarker panel and psychological morbidity differentiates the irritable bowel syndrome from health and provides novel pathophysiological leads. Aliment Pharmacol Ther 2014;39:426–37. [79] Kindt S, Van Oudenhove L, Broekaert D, Kasran A, Ceuppens JL, Bossuyt X, Fischler B, Tack J. Immune dysfunction in patients with functional gastrointestinal disorders. Neurogastroenterol Motil 2009;21(4):389–98. [80] Buckley MM, O’Halloran KD, Rae MG, Dinan TG, O’Malley D. Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome. J Physiol 2014;592(Pt 23):5235–50. [81] Rana SV, Sharma S, Sinha SK, Parsad KK, Malik A, Singh K. Pro-inflammatory and anti-inflammatory cytokine response in diarrhoea-predominant irritable bowel syndrome patients. Trop Gastroenterol 2012;33(4):251–6. [82] McKernan DP, Gaszner G, Quigley EM, Cryan JF, Dinan TG. Altered peripheral toll-like receptor responses in the irritable bowel syndrome. Aliment Pharmacol Ther 2011;33(9):1045–52. [83] Choghakhori R, Abbasnezhad A, Hasanvand A, Amani R. Inflammatory cytokines and oxidative stress biomarkers in irritable bowel syndrome: association with digestive symptoms and quality of life. Cytokine 2017;93:34–43. https:// doi.org/10.1016/j.cyto.2017.05.005 [Epub 2017 May 12]. [84] Mujagic Z, Jonkers DMAE, Ludidi S, Keszthelyi D, Hesselink MA, Weerts ZZRM, Kievit RN, Althof JF, Leue C, Kruimel JW, van Schooten FJ, Masclee AAM. Biomarkers for visceral hypersensitivity in patients with irritable bowel syndrome. Neurogastroenterol Motil 2017;29(12). https://doi.org/ 10.1111/nmo.13137 [Epub 2017 Jul 3]. [85] Ahmed I, Greenwood R, Costello Bde L, Ratcliffe NM, Probert CS. An investigation of fecal volatile organic metabolites in irritable bowel syndrome. PLoS One 2013;8.

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[86] Canani RB, de Horatio LT, Terrin G, Romano MT, Miele E, Staiano A, Rapacciuolo L, Polito G, Bisesti V, Manguso F, Vallone G, Sodano A, Troncone R. Combined use of noninvasive tests is useful in the initial diagnostic approach to a child with suspected inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2006;42:9–15. PMID: 16385247, https://doi.org/10.1097/ 01.mpg.0000187818.76954.9a16385247. [87] Kalva S, Bindusree G, Alexander V, Madasamy P. Interactome based biomarker discovery for irritable bowel syndrome—a systems biology approach. Comput Biol Chem 2018;76:218–24. https://doi.org/10.1016/j.compbiolchem.2018.07.007 [Epub 2018 Jul 10]. [88] Dussik CM, Hockley M, Grozic A, Kaneko I, Zhang L, Sabir MS, Park J, Wang J, Nickerson CA, Yale SH, Rall CJ, Foxx-Orenstein AE, Borror CM, Sandrin TR, Jurutka PW. Gene expression profiling and assessment of vitamin D and serotonin pathway variations in patients with irritable bowel syndrome. J Neurogastroenterol Motil 2018;24(1):96–106. https://doi.org/10.5056/ jnm17021.

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Agata Szymaszkiewicz and Marta Zieli nska Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract For years pharmacotherapy in irritable bowel syndrome (IBS) was based on laxatives or anti-diarrheals accompanied by anti-spasmodics and pain killers. Nowadays, there are several attempts to target the pathways that participate in the proper functioning of the GI tract, i.e. secretagogues (linaclotide or lubiprostone), opioid receptor ligands (eluxadoline), and serotoninergic receptor ligands (alosetron, ramosetron, prucalopride). In this chapter we focus on the efficacy of drugs currently used in IBS. Moreover, we discuss the possible therapeutic options and their future perspectives

Keywords Alosetron, Eluxadoline, IBS pharmacotherapy, Ramosetron, Rifaximin

List of abbreviations 5-HT AE BB-2 BSFS cGMP CIC CSBM CTs DOP FDA FODMAP GC-C GN

5-hydroxytryptamine, serotonin adverse effects bombesin receptor subtype 2 Bristol Stool Form Scale cyclic guanosine monophosphate chronic idiopathic constipation complete spontaneous bowel movements clinical trials δ opioid receptor Food and Drug Administration fermentable oligo-, di-, monosaccharides and polyols guanylyl cyclase C guanylin

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00011-3 # 2020 Elsevier Inc. All rights reserved.

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IBS MOP NHE3 ORs RCTs SBM UGN

irritable bowel syndrome μ opioid receptor sodium-hydrogen exchanger opioid receptors randomized-controlled clinical trials spontaneous bowel movements uroguanylin

IBS is one of the most frequent conditions related to the GI tract encountered in primary and specialty care. As stress and food intolerance are associated with the IBS exacerbation, the general principles of therapy are based on non-pharmacological approach, including: diet modification (increase in fiber consumption, decrease in FODMAP (fermenable oligo-, di-, monosaccharides and polyols) intake, low gluten diet), physical activity and behavioral therapy. However, when there are no satisfactory results, pharmacotherapy is introduced. Patients begin pharmacotherapy with over-the-counter laxatives/anti-diarrheals and anti-spasmodics. However, these groups of drugs only alleviate acute symptoms, they are not effective enough in a long-term therapy. Concurrently, there are already groups of therapeutics approved by FDA in the treatment of IBS. These are listed in Table 1.

Table 1 IBS therapeutics accepted by FDA. IBS-D

IBS-C

Anti-spasmodics: • dicyclomine • hyoscyamine • peppermint oil 5-HT3 antagonist: • alosetron Targeting opioid receptors: • loperamide • eluxadoline Antibiotics: • rifaximin

Laxatives Chloride channels activator: • lubiprostone Targeting guanylyl cyclase C: • linaclotide Sodium-hydrogen exchanger inhibitor: • tenapanor

Chapter 10 Irritable bowel syndrome: Current therapies and future perspectives

In the meantime there are clinical trials (CTs) on drug candidates for IBS; they are based on Food and Drug Administration (FDA) endpoints [1]. According to the FDA guidelines: the primary endpoint is the increase of the portion of patients who were responders during the 12-week treatment period. FDA defines responder as a patient who experienced at least a 30% reduction in the weekly average abdominal pain score (assessed by patients on a 0–10 point scale) compared with baseline and an increase of at least one complete spontaneous bowel movement (CSBM) in weekly average from baseline, in the same week, for at least six of the first 12 treatment weeks. The assessment of secondary endpoints include: the improvement in abdominal pain/discomfort, bloating, stool frequency and consistency, severity of constipation/diarrhea. FDA guidelines improve the process of CT’s design by standardization of measures of IBS symptoms which enable to compare the results of different CTs and thus the efficacy of interventions (drugs/non-pharmacological methods).

Empirical treatment Anti-spasmodics Anti-spasmodics have been used for decades as an empirical treatment of IBS. The family of anti-spasmodics includes among others: mebeverine, trimebutine, otilonium, hyoscine bromide, cimetropium bromide or dicyclomine hydrochloride. Only hyoscine and dicyclomine are currently available in the United States. Ford et al. [2] summed up the data from 23 small CTs (the majority enrolled fewer than 100 patients) on anti-spasmodics and IBS; these studies varied by diagnostic (Rome I or II or none of these) and inclusion criteria (without defining the IBS type), study endpoints and drug dose. The main conclusion was that anti-spasmodics, as a group, significantly improved IBS related symptoms. However, the assessment of each drug is difficult due to small numbers of patients enrolled in the CTs. It was revealed that: otilonium, hyoscine bromide, cimetropium bromide, pinaveriunum bromide and dicyclomine hydrochloride presented beneficial action. The remaining anti-spasmodics: mebeverine, trimebutine, pirenzipine, alverine, rociverine, prifinium and propinox did not have a statistically significant effect on IBS symptoms [2].

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Constipation-predominant IBS (IBS-C) Prostaglandin derivative (lubiprostone) Lubiprostone is a prosecretory agent that has been approved in the treatment of IBS-C in adult women in 2008. Lubiprostone belongs to the family of bicyclic fatty acid prostaglandins E1 and activates chloride channel type 2. The activation of these channels results in an increase in intestinal motility and the improvement in stool passage. Lubiprostone is characterized with low systemic bioavailability and the rapid onset of action [3]. The meta-analysis of nine randomized-controlled CTs (RCTs) on lubiprostone in chronic idiopathic constipation (CIC) and IBS-C revealed that it significantly improved the stool consistency, severity of constipation, abdominal pain and bloating at week 1, month 1 and month 3 in comparison with placebo [4]. The pooled results of two large RCTs on lubiprostone (8 μg, twice daily) in IBSC indicate the improvement in global symptoms in 18% of patients receiving a drug and 10% of patients in placebo group [5]. It was reported that up to 50% of patients receiving lubiprostone and 51% of receiving placebo experienced at least one adverse effect (AE): AE concerned mainly the GI system (nausea, diarrhea or abdominal distension) and were reported by 19% patients (lubiprostone) and 14% (placebo) [5].

Targeting guanylyl cyclase C (linaclotide) Guanylyl cyclase C (GC-C) is an enzyme that participates in the regulation of secretion in the intestines. When activated by endogenous hormones: guanylin (GN) and uroguanylin (UGN), GC-C catalyzes the synthesis of intracellular secondary messenger, cyclic guanosine monophosphate (cGMP). Increase in cGMP level leads to the phosphorylation of the cystic fibrosis transmembrane conductance regulator ion channel and as a consequence, Cl and HCO 3 are secreted into the intestinal lumen and they are followed by water [6]. Linaclotide is a synthetic analog of GN and UGN that has been approved for IBS-C and CIC therapy in 2012. Linaclotide evokes prosecretory effect in the intestines and also possesses antinociceptive activity. It was assessed that linaclotide reduced hyperalgesia in colorectal distension model (no effect was observed in GC-C knockout mice) [7]. Rao et al. [8] and Chey et al. [9] conducted two phase III RCTs on linaclotide in IBS-C. In the study of Rao et al. [8] there were 800 patients enrolled and 50.1% of linaclotide (290 μg, once a day)

Chapter 10 Irritable bowel syndrome: Current therapies and future perspectives

treated patients vs 37.5% (placebo) have met the primary FDA endpoint. In the second study [9], it was reported that the alleviation of abdominal pain was noted in 48.9% (linaclotide) an 34.5% (placebo) patients. The improvement of bowel movements was observed in 47.6% of linaclotide-treated patients (vs 22.6% patients in placebo group). Both studies indicate the improvement in all secondary end points: abdominal pain, bloating, intestinal symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining) during therapy with linaclotide. The most bothersome among adverse effects was diarrhea; it led to discontinuation in 5% of linaclotide receiving patients (0.3% in placebo group). Another agonist of GC-C and UGN analog, plecanatide, is currently accepted by FDA for CIC treatment. The efficacy of plecanatide (3 and 6 mg daily) in IBS-C has been assessed in two phase III RCTs. It was concluded that plecanatide improved IBS related symptoms in comparison with placebo [10].

Sodium-hydrogen exchanger inhibitor (tenapanor) Tenapanor is a first in class inhibitor of sodium-hydrogen exchanger (NHE3) that has been approved for the treatment of IBS-C (50 mg, twice a day) in September 2019. Tenapanor is minimally absorbed and thus acts locally in the intestines reducing sodium absorption. The increased sodium concentration in the gut results in increased secretion of fluids. Furthermore, this NHE3 inhibitor improves the function of tight junctions in the small intestine and enhances transepithelial electrical resistance [11]. In healthy volunteers tenapanor increased sodium excretion in the stool, softened the stool consistency, increased its frequency and weight in comparison with placebo group [12]. The FDA approval was based on the results of two phase III RCTs in IBS-C patients (T3MPO-1 and T3MPO-2 CTs). In both RCTs, the group receiving tenapanor met the primary endpoint in comparison to placebo (T3MPO-1: 27% vs 18.7% tenapanor vs placebo, respectively; T3MPO-2: 36.5% vs 23.7%, tenapanor vs placebo, respectively). In both CTs, the list of AEs included those related strictly to the GI tract: diarrhea, flatulence, and abdominal distention. Third phase III RCTs (T3MPO-3) was conducted to study the long-term safety profile of tenapanor. Tenapanor was well tolerated by almost 98% of patients. Less than 10% of patients reported diarrhea, but only 1.7% decided to withdraw the study due to watery stools [13].

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Diarrhea-predominant IBS (IBS-D) Inhibition of serotonergic pathway (alosetron, cilansetron, ramosetron) Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the maintaining a homeostasis in the GI tract through activation of 14 different types of serotonin receptors. The activation of 5-HT3 receptors located on intrinsic primary afferent neurons with submucosal terminals initiates the peristaltic reflex and modulates intestinal secretion [14]. It has been assessed that the 5-HT3 receptor antagonists (alosetron and cilansetron) slow colonic transit, reduce gastrocolonic reflex, rectal sensitivity and postprandial motility. Therefore, 5-HT3 receptor antagonists were evaluated as potential therapeutics for IBS-D [15]. Alosetron has been applied to clinics in 2000. However, it was withdrawn as several reports indicated rare but severe AE: ischemic colitis, severely obstructed and ruptured bowel [16]. Currently, since 2016 alosetron is approved for the treatment of severe IBS-D in women under a risk management program [17]. The application of alosetron is limited to women, as in CTs it presented higher efficacy in women than men [18]. However, that could be a result of the small numbers of men enrolled in RCTs. Nevertheless, it has been assessed that the pharmacokinetics of alosetron differs between sexes: the concentration of alosetron in women serum was higher than in men [19]. Nowadays, the biggest challenge is to develop biomarkers to assess whether patients are in group of higher risk of life threatening AE and to ensure that alosetron is used only by patients in which the benefits are greater that the risks [20]. Another potent and selective 5-HT3 receptor antagonist is ramosetron. It has been accepted as anti-emetic drug in cancer patients in 1996 in Japan [21]. Nowadays, ramosetron is approved in Japan and several Southeast Asian countries, but not by FDA as anti-emetic in patients with cancer. As assessed in a meta-analysis of 14 RCTs [15], ramosetron and cilasetron improved general IBSrelated symptoms and alleviated abdominal pain/discomfort in comparison to placebo or mebeverine. The beneficial action of ramosetron was observed in both sexes. Moreover, the metaanalysis of four RCTs on ramosetron (2.5–5.0 μg) in both sexes revealed its significant efficacy in alleviation of overall IBS symptoms in comparison to placebo. There was no report of severe adverse effects [22].

Chapter 10 Irritable bowel syndrome: Current therapies and future perspectives

Targeting opioid receptors (loperamide, eluxadoline, asimadoline) Endogenous opioid system participates in the control of the GI functions: μ- (MOP) receptors participate in the control of motility, while δ- (DOP) receptors—secretion. Loperamide, a peripherally restricted agonist of MOP receptors, is one of the most commonly used drugs to treat acute diarrhea. However, as loperamide inhibits GI transit and induces constipation instead, it cannot be applied in patients with chronic diarrhea, for example in IBS-D [23]. Eluxadoline is an opioid with mixed activity at opioid receptors: agonist at MOP and antagonist at DOP that have been accepted for the therapy of IBS in 2015. The antagonist component of eluxadoline at DOP receptors has a positive effect on the GI peristalsis, as it counteracts the inhibitory action of the MOP receptors activation [24]. The results of the two phase III RCTs (IBS-3001 [25], IBS-3002 [26]) indicate that eluxadoline (75 and 100 mg, twice a day) improves the functioning of the GI tract in the course of IBS in comparison with placebo. The efficacy of eluxadoline varied between studies from 23.9% and 28.9% (IBS3001 and IBS-3002, respectively) for the dose of 75 mg and 25.1–29.6% in the eluxadoline 100 mg group in comparison to placebo groups (16.2–17.1%). Up to 8.6% of patients receiving eluxadoline twice a day at the dose of 100 mg suffered with constipation; 7.5% of patients reported nausea. There were also cases of pancreatitis (five patients) and abdominal pain with elevated hepatic enzymes levels (eight patients) [24]. Another opioid agent that was tested as potential IBS-D therapeutic is asimadoline, a highly selective KOP receptor agonist. The results of phase II CT on asimadoline (0.15, 0.5, and 1 mg) in IBS patients show that there was no difference in the number of months with adequate relief of IBS symptoms between treated and placebo group in patients with mean abdominal pain score of 1.5 (on a scale from 0 to 3; 0 ¼ no pain, 3 ¼ severe pain). Nevertheless, in patients with moderate to severe abdominal pain (pain score 2) there was an improvement of IBS symptoms in asimadoline-treated group (0.5 and 1 mg) in comparison with placebo. The list of AEs includes: diarrhea (up to 11.1–13.4% in asimadoline 1 mg vs 7.9% in placebo group), constipation (7.6–13.4% vs 4.6%), headache or nausea. There were not any incidences of severe AEs [27]. In 2013 Tioga Pharmaceuticals completed the phase III CT on asimadoline in IBS-D patients. However, since now the results have not been published [28].

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Targeting gut microbiota (probiotics, antibiotics) Probiotics In general, probiotics showed beneficial effect in IBS, however there was no clear evidence of superiority of one specific probiotic over others [29]. The following species appear to impact positively on host health: Bifidobacterium (B. adolescentis, B. animalis, B. bifidum, B. breve and B. longum) and Lactobacillus (L. acidophilus, L. casei, L. fermentum, L. gasseri, L. johnsonii, L. paracasei, L. plantarum, L. rhamnosus and L. salivarius) [30]. Besides probiotics, prebiotics (substrates that promote the growth of beneficial microorganisms in the intestines) and synbiotics (the combination of pre- and probiotics) are beneficial for human health. However, according to the meta-analysis by Wilson et al. [31] they do not improve IBS symptoms of the quality of life of IBS patients.

Antibiotic (rifaximin) Rifaximin is a non-systemic antibiotic with very low bioavailability that presents anti-inflammatory activity. In 2015 FDA, based on the results of three phase III RCTs (TARGET 1, TARGET 2, TARGET 3) approved Rifaximin (550 mg, three times a day for 2 weeks) for the therapy of IBS-D [32]. In TARGET 1 AND TARGET 2 studies, the greater proportion of patients receiving rifaximin than placebo reported an adequate relief of global IBS symptoms during first 4 weeks after treatment (41% vs 31% in TARGET 1; 41% vs 32% in TARGET 2). TARGET 3 clinical study was performed in order to assess the efficacy of long term and repeated treatment cycles with rifaximin [33]. Patients were treated with rifaximin 550 mg three times daily for 2 weeks, then there was an observation phase; some of them were again randomly assigned to receive rifaximin (550 mg) or placebo three times a day. It has been revealed that the number of patients who report significant improvement in IBS symptoms (decrease in abdominal pain score, decrease in a frequency of loose stools) was higher than in placebo group (38.1% vs 31.5%). AEs rates were low and similar between groups.

Future perspectives Adsorbent—AST-120 AST-120 is an intestinal adsorbent, which is administered orally and deprived of systemic action because it acts locally in the gut. It presents affinity for small molecules that are involved

Chapter 10 Irritable bowel syndrome: Current therapies and future perspectives

in the pathogenesis of IBS, including: neuroactive agents, ligands of Toll-like receptors, bacterial toxins and bile acids [34]. In the only one RCT of AST-120 in non-constipated IBS that has been conducted, AST-120 evoked a positive effect on IBS symptoms. However, the effect was seen only at week 4, not 8. Until now, there were no further studies on AST-120 in IBS [35].

Tryptophan hydroxylase-1 inhibitor—LX1031 Tryptophan 5-hydroxylase 1 (TPH1), that is expressed in enterocytes and mast cells, participates in the serotonin synthesis [36]. In phase II RCT on IBS-D patients TPH1 inhibitor, LX1031 (250 or 1000 mg four times a day) alleviated abdominal pain and improved stool consistency in comparison to placebo at week 1. There was no significant improvement at weeks 2–4 [37]. Notably, Brown et al. observed that alleviation of symptoms was associated with a decrease in 5-hydroxyindoleacetic acid (the marker of LX1031 pharmacodynamic activity) level. Therefore, it was concluded that 5-hydroxyindoleacetic acid could be used as a marker to identify the responders to therapy with TPH1 inhibitor [37].

Tachykinin receptor inhibitor—Ibodutant Tachykinins (substance P, neurokinin A, neurokinin B, neuropeptide-K and others) are neurotransmitters and neuromodulators in the central and peripheral nervous system (i.e., GI tract). Preclinical studies showed that inhibition of the tachykinin receptors, mainly tachykinins NK2 receptor may constitute a novel attractive option in IBS [38]. The clinical potency of NK2 receptor antagonist, ibodutant, as potential therapeutic for IBSD has been evaluated in several phase II and phase III RCTs. In the IRIS and IRIS-2 RCT, ibodutant (10 mg) was superior to placebo in alleviation of overall IBS-D symptoms. However, the results of phase II RCT have not been confirmed in phase III trials on female IBS-D patients: ibodutant was not effective in alleviation of IBS-related symptoms in women (IRIS-3, IRIS-4 CTs). IRIS-05 has been withdrawn prior to enrollment. No additional information is presently available [38].

5-HT4 agonists—Tegaserod, prucalopride The activation of 5-HT4 receptors stimulates propulsive motility and increases intestinal secretion [39]. Due to this prokinetic action, a 5-HT4 agonist, tegaserod, has been accepted for the treatment of CIC. However, it has been withdrawn in 2007 from

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the market due to AEs in the cardiovascular system. However, there was no evidence of clear relationship between the usage of tegaserod and cardiovascular incidences. In 2018 tegaserod was resubmitted to the FDA to be used in population with low cardiovascular risk, as it was effective in CIC in women younger than 65 years old [40]. Prucalopride, a highly selective 5-HT4 agonist, increases GI and colonic transit in patients with constipation [41]. Prucalopride has been evaluated in patients with chronic (severe, life threating) constipation in phase III RCT. The study has been completed in 2017 but until now there were no results published [42]. Renzapride is a novel substitute of benzamide, that is an agonist of 5-HT4 receptor and antagonist at 5-HT2b and 5-HT3 receptors. It improves GI transit and could become a novel therapeutic agent in patients with constipation [43]. Renzapride was described as safe as it does not induce AEs from the CVS. In IBS-C women renzapride (4 mg four times a day) accelerated colonic transit in comparison to placebo [44]. The meta-analysis from 2014 by Mozaffari et al. [45] revealed that renzapride does not improve IBS-related symptoms in comparison to placebo.

Glucagon-like peptide 1 analog—ROSE-010 ROSE-010 is an analog of glucagon-like peptide 1 that was tested in clinical trial as a potential therapeutic for IBS [46]. The proportion of patients who received ROSE-010 (100 or 300 μg once daily, subcutaneously) and reported at least 50% reduction in abdominal pain was two-fold higher than in placebo. However, the main bothersome adverse effect was nausea; it was reported in 19% and 37% of patients (ROSE-010, 100 and 300 μg, respectively) vs 0% in placebo [46].

Muscarinic receptor type 3 antagonist—Solifenacin Solifenacin is currently applied in the therapy of overactive bladder [47]. The effect of solifenacin in IBS-D was assessed in one open label 12 weeks long clinical trial: first 0–2 weeks of observation, 3–8 weeks solifenacin (5 mg, once a day), 9–12 ramosetron (5 μg, once a day). Fukushima et al. [48] observed that the overall improvement was observed in 95% patients at week 8 (after solifenacin treatment) and 85% at the end of the study in comparison to baseline. The efficacy of solifenacin was not inferior to that of ramosetron, further placebo controlled studies are needed [48].

Chapter 10 Irritable bowel syndrome: Current therapies and future perspectives

Tyrosine derivative—Tiropramide Tiropramide is a tyrosine derivative that decreases the Ca2+ release into myocytes in the intestines and thus it abolishes smooth muscles contractions and thus evokes spasmolytic action [49]. In a randomized trial performed by Lee et al. on IBS patients, there was a reduction in abdominal pain assessed with visual analog scale in patients receiving tiropramide (100 mg, three times a day) at week 4 in comparison to baseline [50].

Bombesin receptor subtype 2 antagonist—ASP-7147 Bombesin receptors subtype 2 (BB-2) belong to the family of G protein-coupled receptors, that are highly expressed in the GI tract. These receptors participate in the regulation of secretion and motility in the GI tract: the activation of BB-2 improves GI peristalsis [51]. The blockage of BB-2 related signaling was found to be promising in the animals models of IBS. Therefore, ASP7147, a highly selective BB-2 antagonist, was evaluated in both sexes in RCT performed by Lembo et al. [52]. However, further studies are warranted.

Melatonin Melatonin is an endogenous hormone that participates in the control of day/night rhythm. However, melatonin is also involved in the regulation of GI peristalsis and visceral sensation. It has been assessed that melatonin improved IBS related symptoms in patients without affecting sleep [53, 54].

Conclusion Research of last two decades indicate that several signaling pathways are involved in the pathogenesis of IBS (i.e., opioidergic, serotoninergic, tachykininergic systems) as well as dysregulation in intestinal microbiota composition. According to that, numerous therapeutics currently available on the pharmaceutical market are proposed to IBS patients, when non-pharmacological approach is not sufficient. Unfortunately, effectiveness of these drugs, in general, it is still not satisfactory. Moreover, drug response differs between women and men. Therefore, more detailed research on new pharmacological targets, IBS biomarkers and biomarkers of drug-response are warranted.

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Acknowledgments Supported by grant from the Polish Ministry of Science and Higher Education (Diamentowy Grant Program, #0064/DIA/2017/46 to AS).

References [1] Irritable bowel syndrome—clinical evaluation of products for treatment j FDA. Available from: https://www.fda.gov/regulatory-information/searchfda-guidance-documents/irritable-bowel-syndrome-clinical-evaluationproducts-treatment. [2] Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109:S2–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 25091148. [3] McKeage K, Plosker GL, Siddiqui MAA. Lubiprostone. Drugs 2006;66(6):873–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16706562. [4] Li F, Fu T, Tong W-D, Liu B-H, Li C-X, Gao Y, et al. Lubiprostone is effective in the treatment of chronic idiopathic constipation and irritable bowel syndrome. Mayo Clin Proc 2016;91(4):456–68. Available from: http://www.ncbi. nlm.nih.gov/pubmed/27046523. [5] Drossman DA, Chey WD, Johanson JF, Fass R, Scott C, Panas R, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome—results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther 2009;29(3):329–41. Available from: http://www.ncbi.nlm. nih.gov/pubmed/19006537.  ska M, Storr M, Fichna J. Emerging treatments in neurogas[6] Jarmuz A, Zielin troenterology: perspectives of guanylyl cyclase C agonists use in functional gastrointestinal disorders and inflammatory bowel diseases. Neurogastroenterol Motil 2015;1057–68. [7] Castro J, Harrington AM, Hughes PA, Martin CM, Ge P, Shea CM, et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 30 ,50 -monophosphate. Gastroenterology 2013;145(6):1334–46. e11. Available from: http://www.ncbi. nlm.nih.gov/pubmed/23958540. [8] Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012;107(11):1714–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22986440. [9] Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012;107(11):1702–12. Available from: http://www.ncbi.nlm. nih.gov/pubmed/22986437. [10] Brenner DM, Fogel R, Dorn SD, Krause R, Eng P, Kirshoff R, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J Gastroenterol 2018;113(5):735–45. Available from: http://www.ncbi. nlm.nih.gov/pubmed/29545635.

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 ska M, Wasilewski A, Fichna J. Tenapanor hydrochloride for the treat[11] Zielin ment of constipation-predominant irritable bowel syndrome. Expert Opin Investig Drugs 2015;24(8):1093–9. [12] Rosenbaum DP, Yan A, Jacobs JW. Pharmacodynamics, safety, and tolerability of the NHE3 inhibitor tenapanor: two trials in healthy volunteers. Clin Drug Investig 2018;38(4):341–51. Available from: http://link.springer.com/10. 1007/s40261-017-0614-0. [13] Ardelyx showcases new data from T3MPO-3 long-term safety trial of tenapanor for IBS-C in presidential poster at ACG 2018 annual meeting. Available from: https://www.prnewswire.com/news-releases/ardelyx-showcasesnew-data-from-t3mpo-3-long-term-safety-trial-of-tenapanor-for-ibs-c-inpresidential-poster-at-acg-2018-annual-meeting-300726693.html. [14] Smith TK, Park KJ, Hennig GW. Colonic migrating motor complexes, high amplitude propagating contractions, neural reflexes and the importance of neuronal and mucosal serotonin. J Neurogastroenterol Motil 2014;20(4):423–46. http://www.ncbi.nlm.nih.gov/pubmed/25273115. [15] Andresen V, Montori VM, Keller J, West CP, Layer P, Camilleri M. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol 2008;6(5):545–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 18242143. [16] Letter regarding Lotronex from Dr. Janet Woodcock, Director, Center for Drug Evaluation and Research (12/18/2000) j FDA. Available from: https://www.fda. gov/drugs/postmarket-drug-safety-information-patients-and-providers/letterregarding-lotronex-dr-janet-woodcock-director-center-drug-evaluation-andresearch-12182000. [17] Tong K, Nicandro JP, Shringarpure R, Chuang E, Chang L. A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program. Therap Adv Gastroenterol 2013;6(5):344–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24003335. [18] Bardhan KD, Bodemar G, Geldof H, Schutz E, Heath A, Mills JG, et al. A doubleblind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2000;14(1):23–34. Available from: http://www.ncbi.nlm. nih.gov/pubmed/10632642. [19] Koch KM, Palmer JL, Noordin N, Tomlinson JJ, Baidoo C. Sex and age differences in the pharmacokinetics of alosetron. Br J Clin Pharmacol 2002;53 (3):238–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11874386. [20] Dear irritable bowel syndrome (IBS) patient (1/24/2002) j FDA. Available from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patientsand-providers/dear-irritable-bowel-syndrome-ibs-patient-1242002. [21] Rabasseda X. Ramosetron, a 5-HT3 receptor antagonist for the control of nausea and vomiting. Drugs Today (Barc) 2002;38(2):75–89. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12532186. [22] Qi Q, Zhang Y, Chen F, Zuo X, Li Y. Ramosetron for the treatment of irritable bowel syndrome with diarrhea: a systematic review and meta-analysis of randomized controlled trials. BMC Gastroenterol 2018;18(1):5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29310568.  ska M, Len  K, Banaszek M, Storr M, Fichna J. Review: the role [23] Jarmuz A, Zielin of MOP and DOP receptors in treatment of diarrheapredominant irritable bowel syndrome. Mini Rev Med Chem 2016;16(18):1462–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27494159. 

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[24] Lembo AJ, Lacy BE, Zuckerman MJ, Schey R, Dove LS, Andrae DA, et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med 2016;374(3):242–53. Available from: http://www.nejm.org/doi/10.1056/ NEJMoa1505180. [25] Efficacy, safety, and tolerability of eluxadoline in the treatment of participants with diarrhea-predominant irritable bowel syndrome (IBS-d)—study results. ClinicalTrials.gov Available from: https://clinicaltrials.gov/ct2/show/results/ NCT01553747?term¼eluxadoline&cond¼IBS&rank¼3&view¼results. [26] Efficacy, safety, and tolerability of eluxadoline in the treatment of participants with diarrhea-predominant irritable bowel syndrome (IBS-d)—study results. ClinicalTrials.gov Available from: https://clinicaltrials.gov/ct2/show/results/ NCT01553591?term¼eluxadoline&cond¼IBS&rank¼4. [27] Mangel AW, Bornstein JD, Hamm LR, Buda J, Wang J, Irish W, et al. Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome. Aliment Pharmacol Ther 2008;28(2):239–49. Available from: http://www.ncbi. nlm.nih.gov/pubmed/18466359. [28] Study of asimadoline to treat diarrhea-predominant irritable bowel syndrome (D-IBS)—tabular view. ClinicalTrials.gov Available from: https://clinicaltrials. gov/ct2/show/record/NCT01100684. [29] Ford AC, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol 2014;109(10):1547–61. Available from: http://www.ncbi.nlm. nih.gov/pubmed/25070051. [30] Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11(8):506–14. Available from: http://www.ncbi. nlm.nih.gov/pubmed/24912386. [31] Wilson B, Rossi M, Dimidi E, Whelan K. Prebiotics in irritable bowel syndrome and other functional bowel disorders in adults: a systematic review and metaanalysis of randomized controlled trials. Am J Clin Nutr 2019;109(4):1098–111. [32] FDA approves Xifaxan (rifaximin) for the treatment of IBS-D (irritable bowel syndrome with diarrhea). Available from: https://www.drugs.com/newdrugs/ fda-approves-xifaxan-rifaximin-ibs-d-irritable-bowel-syndrome-diarrhea-4218. html. [33] Lembo A, Pimentel M, Rao SS, Schoenfeld P, Cash B, Weinstock LB, et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology 2016;151 (6):1113–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27528177.  ska P, Storr M, Fichna J. The role of AST-120 and protein-bound uremic [34] Mosin toxins in irritable bowel syndrome: a therapeutic perspective. Therap Adv Gastroenterol 2015;8(5):278–84. Available from: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid¼4530433%7B&%7Dtool¼pm centrez%7B&%7Drendertype¼abstract. [35] Tack JF, Miner PB, Fischer L, Harris MS. Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome—a double-blind, placebo-controlled study. Aliment Pharmacol Ther 2011;34 (8):868–77. Available from: http://doi.wiley.com/10.1111/j.1365-2036.2011. 04818.x. [36] Camilleri M. LX-1031, a tryptophan 5-hydroxylase inhibitor that reduces 5-HT levels for the potential treatment of irritable bowel syndrome. IDrugs 2010;13 (12):921–8.

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[37] Brown PM, Drossman DA, Wood AJJ, Cline GA, Frazier KS, Jackson JI, et al. The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome. Gastroenterology 2011;141(2):507–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 21684281. [38] Szymaszkiewicz A, Malkiewicz A, Storr M, Fichna J, Zielinska M. The place of tachykinin NK2 receptor antagonists in the treatment diarrhea-predominant irritable bowel syndrome. J Physiol Pharmacol 2019;70(1):15–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31019119. [39] The serotonin signaling system: from basic understanding to drug development for functional GI disorders—ClinicalKey. Available from: https://www. clinicalkey.com/#!/content/playContent/1-s2.0-S001650850602436X? scrollTo¼%23bib241. [40] Thomas RH, Luthin DR. Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents. Pharmacother J Hum Pharmacol Drug Ther 2015;35 (6):613–30. Available from: http://doi.wiley.com/10.1002/phar.1594. [41] Bouras EP, Camilleri M, Burton DD, Thomforde G, McKinzie S, Zinsmeister AR. Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder. Gastroenterology 2001;120(2):354–60. Available from:http://www.ncbi.nlm. nih.gov/pubmed/11159875. [42] An efficacy and safety study of prucalopride in participants with chronic constipation—full text view. ClinicalTrials.gov Available from: https:// clinicaltrials.gov/ct2/show/NCT01116206?term¼prucalopride&rank¼5. [43] Meyers NL, Hickling RI. Pharmacology and metabolism of renzapride: a novel therapeutic agent for the potential treatment of irritable bowel syndrome. Drugs R D 2008;9(1):37–63. Available from:http://www.ncbi.nlm.nih.gov/ pubmed/18095752. [44] Camilleri M, McKinzie S, Fox J, Foxx-Orenstein A, Burton D, Thomforde G, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol 2004;2(10):895–904. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15476153. [45] Mozaffari S, Nikfar S, Abdollahi M. Efficacy and tolerability of renzapride in irritable bowel syndrome: a meta-analysis of randomized, controlled clinical trials including 2528 patients. Arch Med Sci 2014;10:10–8. € m PM, Hein J, Bytzer P, Bjo € rnsso € n E, Kristensen J, Schambye H. Clin[46] Hellstro ical trial: the glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome: a randomized, placebocontrolled, double-blind study. Aliment Pharmacol Ther 2009 Jan;29 (2):198–206. [47] Solifenacin LiverTox: clinical and research information on druginduced liver injury. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 31644025; 2012. [48] Fukushima Y, Suzuki H, Matsuzaki J, Kiyosue A, Hibi T. Efficacy of solifenacin on irritable bowel syndrome with diarrhea: open-label prospective pilot trial. J Neurogastroenterol Motil 2012;18(3):317–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22837880. [49] Takayanagi I, Hisayama T, Iwase M, Sakuma N, Nagai H. Pharmacological properties of tiropramide, an antispasmodic drug. Gen Pharmacol 1989;20 (3):335–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2744399. [50] Lee KN, Lee OY, Choi M-G, Sohn CI, Huh KC, Park KS, et al. Efficacy and safety of tiropramide in the treatment of patients with irritable bowel syndrome: a

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Pain in irritable bowel syndrome

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Anna Zieli nska Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract Irritable bowel syndrome (IBS) is a functional gut disorder manifesting typically in early adults. The patients report pain as the most distressing symptom, causing the greatest decrease in quality of life. Intense, recurrent, visceral pain is very common, with prevalence of even 20% in some regions of the world, affecting more women than men. It can be either relieved or exacerbated by defecation. What is more, it is challenging both to patients and healthcare providers. This chapter focuses on abdominal pain in IBS and describes current treatment possibilities. One must acknowledge that pain is the main contributor to severity in IBS. Seeking pain alleviation is the most common reason that IBS sufferers consult with their doctors.

Keywords Irritable bowel syndrome, Visceral pain, Abdominal pain, Pharmacotherapy, Pain management

List of abbreviations 5HT 5HT-3 5HT-4 b.i.d. CB2 CBT CNS FDA FODMAPs GABA GC-C

serotonin type 3 serotonin receptor type 4 serotonin receptor bis in die; twice a day cannabinoid receptor 2 cognitive behavioral therapy central nervous system U.S. Food and Drug Administration fermentable oligosaccharides, disaccharides, monosaccharides and polyols gamma-aminobutyric acid guanylate cyclase type-C

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00010-1 # 2020 Elsevier Inc. All rights reserved.

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GI IBS IBS-A IBS-C IBS-D MOR1 MRI NMDA RCT SCFAs SM SNRIs SSRIs t.i.d. TCAs TRP

gastrointestinal irritable bowel syndrome atypical irritable bowel syndrome constipation predominant irritable bowel syndrome diarrhea predominant irritable bowel syndrome μ-opioid receptor magnetic resonance imaging methyl-D-aspartate receptor randomized clinical trial short chain fatty acids self-management dual serotonin/noradrenalin reuptake inhibitors selective serotonin reuptake inhibitors ter in die; three times a day tricyclic antidepressants transient receptor potential

The clinical presentation of irritable bowel syndrome is varied and includes changes in bowel habit, bloating, altered defecation pattern with diarrhea and/or constipation and abdominal pain. The latter is the dominant syndrome experienced by the patients: three out of four IBS sufferers report frequent or continuous abdominal pain, making IBS a debilitating entity decreasing the quality of life [1–3]. IBS is an archetype of chronic gut hypersensitivity and visceral pain. The symptoms do not have an identifiable organic cause and are strongly correlated with stress and anxiety [4]. No specific mechanism has been established to explain all causes of IBS symptoms-pain sensation in IBS is multifactorial [5]. Therefore IBS treatment is a great challenge for physicians taking into consideration the complexity and diversity of its presentation. Intense, recurrent, visceral pain is very common, affecting more women than men, and more the young than the adults [4, 6]. Importantly, and unlike chronic pain in general, IBS pain is often associated with alterations in bowel habit (diarrhea, constipation, or both). It can be either relieved or exacerbated by defecation and may be worsened or relieved postprandially [5, 7]. The main reason IBS patients visit a physician is for relief of abdominal pain [8, 9]. All treatment for IBS begins with education to understand the nature of the disease, including why and how symptoms arise. IBS is a brain-gut disorder, and mild IBS can be managed at the level of gastrointestinal (GI) tract. More severe, chronic pain needs to be treated at the level of the central nervous system (CNS). The main activity of the newly developed medications is at the level of the gut and it addresses the bowel irregularity of IBS. Yet, the analgesic

Chapter 11 Pain in irritable bowel syndrome

effect is limited. In this chapter we present IBS-related abdominal pain treatment methods, available to date on the market.

Non-pharmacological treatment Psycho- and hypnotherapy in IBS Psychological problems, such as anxiety and depression are very common in IBS patients, with anxiety disorders being the most prevalent co-morbidity [10]. Fifty to seventy percent of the patients report additional somatic and psychological symptoms. Therefore a stepped-care approach should be applied, including cognitive and interpersonal therapy based on predominant syndromes [11]. Psychosocial therapies are gaining interest-albeit modest proven efficacy, they are often employed and help patients managing visceral pain [12]. Psychological therapies, such as cognitive behavioral therapy (CBT) and psychodynamic therapy benefit the global well-being of IBS patients and are being recommended in guidelines and treatment recommendations [13, 14]. These interventions are mainly successful in patients with pain-predominant syndromes refractory to pharmacotherapy, with co-morbid psychiatric disease, with high motivation and stress triggers [13, 14]. Treatment should focus on reducing psychological distress, catastrophizing and general hyper-vigilance [11]. The best evidence is available for CBT, as it is the most extensively studied method [11, 14]. It aims at breaking the “vicious cycle” of avoidance behaviors, symptom severity and functional impairment [14]. CBT can improve IBS symptoms with medium- to large significant pooled effect sizes. What is more, it benefits quality of life and psychological co-morbid symptoms. Yet, there is no data showing superiority of this method compared with other psychological interventions [11]. In a meta-analysis of seven different CBT studies on total of 491 patients, 57% of patients with CBT reported a significant improvement of pain (or general syndromes when pain was not mentioned) in comparison to 39% patients in the placebo group [14]. CBT is not available in primary care, but it is accessible in local hospitals and healthcare systems [11]. Psycho-dynamic (interpersonal) therapy has only been validated in a small number of treatment centers, therefore the generalization of this treatment method is limited. The same applies to mindfulness therapy, that presents promising results in female IBS patients subgroup [11, 15]. The National Institute of Health and Care Excellence (NICE) advocates that IBS patients, who are unresponsive to pharmacological treatment

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after 12 months and who develop refractory IBS, should be referred to CBT, other psychological therapy (e.g., psychodynamic or mindfulness based) or to gut-directed hypnosis [11, 16]. Hypnotherapy, pioneered by the Manchester group, has a documented efficacy with long-term symptom response and reduction in health-seeking behaviors, health-care utilization and increase in quality of life [13, 14]. Improvement of pain has been observed in 65% of patients in hypnotherapy arm in comparison to 25% in the control group. The mechanism of action remains unclear, but several studies report diminished sensitivity to rectal distention [14].

Self-management Without appropriate pain self-management (SM) that targets individual, context-specific factors of pain, patients get on a long and frustrating path to learn how to self-sufficiently manage the pain. SM of IBS symptoms, especially pain, is thus a mainstay of successful treatment. Therefore, the strategies to support the daily integration of health behaviors to reduce the negative impact of the disease are essential. Several study groups have developed and tested SM programs in IBS patients, to find out that telephone- or web-based and individual or group interventions help increasing the IBS knowledge in patients [6]. In one of such studies, 8-week-long SM intervention in IBS, which was led by a nurse significantly improved symptoms at months 3 and 6, while compared to standard care. Young adults/adolescents (the group most affected by IBS) declared a high level of satisfaction with selfguided SM resources, including coping skills. Pain neuroscience education was also helpful in reducing the fear of pain, pain intensity and pain catastrophizing [4, 6].

Education Informative, multidisciplinary educational programs are beneficial to IBS patients, especially in comparison to written information [14, 17]. In a randomized study, sessions of 2 h, conducted five times a week in small groups, led by a therapist and a gastroenterologist proved to decrease overall symptom severity, improve IBS-related quality of life and several psychological factors (depression included), compared to a waiting-list control group. What is important, the results persisted at 3-month control visit [17].

Chapter 11 Pain in irritable bowel syndrome

Patient-doctor relationship Properly established diagnosis is of course an essential step in a proper IBS therapy. Physician’s attitude is of great importance, as well as ensuring the patient that IBS is an established entity. The patient shall be provided with a logical and comprehensible disease model, to avoid possible misconceptions. Positive communication between a patient and a doctor helps reducing the number of return visits, improves long-term outcome and helps relieve the burden on health system [14].

Dietary modifications Although IgE-mediated food allergies in IBS patients are uncommon, many find a relation between their functional abdominal symptoms and specific foods. Most adverse reactions are due to non-immunological food-intolerance [14]. One study focused on gluten-free dieting patients. In all of 34 IBS probands celiac disease was excluded, yet all of them experienced an improvement of abdominal pain with a gluten-free diet prior to the study. During the study the diet was continued. Patient receiving gluten-free supplements reported notably less abdominal pain, bloating, tiredness, satisfaction with overall well-being and stool pattern [14, 18].

FODMAP-diet FODMAPs are fermentable, short-chained carbohydrates that include fructo-oligosaccharides, galacto-oligosaccharides, disaccharides (lactose), monosaccharides (fructose) and polyols (sorbitol) [10]. They are poorly absorbed in the small intestine and can be fermented in the colon. Digestion of these products results in bloating, gas production, diarrhea, constipation and pain [19]. A low FODMAP diet proved effective in preventing abdominal pain bloating and stool pattern improvement [14]. Its mechanisms and efficacy have been well reviewed in many randomized controlled trials and randomized comparative trials with response rate as high as 50–80% [2]. In a study on 82 IBS patients, low FODMAP diet has been found to be superior to conventional dietary advise (reduction in alcohol, caffeine; adjusting fiber intake, regular ingestion) in reducing abdominal pain (85% vs 61% of patients experiencing improvement) [20]. In another single-blind, controlled cross-over study, comprising 30 IBS patients, abdominal pain was notably lower in low-FODMAP group vs regular diet [21].

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Studies with the use of magnetic resonance imaging (MRI), breath testing and ileostomy models helped understand FODMAP diet’s results on GI tract. For example, high doses of fructose or mannitol result in increased luminal water in small intestine, whereas high oligosaccharides doses increase colonic gas production as a result of bacterial fermentation [2, 22]. To sum up, high doses of FODMAPs induce abdominal symptoms, such as pain, bloating and diarrhea because of increased colonic gas and intestinal water. Yet not all IBS sufferers are susceptible to FODMAPs; visceral hypersensitivity is speculated to cause FODMAP-related symptoms, although pain thresholds and somatization are also suspected to play a role [23].

Fiber Food with high amounts of insoluble fiber, like vegetables or wheat, usually contain large amounts of FODMAPs, so they also exacerbate IBS symptoms due to their osmotic effect and fermentation. Fermented fiber causes an increased production of gas and short-chain fatty acids (SCFAs). They in turn, have an antiinflammatory effect and are an energy source for colonic cells [10, 24]. What is more, through SCFAs production luminal osmotic load is increased, water attracted and microbiome influenced to increase biomass. This way dietary fiber increases stool bulk, accelerates colonic transit time and defecation frequency [10, 14, 24]. Therefore, dietary insoluble fiber has both beneficial and harmful effect in IBS. The exact benefit of fiber in IBS is not conclusively proved. A Cochrane meta-analysis found no advantageous effect of fiber on pain or overall symptoms in IBS [25]. The effect of different fiber types and their influence on IBS symptoms have gained further interest. Dietary fiber, both synthetic (methylocellulose) and natural (psyllium) have randomized, controlled data describing global syndrome relief, but with no superiority over placebo arm [26]. In subgroup analysis only psyllium (isphagula), soluble fiber, is effective in reducing IBS symptoms, in contrast to bran, an insoluble type of fiber [14]. In other large study of 3-month duration bran, psyllium and rice-flower (as placebo) were compared. Psyllium was superior to placebo in abdominal pain and discomfort relief at 1 and 2, but not at 3 months. Bran in contrary brought improvement only at 3-month point [8, 27].

Chapter 11 Pain in irritable bowel syndrome

Probiotics In recent years use of probiotics in IBS has become a matter of much attention. There is a number of mechanisms probiotics have been hypothesized to work through: visceral hypersensitivity, GI motility, intestinal permeability, reinforcement of the mucosal barrier, intestinal immune function (reversal of the imbalance between pro- and anti-inflammatory cytokines) and increased mass of beneficial microbiota [2, 14, 28]. Results concerning this type of IBS treatment are conflicting: some published studies promote a notion that probiotics, as a class, relieve abdominal pain [8]. Other studies describe modest benefit of probiotics in IBS [2]. Probiotic comparison is difficult due to different study designs (size of the study, its duration, probiotic dose and strains: single or mixed) [4]. A large meta-analysis of 19 RCTs, comprising 1650 patients, described an improvement of abdominal pain and global IBS symptoms [29]. When comparing two strains of bacteria, Bifidobacterium infantis proved more effective in abdominal pain reduction than Lactobacillus salivarius [30]. Both strains, as well as other commensal microorganisms, are regarded as safe [4]. In another systematic review, the group focused only on Bifidobacteria and their efficacy on abdominal pain. Eight RCTs, involving a total of 1045 patients were included, with duration of the study between 2 and 8 weeks, and total Bifidobacteria from 106 to 1011 colony forming units. Fifty percent of those studies found a significant improvement in abdominal pain in patients with bacterial supplementation compared to placebo; 38% found no improvement and 12% a significant dose-response effect of improvement. None of those studies described adverse effects or increase of pain. Many reviews describe studies on composite probiotic mixtures containing Lactobacillus, Propionibacterium and Bifidobacterium what hampers, however, the assessment of particular strains in IBS symptoms relief [31]. More data come from studies on animals. There, probiotics proved to have the ability to modulate visceral sensitivity and enhance intestinal barrier and immunity [4]. Lactobacillus paracasei, for example, prevented colonic mucosa from alternations in gut microbiota, inflammatory tone, enhanced visceral sensitivity and substance P expression induced by treatment with a nonabsorbable antibiotic [32]. Oral treatment with Lactobacillus acidophilus NCFM caused a decrease in normal visceral perception and consequently chronic colonic hypersensitivity, connected with an enhanced expression of μ-opioid (MOR1) and cannabinoid receptors (CB2) in intestinal epithelial cells [33]. Treatment with

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Lactobacillus reuteri (live killed or conditioned) prevents from pain response to rectal distention [34].

Red pepper-capsaicin Analgesic therapy that aims at transient receptor potential (TRP) acts directly on the “roots” of pain, making it a very promising target. A use of red pepper was postulated as a possible therapeutic approach in IBS patients, since capsaicin in red peppers is a potent TRPV1 agonist. After multiple administrations capsaicin desensitizes the TRPV1 receptor causing stable improvement or complete receding of pain sensation after just a short period of sensitization [4, 35]. While administered to IBS-D patients for 6 weeks, with meals, red pepper powder has only obtained an improvement of gastricrelated symptoms, but no effect on IBS symptoms, including pain. This was because red pepper capsaicin is absorbed almost entirely in the small intestine [35]. For that reason in the next controlled double-blind study of 6-week duration, IBS patients were given an enteric-coated red pepper powder capsule, releasing its content only in the distal ileum and colon. This way, after 6 weeks, a noteworthy improvement in pain score was reached. Red pepper is considered as a safe agent by the U.S. Food and Drug Administration (FDA) [35].

Peppermint oil Peppermint oil is an antispasmodic agent due to its ability to block the calcium channels and it constitutes the first-line therapy for abdominal pain in IBS. It also improves overall symptoms and is considered safe [8, 14, 36]. In a large RCT, performed with 101 patients in secondary care, 79% of patients treated with peppermint oil reported pain alleviation (56% pain-free), while in placebo arm only 43% patients declared pain mitigation (8% pain-free) [37]. Abdominal pain alleviation was also reported in a metaanalysis of five studies, comprising of 375 patients. Fifty-seven percent of patients experienced pain alleviation vs 22% of patients treated with placebo at 2–8 weeks [14]. In all the above mentioned studies, peppermint oil capsules were enteric-coated [14, 36, 37]. Peppermint oil is also attractive because—as red pepper—it possesses an ability to desensitize TRPV1 with low prevalence of side effects [38].

Chapter 11 Pain in irritable bowel syndrome

Herbal supplements There are not many well designed RCTs focusing on herbal remedies. They present however a rather promising intervention. In a double-blind RCT of 208 patients with all types of IBS iberogast, a mixture of nine plant extracts was studied. After 4 weeks of treatment patients reported improvement in abdominal pain and quality of life. The mechanism of action remains unclear, but seems to be connected with 5-HT, opioid and acetylocholine receptors in GI tract [39]. Since a number of patients uses herbs or herbal supplements, this field should be explored further.

Pharmacological treatment Antidepressants This class of pharmaceutics is very often prescribed to IBS patients suffering from pain resistant to non-pharmacological or peripherally acting treatment. One in about eight IBS patients will be prescribed antidepressants at some point of the therapy [14]. Lower doses are especially advantageous in patients with severe, refractory abdominal pain without depression. They modulate central pain via modulation of ascending visceral sensory afferents and central transmission, have peripheral analgesic effect via alternations of histaminergic and/or cholinergic transmission within the GI tract, improve the quality of sleep and influence GI motility [11, 14, 40]. Three classes are used in IBS therapy: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and dual serotonin/noradrenalin reuptake inhibitors (SNRIs). A Cochrane meta-analysis described superiority of antidepressants over placebo in general well-being and abdominal pain. In subgroup analysis TCAs, but not SSRIs were modestly superior to placebo in abdominal pain relief [25]. Another meta-analysis of 13 RCTs, on total of 789 patients also reported efficacy of TCAs and SSRIs in relief of persisting IBS-related symptoms: the proportion of persisting symptoms in antidepressants arm was lower than in placebo arm (42% vs 65%) [41]. Both, TCAs and SSRIs are recommended in moderate to severe IBS cases refractory to antispasmodics and dietary alternations [11].

TCAs TCAs seem to be preferred antidepressant class in patients with IBS-D, with pain refractory to antispasmodics as the main symptom. They act as serotonin-noradrenaline reuptake

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inhibitors and present antagonistic/agonistic effect at several serotonin receptors, NMDA receptors and sigma receptors [1]. This class causes many side effects due to anticholinergic and antihistaminic actions: drowsiness, xerostomia, hypotension, palpitations, weight gain, constipation, dry mouth, fatigue [11, 16]. One should begin the therapy with caution, at low dosages with a slow dose increase until the effective or maximal dose is reached (e.g., amitriptyline 10 mg at bedtime until 25–50 mg)—this helps avoiding or diminishing unfavorable side effects [13, 42]. Amitriptyline was found to improve overall symptoms and abdominal pain in two trials performed on patients with all IBS subtypes, and to improve the pain, but only in the isolated areas, in one study on adolescent population [8]. Doxepin not only was found to relieve the abdominal pain, but also to improve incomplete evacuations and overall symptoms in one study [8, 43]. Desipramine improved pain in a study with a crossover design, and overall symptoms, frequency and pain in other study with a parallel design [44]. The differences in the efficacy of TCAs may be a cause of the differences in the serotonin and noradrenaline receptor selectivity.

SSRIs This class has much more limited pharmacological target than TCAs [42]. Consequently, adverse effects of this class include: nausea, weight gain, agitation, sleeplessness. Citalopram has an effect on colonic tone and sensitivity [13]. However, outcomes from clinical trials with citalopram are inconsistent: some of them show improvement of IBS symptoms, while others report no significant changes in IBS symptoms [42]. In a small, crossover trial of short duration, citalopram improved overall symptoms, including abdominal pain [8]. In a larger study of parallel design and longer duration no improvement was found in overall symptoms, frequency or abdominal pain [45]. Paroxetine has anticholinergic action, that can be beneficial to IBS-D patients. In one of the studies with paroxetine it was reported not to improve abdominal pain, but overall symptoms [13]. In another trial of 12-week duration, paroxetine helped ameliorate the overall well-being, but not IBS-symptoms [46]. Fluoxetine also has conflicting study results. One, performed on all IBS subtypes, described no improvement in overall symptoms or abdominal pain [47]. In another, 12-week study, it significantly mitigated pain perception, improved stool consistency and bloating [48]. Additional, large studies are essential to verify the efficacy of SSRIs in IBS symptoms. As in TCAs, the differences in action between the drugs are caused by the differences in receptor selectivity.

Chapter 11 Pain in irritable bowel syndrome

SNRIs Data on this class remains very limited. They are centrally acting agents, with greater pain suppression possibilities than SSRIs [13]. In one small-label study duloxetine was reported to decrease the abdominal pain and increase the quality of life [49]. Venlafaxine presented peripheral effects, including colonic relaxation, however in healthy volunteers [50]. Bigger RCTs are needed to confirm the efficacy of this class in IBS treatment. The adverse effects include: insomnia, agitation and nausea [42]. SSRIs and SNRIs should be prescribed to IBS patients with co-morbid depression, as they only present a moderate efficacy in IBS symptoms alleviation, but benefit significantly affective disorders.

Pregabalin and gabapentin Originally they have been designed as GABA analogues, but were found not to have a binding affinity to GABA receptors. They are used in neuropathic pain in diabetes, fibromyalgia, post herpetic neuralgia, and have been recently proposed for IBS-treatment. They relieve the pain through binding with α2δ1 auxiliary subunit of voltage gated calcium channels [42]. Small scale studies supported the use of those two drugs in IBS symptoms improvement: abdominal pain urgency and bloating [51]. A well-designed, exploratory study reported that pregabalin mitigated abdominal pain and urgency in IBS patients with non-severe symptoms [52]. Adverse effects of those therapeutics are drowsiness and dizziness. Again, the benefits of gabapentin and pregabalin in IBS treatment need to be explored further.

Benzodiazepines They are often used in IBS patients, when an affective co-morbidity is present. They enhance GABA-A receptor function-as a result they inhibit neural activity CNS. A couple of studies analyzed the use of benzodiazepines in IBS management, but none of them presented satisfactory antinociceptive effect. Therefore, they should only be considered in patients with co-morbid anxiety [42].

Antibiotics Rifaximin, a synthetic derivative of rifamycin acting locally in GI tract, is a broad-spectrum, poorly absorbed antibiotic, with strong clinical evidence emerging in IBS treatment [4, 14]. In two II phase trails, that included a total of 1258 IBS patients without

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constipation, patients were treated with 550 mg t.i.d. for 2 weeks and later followed up for 10 weeks. Significantly more patients reported abdominal pain mitigation in rifaximin arm in comparison to placebo (44% vs 35%) [53]. In a phase III double-blind, placebocontrolled study, a 2 week treatment resulted in improvement of bloating, abdominal pain and stool consistency and had a response to the therapy during the first 4 weeks after completion of the treatment. In a phase IV trial, the previous data was confirmed. What is more, IBS symptoms improvement was reported for 3 months after 2-week treatment with rifaximin [4]. So far, no antimicrobial resistance or Clostridium difficile infections have been reported [14].

Antispasmodics Colonic smooth muscle contractions can be partially responsible for functional abdominal pain in IBS, so antispasmodic drugs remain the first line therapy [1, 11, 14]. Antispasmodics include various classes: smooth muscle relaxants (mebeverine, trimebutine), calcium channel blockers (otilonium, pinaverium) and anticholinergic agents (hyoscine, butylscopolamine) [1]. Their way of action is through their ability to antagonize the binding of acetylcholine to the muscarinic receptor at the neuromuscular junction. As a consequence, smooth muscles relax. Because of their strong inhibition of intraluminal fluid secretion, the adverse effects of antispasmodics include constipation [14]. As a result, those drugs should be used in IBS-D patients, preferably 20 min preprandially, to ease the postprandial symptoms. A Cochrane meta-analysis of 13 RCTs comprising 1392 IBS patients reported improvement in abdominal pain in IBS patients, however only pinaverum and trimebutine reached statistical significance in pain relief. Scopolamine, otilonium, mebeverine, pirenzepine and alverine reached no significant benefit [25]. A meta-analysis of the use of 12 different antispasmodics, comprising 1778 IBS patients, the relative risk of persistent symptoms was 0.68 compared to placebo, with otilonium and hyoscine being the most efficacious [1]. In another high-quality, multi-center RCT performed during 15 weeks on 356 patients, otilonium was found to reduce frequency, abdominal bloating, but not severity of abdominal pain in IBS patients [54]. What is more, it has been suggested that the improvement can persist after the treatment discontinuation [1]. During a 10 week follow-up, after treatment withdrawal, otilonium protected from symptom release with significantly greater relapse-free probability compared to placebo [21]. In a recent meta-analysis otilonium and alverine produced significant global improvement [55].

Chapter 11 Pain in irritable bowel syndrome

Laxatives In IBS-C patients the most essential part of successful pain treatment is normalization of the stooling pattern. A new class of drugs—chloride secretagogues—has been introduced for chronic constipation treatment: they include lubiprostone (chloride channel stimulator) and linaclotide (guanylate cyclase agonist) [1, 14].

Lubiprostone This oral, minimally absorbed bicyclic fatty acid derivative of prostaglandin E1 selectively activates type 2 chloride channel in the apical membrane of the intestinal epithelial cells. As a result, it stimulates chloride secretion with passive secretion of sodium and water, inducing laxation and peristalsis [10, 11]. Its effect is restricted to the GI tract—it metabolizes rapidly within the lumen [42]. It has been approved by the FDA in 2006 for women suffering from IBS-C [10, 14]. In a 12-week phase III clinical trial including 1171 subjects, mitigation of overall IBS-C symptoms has been reported, which has been confirmed by an extension trial conducted for 9–13 months, along with long-term safety and tolerability of lubiprostone [10, 42, 56]. Improvement of abdominal pain and discomfort scores was significantly better with lubiprostone 8 μg b.i.d. for 12 weeks [11, 56]. Japanese data supports US data—a significant improvement in abdominal pain, discomfort, bloating, severity of constipation, lumpy stool and straining has been reported in IBS-C sufferers [1]. Adverse effects of lubiprostone include: nausea, vomiting, diarrhea, flatulence, abdominal pain and headache. Yet, no evidence of abdominal pain increase has been reported [42]. Known contradiction to use this drug is mechanical GI obstruction [10].

Linaclotide Linaclotide is a minimally absorbed, pH independent 14-amino acid guanylate cyclase type-C (GC-C) agonist, and can be used in as second-line therapy after laxatives have failed in IBS-C patients and symptoms have lasted for more than 1 year [8, 10, 11]. It has a dual action: it increases intraluminal water secretion resulting in laxation, but also analgesic effect through inhibition of colonic nociceptors (by extracellular release of cGMP) resulting in mitigation of abdominal pain and bloating [11, 42]. It has been approved by the FDA in 2012 for IBS-C in adults.

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Action of linaclotide is restricted to GI tract due to its low bioavailability, fast metabolism and restricted expression of it’s target: GC-C receptors within intestinal mucosal layer [42]. In two parallel clinical trials, lasting 12 weeks, linaclotide was found superior to placebo in improving abdominal pain and spontaneous bowel movement frequency [57]. Both safety and effectiveness were established [10]. The most common adverse effects reported in clinical trials were: flatulence, abdominal distention, abdominal pain and diarrhea. Diarrhea is experienced with high dosages (290 μg), it decreases however with continuation of the treatment and administration with meals [10, 13]. Known contradiction to linaclotide use is mechanical GI obstruction [58].

Tegaserod It is a type 4 serotonin receptor (5HT-4) agonist stimulating abdominal motility. It was a first drug to relieve abdominal discomfort, bloating and constipation for IBS-female patients. It was first approved by the FDA in 2002 and withdrawn in 2007 due to possible cardiovascular adverse effects [59]. However, in 29 placebo controlled clinical studies, including 18,654 subjects screened for ischemic events, no significant differences were found compared to placebo. Tegaserod provided consistent, significant, rapid relief of overall IBS symptoms and relief of individual symptoms such as abdominal pain. Therefore, tegaserod was reintroduced to treatment for IBS female patients under 65 years of age [10].

Antidiarrheals Serotonin is a neurotransmitter in the CNS, but it is mostly present in enterochromaffin cells in the GI tract—in more than 90%. It plays a vital role in neurotransmission and GI motility. Its release in the intestine causes muscle relaxation or contraction, GI transit and luminal secretion [14, 42]. Serotonin receptors 5HT-3 and 5HT-4 are located in the mucosa of small and large intestine and on epithelial cells of distal colon. Stimulation of 5HT-3 causes muscle contraction, while 5HT-4-relaxation [42]. 5HT-3 antagonism decelerates fecal discharge through large intestine, increases water absorption in the intestinal wall and controls the moisture content and volume of the remaining waste particles. 5HT-3 antagonists, agents that can slow colonic transit targeting diarrhea, are available for IBS patients.

Chapter 11 Pain in irritable bowel syndrome

Alosetron Alosetron improves bowel consistency and frequency and relieves pain in IBS-D. It was withdrawn from the market for 2 years because of the risk of acute ischemic colitis and complicated constipation, but was reintroduced for chronic, severe IBS-D in females, refractory to conventional therapy under a risk managing program [1, 13]. In a systematic review of eight RCTs, on total of 4987 patients, IBS symptoms resisted in 49% of patients in comparison to 64% of patients with placebo [60]. A meta-analysis of seven studies underlined the effect of alosetron on abdominal pain and discomfort [61]. Studies based on clinical trials reported improvement in fecal discharge pattern, reduction of urgency and abdominal pain relief.

Ramosetron It is a 5HT-3 antagonist of mostly peripheral effect. It is currently available only in Korea, Thailand and Japan for male IBSD patients. In a Korean study on 343 male subjects, an antispasmodic mebeverine and ramosetron had similar effect in abdominal-pain and discomfort relief (35% and 40% respectively) [62]. Another study on 296 male IBS-D patients also reported improvement of abdominal pain—ramosetron vs placebo (32% vs 10.1%). In a phase III study, comprising 539 patients, 46% declared adequate pain relief, compared to 33% of patients in placebo arm [63]. Ramosetron presents lower rates of constipation than alosetron and no cases of ischemic colitis have been reported. However, since the total number of studied patients is significantly lower, caution is required [14].

Ondansetron and granisetron They are less potent than alosetron and are mostly used in nausea alleviation in chemotherapy patients. Ondansetron has been found to significantly reduce pain perception by increasing rectal sensory threshold to electric stimulation. What is more, patients reported fewer daily pain attacks [64]. Granisetron significantly reduced rectal sensitivity to balloon distention in a dose dependent manner [42]. Both drugs seem to possesses potential efficacy in IBS-D. Peripherally restricted opioids also have an important role in IBS-D treatment. They can modify GI function by binding with opioid receptors on enteric circuitry and primary afferent nerve

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endings. Through opioid receptors in the GI tract motility, secretion and visceral sensation are regulated [42].

Loperamide It is the only antidiarrheal with randomized, controlled data supporting its place in IBS-D treatment [13]. It is a nonabsorbable μ-opioid receptor agonist, with low bioavailability and inability to diffuse through the blood-brain barrier, originally used in acute diarrhea [42]. One study reported improvement in abdominal pain and overall symptoms in patients treated with loperamide. Another one described abdominal pain relief, but only in IBS-A patients, with abdominal pain increase in IBS-C [8, 65]. Clinical studies also report global symptoms improvement, increased stool consistency and reduction in abdominal pain after 3–5 weeks of treatment [42]. Adverse effects include nausea, cramping and constipation, so it has to be used with caution in IBS-C patients.

Eluxadoline It is a newly approved IBS-D drug. It is an orally active μ-opioid receptor agonist and δ-opioid receptor antagonist. Its action is restricted to GI tract and it has almost no effect on CNS [4]. Different studies have proven that this mixed μ-agonist/δ-antagonist can attenuate visceral hypersensitivity without inhibiting GI motility [66]. Through action on μ-opioid receptor it slows down GI motility, decreases visceral sensation, and inhibits secretion. Through inhibition of δ-opioid receptor it acts against some μ-opioid effects, like excessive motility deceleration (mostly identified as adverse effect). Therefore eluxadoline appears very suitable in IBS therapy for decreasing abdominal pain and improving colonic transit without inducing severe constipation [4].

Centrally acting opioids They relieve the pain through CNS opioid receptors mediation. However, they cause several adverse effects due to non-specific targeting of the CNS: habituation, dependence, addiction and opioid-induced hyperalgesia or narcotic bowel syndrome; ultimately opioids worsen abdominal pain and constipation [13, 42]. Opioids are effective in acute pain alleviation, but have no use in long-term IBS treatment.

Chapter 11 Pain in irritable bowel syndrome

Non-steroidal anti-inflammatory drugs (NSAIDs): Acetaminophen, acetylsalicylic acid Those therapeutics are used in abdominal pain due to their analgesic and anti-inflammatory properties. However, there is no data coming from clinical studies or trials confirming their efficacy in IBS-related abdominal pain. What is more, continuous usage of those pharmaceutics may cause chronic constipation. Adverse effects of NSAIDs comprise: enteropathy, intestinal strictures, ulcers, colitis, rectitis and mucosal damage. Acetaminophen, when overdosed, may cause liver damage or necrosis. All in all, those drugs are not recommended for IBS pain treatment [42].

Conclusion Treatment of functional abdominal pain in IBS is a very challenging task. The treatment has to be individually tailored for every patient. Another challenge is multivariability of IBS pain pathophysiology. Multidisciplinary teams, consisting of gastroenterologists, pain specialists, psychiatrists, therapists/psychologists and dieticians should be responsible for patient’s treatment in order to provide the patients with best possible care, but also to relieve the burden from National Health Fund by decreasing the number of doctor-visits and health-seeking behaviors.

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[31] Pratt C, Campbell MD. The effect of Bifidobacterium on reducing symptomatic abdominal pain in patients with irritable bowel syndrome: a systematic review. Probiotics Antimicrob Proteins 2019. [32] Verdu´ EF, Bercik P, Verma-Gandhu M, Huang X-X, Blennerhassett P, Jackson W, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut [Internet]. 2006 [cited 2019 Dec 31]; 55(2):182–90. Available from: http://gut.bmj.com/cgi/doi/10.1136/gut.2005.066100. [33] Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med [Internet]. 2007 [cited 2018 May 21];13(1):35–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17159985. [34] Kamiya T, Wang L, Forsythe P, Goettsche G, Mao Y, Wang Y, et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut [Internet]. 2006 [cited 2019 Dec 31]; 55(2):191–6. Available from: http://gut.bmj.com/cgi/doi/10.1136/gut.2005.070987. [35] Bortolotti M. Letter: the neglected analgesic properties of red pepper in the clinical management of the irritable bowel syndrome pain. Aliment Pharmacol Ther [Internet]. 2018 [cited 2018 Mar 16];47(1):153–4. Available from: http://doi.wiley.com/10.1111/apt.14417. [36] Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio L. Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: a prospective double blind placebo-controlled randomized trial. Dig Liver Dis [Internet]. 2007 [cited 2019 Dec 31];39(6):530–6. Available from: https://linkinghub.elsevier. com/retrieve/pii/S1590865807000618. [37] Liu JH, Chen GH, Yeh HZ, Huang CK, Poon SK. Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroenterol [Internet]. 1997 [cited 2018 May 21];32(6):765–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9430014. [38] Beckers AB, Weerts ZZRM, Helyes Z, Masclee AAM, Keszthelyi D. Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome. Aliment Pharmacol Ther [Internet]. 2017 [cited 2018 Mar 16];46(10):938–52. Available from: http://doi.wiley.com/10.1111/ apt.14294. [39] Simmen U, Kelber O, Okpanyi SN, Jaeggi R, Bueter B, Weiser D. Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors. Phytomedicine [Internet]. 2006 [cited 2019 Dec 31]; 13 (Suppl. 5):51–5. Available from: https://linkinghub.elsevier.com/retrieve/ pii/S0944711306000717. [40] Clouse RE, Lustman PJ. Use of psychopharmacological agents for functional gastrointestinal disorders. Gut [Internet]. 2005 [cited 2019 Dec 30]; 54(9):1332–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/160 99800. [41] Ford AC, Talley NJ, Schoenfeld PS, Quigley EMM, Moayyedi P. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut [Internet]. 2009 [cited 2019 Dec 30]; 58(3):367–78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 19001059. [42] Chen L, Ilham SJ, Feng B. Pharmacological approach for managing pain in irritable bowel syndrome: a review article. Anesthesiol Pain Med [Internet]. 2017 [cited 2018 May 21];7(2):e42747. Available from: http://www.ncbi.nlm. nih.gov/pubmed/28824858. [43] Wang W, Qian J, Pan G. Treatment of refractory irritable bowel syndrome with subclinical dosage of antidepressants. Zhongguo Yi Xue Ke Xue Yuan Xue Bao [Internet]. 2003 [cited 2019 Dec 31];25(1):74–8. Available from: http://www. ncbi.nlm.nih.gov/pubmed/12905614.

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[44] Greenbaum DS, Mayle JE, Vanegeren LE, Jerome JA, Mayor JW, Greenbaum RB, et al. Effects of desipramine on irritable bowel syndrome compared with atropine and placebo. Dig Dis Sci [Internet]. 1987 [cited 2019 Dec 31];32(3):257–66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3545719. [45] Talley NJ, Kellow JE, Boyce P, Tennant C, Huskic S, Jones M. Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial. Dig Dis Sci [Internet]. 2008 [cited 2019 Dec 31];53(1):108–15. Available from: http://link.springer. com/10.1007/s10620-007-9830-4. [46] Tabas G, Beaves M, Wang J, Friday P, Mardini H, Arnold G. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol [Internet]. 2004 [cited 2019 Dec 31];99(5):914–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 15128360. [47] Kuiken SD, Tytgat GNJ, Boeckxstaens GEE, et al. Clin Gastroenterol Hepatol [Internet]. 2003 [cited 2019 Dec 31];1(3):acgh50032. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/15017494. [48] Vahedi H, Merat S, Rashidioon A, Ghoddoosi A, Malekzadeh R. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther [Internet]. 2005 [cited 2019 Dec 31];22(5):381–5. Available from: http:// doi.wiley.com/10.1111/j.1365-2036.2005.02566.x. [49] Brennan BP, Fogarty KV, Roberts JL, Reynolds KA, Pope HG, Hudson JI. Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study. Hum Psychopharmacol Clin Exp [Internet]. 2009 [cited 2019 Dec 30];24(5): 423–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19548294. [50] Grover M, Camilleri M. Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases. J Gastroenterol [Internet]. 2013 [cited 2019 Dec 31];48(2):177–81. Available from: http://link.springer.com/10.1007/s00535-012-0726-5. [51] Lee KJ, Kim JH, Cho SW. Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther [Internet]. 2005 [cited 2019 Dec 31];22(10):981–8. Available from: http://doi.wiley.com/10.1111/j.1365-2036. 2005.02685.x. [52] Houghton LA, Fell C, Whorwell PJ, Jones I, Sudworth DP, Gale JD. Effect of a second-generation alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome. Gut [Internet]. 2007 [cited 2019 Dec 31];56(9):1218–25. Available from: http://gut.bmj.com/cgi/ doi/10.1136/gut.2006.110858. [53] Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A doubleblind, randomized, placebo-controlled study. Am J Gastroenterol [Internet]. 2003 [cited 2019 Dec 31];98(2):412–9. Available from: http://www.nature. com/doifinder/10.1111/j.1572-0241.2003.07234.x. [54] Clav e P, Acalovschi M, Triantafillidis JK, Uspensky YP, Kalayci C, Shee V, et al. Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome. Aliment Pharmacol Ther [Internet]. 2011 [cited 2019 Dec 31];34(4):432–42. Available from: http://doi.wiley.com/10.1111/j.1365-2036. 2011.04730.x. [55] Martı´nez-Va´zquez MA, Va´zquez-Elizondo G, Gonza´lez-Gonza´lez JA, rrez-Udave R, Maldonado-Garza HJ, Bosques-Padilla FJ. Effect of antiGutie spasmodic agents, alone or in combination, in the treatment of irritable bowel syndrome: systematic review and meta-analysis. Rev Gastroenterol Mexico

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Non-pharmacological approach in irritable bowel syndrome therapy

12

Mikołaj S´wierczy nski and Agata Szymaszkiewicz Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract Irritable bowel syndrome (IBS) is a heterogenous functional condition of the gastrointestinal (GI) tract, which significantly decreases quality of life. The Rome IV criteria classify IBS into four subtypes—with constipation, diarrhea, mixed and unsubtyped IBS. Since its pathophysiology is still not fully understood, the first line treatment should involve the non-pharmacological interventions which are free from adverse effects. The group of most important interventions includes: diet (especially low-FODMAP and classical dietary strategies such as increased fiber intake), physical activity, fecal microbiome transplantation and psychological treatment such as cognitive behavioral therapy, gut-directed hypnosis or psychodynamic interpersonal therapy. This chapter describes in brief each of these main directions in non-pharmacological treatment of IBS.

Keywords Diet, Fecal microbiota transplantation, Irritable bowel syndrome, Physical activity, Psychological treatment

List of abbreviations ANS BDA CBT FMT FODMAP GDH GI IBS Ig

autonomic nervous system British Dietetic Association cognitive behavioral therapy fecal microbiota transplantation fermentable oligo-, di-, monosaccharides and polyols gut-directed hypnosis gastrointestinal irritable bowel syndrome immunoglobulin

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00014-9 # 2020 Elsevier Inc. All rights reserved.

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IL MC-CBT NICE QoL S-CBT TRPV1

interleukin minimal contact cognitive behavioral therapy The National Institute for Health and Care Excellence quality of life standard cognitive behavioral therapy transient receptor potential vanilloid type 1

Irritable bowel syndrome (IBS) is a functional condition of the gastrointestinal (GI) tract, classified on the basis of Rome Criteria IV into four subtypes: with constipation, diarrhea, mixed and unsubtyped [1]. IBS decreases the quality of life (QoL) since its manifestations comprehensively affect patients’ daily activities (e.g., ability to work and social life). Using the Euroqol-5 Dimensions questionnaire, which takes into account possible quality of life outcomes, it was evidenced that IBS patients would be ready to choose 10–15 years shorter life in exchange for immediate cure [2]. Despite years of research, pathophysiology of IBS remains not fully understood. Nowadays, there is an arousing concept that each subtype of IBS may have its own pathophysiology [1]. The most grounded view on IBS pathophysiology is the involvement of the brain-gut axis. For example, patients who had undergone trauma in childhood were found to be at higher risk of developing IBS [3]. This finding can be explained with stress-induced and mind-modulated higher activity of the sympathetic nervous system and its superiority over parasympathetic nervous system which directly influences the guts [4]. On the other hand, 39.7% of IBS patients with mood disorders had an onset of their manifestations after IBS occurred. Therefore it was suggested that this axis can act in both directions: from brain to gut and from gut to brain [5]. Other possible direction in IBS pathophysiology is dysregulation in immune system, i.e. imbalance in the pro- and antiinflammatory cytokines levels [6]. Moreover, it was found that IBS patients have altered gut microbiota with lower amount of anaerobic bacteria especially from the genera of Bacteroides spp., Eubacterium spp. or Faecalibacterium prausnitzii [7]. The changes in microbiota composition may also be an explanation of post-infectious IBS, which appear as a consequence of acute infectious gastroenteritis [8]. Unfortunately, for now IBS is a treatable but still incurable disease and generates high annual costs—in the United States of America estimated at about 1.6 billion dollars [9]. Because of the complexity of IBS and its multifactorial pathophysiology, the treatment should involve both pharmacological and

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non-pharmacological interventions [10]. However, commonly administered drugs act symptomatically or are insufficiently effective. Moreover, they may cause significant adverse effects, that further emphasize the necessity to maximize the effects of non-pharmacological treatment. In this chapter we discuss main directions in non-pharmacological therapy of IBS, their mechanism of action and effectiveness.

Non-pharmacological approach Complex and unclear pathophysiology of IBS requests comprehensive approach in the therapeutic strategy. Therefore, the first-line therapy should be based on lifestyle change (stress avoidance, dietary interventions) accompanied by other nonpharmacological methods like: physical activity or psychological therapy (methods are summed up on the Fig. 1).

Diet The idea of a relationship between food and IBS manifestations has arisen years ago and finds confirmation in research. n et al. [11] found that 64% of patients that parFor example, Simre ticipated in their research noticed the connection between meals and GI symptoms, i.e. they discovered that cabbage and onion were most often pointed out as aggravating triggers.

Fig. 1 Main directions in non-pharmacological treatment of IBS.

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Many authors emphasize the co-existence of IBS and food allergy or food hypersensitivity: over 80% of IBS patients report that their symptoms (i.e., abdominal pain or diarrhea) are related to meals [12, 13]. Most often patients attribute triggered symptoms to the consumption of products like wheat, milk, tomato or onion [14]. Interestingly, in the colonic biopsies of IBS patients it was found that intestinal mucosa is slightly inflamed with increased number of mast cells, eosinophils and lymphocytes [15]. Moreover, the examination of stool revealed the increased levels of immune-related proteins like immunoglobulin E (IgE) or tryptase (a marker of mast cells activation). Supporting this hypothesis, the local IgE-dependent reaction can be triggered in colonoscopic allergen provocation test, which requires intramucosal administration of selected food antigens during colonoscopy. About ¾ of IBS patients declaring food allergy have a positive response in this test with abdominal manifestations, while no such outcomes are observed in healthy people [16]. Furthermore, there are proofs that the connection between IgE and IBS may be not only local, but also systemic. Slight, systemic, IgE-dependent inflammation (“atopy”) is responsible for a variety of atopic diseases like asthma or allergic rhinitis. Many studies concerning IBS and atopy revealed that IBS prevalence is higher in patients suffering from atopic diseases than in healthy populations. The possible explanation of this finding is that the origin of inflammation is in the guts. Moreover, there are also suggestions that this connection may be bidirectional—the atopic disease could predispose to developing IBS [14]. Finally, the food allergens can sensitize immune system through a selectively permeable intestinal barrier. This mechanism leads to IgG production, especially IgG4, the most important one in case of food hypersensitivity [13]. In research conducted by Zar et al. [17] it was found that the IBS patients had elevated foodspecific IgG4 level, especially against wheat. Immune response is not the only mechanism in which food can influence GI functions. For example, some ingredients have their own chemical activity which directly interacts with mucosa and therefore may trigger GI symptoms. Among such ingredients, caffeine, capsaicin, fat products and alcohol can be found. Caffeine activates gastric acid production and stimulates colonic motility [18], however the precise mechanism in which caffeine affects GI motility is unknown. Although caffeine was found to trigger IBS symptoms, there were no differences in coffee drinking habits between IBS patients and healthy people. Because there is no clear indication on the amount of caffeine daily in a

Chapter 12 Non-pharmacological approach in IBS therapy

diet in IBS, the amount of daily caffeine intake should be restricted to the population value of 400 mg/day [19]. Capsaicin is the main ingredient responsible for spiciness of chili peppers. Molecularly, capsaicin is an agonist of the transient receptor potential vanilloid type 1 (TRPV1) [20], whose over expression was associated with visceral hypersensitivity. Chan et al. [21] discovered that in patients with rectal hypersensitivity the expression of TRPV1 receptors was significantly higher than in control group. Moreover, it was demonstrated that the expression of TRPV1 is about 3.5-fold greater in IBS patients in comparison to healthy control [20], what is in agreement with the theory of visceral hyperalgesia as important factor in IBS pathogenesis. Bortolotti et al. [22] conducted research concerning the influence of capsaicin on GI symptoms, especially abdominal pain. The IBS patients were given capsules with 150 mg of red pepper powder containing 0.5 mg of capsaicin or placebo and capsaicin was found to effectively reduce abdominal pain after the initial exacerbation period. These results can be explained with sensitization-desensitization mechanism that includes activation of TRPV-1 receptors firstly, and then their blockage in inactive state. Several studies indicated that fatty products exacerbate IBS symptoms including bloating and nausea. The action of lipids vary depending on different parts of the GI tract—in the small bowel lipids inhibit motility while in the colon they stimulate the so-called “gastrocolonic reflex.” As in IBS patients these reactions are even stronger in comparison to healthy controls, the term “fat hypersensitivity” is sometimes used in description of IBS [13, 23]. Alcohol consumption interferes with GI homeostasis by influencing motility, absorption and permeability of the intestinal wall [18]. It was revealed that in the mouse model chronic alcohol consumption decreased stomach emptying and inhibited motility of a small intestine [24]. Despite the known effects of alcohol on GI tract the results of research concerning alcohol’s impact on IBS course are ambiguous [18]. It seems that drinking pattern has the strongest correlation between alcohol and symptoms [25]. Reding et al. [26] reported that the most clear association was found between binge drinking (defined as four or more drinks per day) and next day symptoms like diarrhea, nausea or abdominal pain. Less intense drinking had not such relation with GI manifestations. Noteworthy, the main IBS manifestations like abdominal pain or bloating can be also triggered indirectly through mechanical distension of the bowel. It may be a result of gas generation as

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a product of bacterial fermentation. Among the most “gasogenic” food contents lactose is definitely high-ranked. Moreover, the excessive fermentation is considered as potential explanation of GI symptoms in a so-called “non-celiac hypersensitivity” to wheat [13].

FODMAP The term “FODMAPs” stands for a group of carbohydrates described as “fermenable oligo-, di-, monosaccharides and polyols.” This group includes many commonly appearing compounds including fructo-oligosaccharides, galacto-oligoosaccharides, fructans, inulin, lactose, sucrose and polyols like sorbitol and mannitol which are reduced forms of glucose or mannose [27]. The examples of food products reach in respective FODMAPs are presented in Table 1. Concerning the ability of food to exacerbate GI symptoms, one of the most important features of FODMAPs is their poor absorption in the intestines. Staying inside the bowels, smaller molecules from this group exert osmotic pressure that results in water migration towards the lumen of a gut increased intestinal transit. Larger, polymeric compounds go through small intestine and undergo the fermentation process by gas-producing bacteria in the large intestine. The impact of FODMAPs on GI symptoms is not IBS-specific. The lactose intolerance is caused mainly by the lactose malabsorption. It is a common worldwide problem affecting about 10% of European population and even about 90% of Chinese population [27]. Even though the mechanism of action is the same in classic lactose intolerance and IBS; the difference in the intensity of symptoms suggests that IBS patients may have a hypersensitivity to lactose.

Table 1 FODMAPs in food products [25, 28]. FODMAPs

Example

Food products

Oligosaccharides Disaccharides Monosaccharides Polyols

Fructans (e.g., inulin) Lactose Fructose Sorbitol

Wheat, onion, garlic, nectarine, peaches Cheese, milk, yoghurts, ice creams Honey, pears, natural juices Apples, watermelons, cauliflowers, mushrooms

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Medical foods According to Simren and Tack [29], the term “medical food” is defined as “food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” The idea of medical foods stems from the assumption that specific diseases can be treated in a much safer way with the use of compounds that humanity has got accustomed to through the past centuries. Nowadays, medical foods are used in treatment of broad spectrum of diseases, i.e. osteoporosis, Alzheimer’s disease or GI diseases, including IBS or inflammatory bowel diseases [30]. Some of medical foods are briefly presented in Table 2.

Dietary advices for IBS patients There are two main diet strategies which are alternately classified as first and second line of intervention in IBS: the traditional dietary advice and low-FODMAP diet. Both recommendations are based on IBS pathophysiology and mechanisms of food interactions (described earlier). The National Institute for Health and Care Excellence (NICE) as well as the British Dietetic Association (BDA) recommend the so-called “traditional dietary advice” as first-line dietary

Table 2 Medical foods in IBS. Medical food

Description

Peppermint oil Serum derived bovine immunoglobulin/ protein isolate Glutamine Palmitoylethanolamide and polydatin

Alleviates abdominal pain, decreases urgency and bloating Interacts with microbial ligands, regulates immune responses in the gut and improves intestinal barrier Normalizes intestinal membrane permeability Reduces mast cells’ activity Alleviates abdominal pain through interaction with endocannabinoid receptors Display anti-inflammatory properties and modulate GI motility

Herbal products (e.g., Aloe vera, curcumin, fennel essential oil)

Based on Simren M, Tack J. New treatments and therapeutic targets for IBS and other functional bowel disorders. Nat Rev Gastroenterol Hepatol [Internet] 2018;15(10):589–605. https://doi.org/10.1038/s41575-018-0034-5.

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intervention in IBS [18]. This strategy favors regular eating with balanced intake of fiber in doses of 20–30 g/day. Because of the fermentable character of fiber, the final dose should be determined progressively. Moreover, the soluble version of fiber seems to be more effective than insoluble one, especially in the earliest week of this diet, since later, in the 12th week of treatment, products comprising insoluble form of fiber have positive impact on IBS symptoms. On the other hand, the consumption of certain products like alcohol, caffeine or spicy meals requires patients to take some precautions and decrease their daily intake. Finally, fat consumption should also be lowered [25]. The low-FODMAP diet is the second-line intervention in NICE and BDA guidelines, however it is also considered as first-line by other authors [18]. In fact, the efficiency of traditional and low-FODMAP therapies are similar, however the traditional one is easier to follow and therefore is recommended in the first line [31]. On the basis of randomized controlled trials it was found that low-FODMAP diet results in clinical response in 50–80% of patients in case of reducing symptoms like bloating or diarrhea [32]. The therapy consists of three phases: The FODMAP restriction, reintroduction and personalization phases. Notably, during the therapy the patient is required to have at least two appointments with professional dietician. The phases of a low-FODMAP diet are presented in Table 3.

Table 3 The phases of low-FODMAP diet on the base of Whelan et al. [31].

Phase

Duration

Appointment with dietician

Restriction

4–8 weeks

Required

Reintroduction

6–10 weeks

Required

Personalization

Long-term personalized diet

Optional

Description The aim of this phase is the reduction of FODMAP intake below the level at which they induce GI symptoms. Use of low-containing FODMAP products is recommended (not longer than for 6 weeks; risk of nutritional inadequacy and microbiota alternations) This phase allows the patients to learn which FODMAP products they can eat without triggering the symptoms. The FODMAPS reintroduction is phased with dose-controlled FODMAP challenges. All types of FODMAPS should be tested with washout periods between the challenges This stage allows to increase dietary variety and nutritional adequacy. The patients can manage themselves with the knowledge from previous phases

Chapter 12 Non-pharmacological approach in IBS therapy

Psychological interventions The legitimacy of the psychological therapy in IBS stems from the hypothesis of brain-gut axis involvement in the pathogenesis of this disease. One of the most intuitive correlations in this axis is the activating effect of stress on the autonomic nervous system (ANS). As a result, the ANS influences the enteric nervous system that controls intestinal motility. Van Tilburg et al. [33] created a model of psychological aspects of IBS pathophysiology. They found only two psychiatric variables correlated with IBS severity: • Somatization known as disorder in which patient reports unexplained symptoms • Catastrophizing which is characterized by excessively negative approach in thinking and worrying [34] The most popular among psychological interventions techniques are cognitive behavioral therapy (CBT), gut-directed hypnosis (GDH) and psychodynamic interpersonal therapy. Even though the precise mechanism of their action in IBS patients is still not fully understood, however the statistical analysis shows promising results.

Cognitive behavioral therapy The CBT is a technique with the most documented proofs of efficiency. It was found that CBT improves many IBS-related parameters, including the bowel symptoms score or the QoL. Generally, the aim of CBT is to implement the positive behaviors in patients’ lives instead of maladaptive coping strategies [34]. The whole idea is based on an assumption that patients lack specific skills which makes them prone to symptoms deterioration. In this case, the CBT is a way to gain the missing skills and to learn the patients how to manage their symptoms [35]. In fact, the CBT is not just a simple technique, but more properly—a family of techniques, which are classified into two main groups: the minimal contact CBT (MC-CBT) and standard CBT (S-CBT) [36]. The standard therapy (from 8 to 20 sessions) is based on weekly, 1 h sessions [34] and consists of six stages that overlap each other [36]: (1) education about stress and its connection to IBS, (2) self-control of IBS-related stressful events, (3) muscle relaxing techniques, (4) managing with negatively moderated thoughts, (5) editing harmful beliefs responsible for threating cognitions, (6) practicing problem solving. The second option, MC-CBT, is focused on patients’ own work with self-study materials, however they still go through the same stages as in the S-CBT. One of the MC-CBT forms is the internetdelivered CBT (ICBT). Ljotsson et al. [37] compared the ICBT with

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specially designed internet stress management protocol (ISM) in IBS patients group. The biggest differences between ICBTand ISM were: lack of direct advice on symptom managing in ICBT while the ISM was missing the elements that would encourage patients to activities despite their disease. The ICBT turned out to be more efficient: 65% of patients reporting adequate relief in a 6-month follow-up in comparison to 44% in case of ISM. Moreover, Lackner et al. [36] found that both, MC-CBT and S-CBT, are more effective than passive wait list protocol. The MC-CBT had higher efficacy than S-CBT in relieving the abdominal pain however this value of difference was not enough to make it statistically significant. In addition, the research conducted by Jang et al. [38] on patients who suffered IBS with constipation proved that CBT normalizes ANS by decreasing the sympathetic effect and increasing parasympathetic effect. Notably, this finding is important from the point of IBS pathophysiology, in which one of theories is the ANS imbalance [39].

Gut-directed hypnosis Another type of psychological intervention in IBS is the GDH. In hypnotic techniques the aim is to induce a trance in which patient is able to relax and then provide a hypnotic suggestion directed to gut, which enables the patient to reach a planned target, e.g. to alleviate abdominal pain [35]. The therapy is carried out in approximately 7 weekly sessions, 30–40 min each [34]. Gut-directed hypnosis leads to improvement in IBS-related symptoms. Interestingly, Palsson et al. noticed that GDH led to normalization of stool consistency from both states of diarrhea and constipation [40]. However, the impact on ANS was not found. Perhaps, GDH exerts its effect through decreasing the distress and somatization [40]. Furthermore, using the more objective techniques, the records of magnetic resonance imagining revealed that hypnosis normalizes the central processing of pain [41].

Psychodynamic interpersonal therapy Psychodynamic interpersonal therapy is the most empirically investigated non-behavioral technique which is used in IBS treatment [42]. The main idea of this form of therapy is to encourage the patients to explore interpersonal conflicts. The therapy is generally divided into eight sessions in 3 months: one 2-h session and seven, significantly shorter—45 min each. During session with a therapist, the patients discuss the connection between the IBS

Chapter 12 Non-pharmacological approach in IBS therapy

symptoms and features of their personalities including emotions [35, 43]. Even though the psychodynamic interpersonal therapy was not found to have advantage over continuation of patients treatment on reducing symptoms of IBS, it was significantly better in increasing health-related quality of life [44].

Physical activity While discussing non-pharmacological approach in IBS therapy, there is no possibility to not mention physical activity and their profitable impact on human organism in terms of IBS. Johannesson et al. [45] tested the impact of physical activity on a group of IBS patients. The exercised group was consulted individually with specialists twice a month within 12 weeks period. It was found that IBS symptom scores were significantly lower in IBS patients that were asked to maintain their lifestyle in comparison to control group. Other research conducted by Maleki et al. [46] showed that aerobic at low or moderate intensity also improves IBS scores. They also examined the correlations between exercises and specific cytokines levels. As expected, the physical activity decreased the level of proinflammatory agents, like interleukin1β (IL-1β), IL-6 or IL-8 and increased concentrations of antioxidant factors including superoxide dismutase or glutathione peroxidase. In fact, these findings may be the explanation of the impact of physical activity on IBS symptoms, since it is known that IBS patients have imbalance of cytokines participating in inflammation on the favor of these acting proinflammatory [46]. Moreover, the physical activity interacts with IBS by affecting gut microbiota. As it was mentioned earlier, IBS patients have altered gut microbiota, most characteristically with a decreased number of anaerobes. It was found that physical activity increases microbiome diversity and favors profitable genera of bacteria [47]. Noteworthy, physical activity was proved to have positive impact on IBS-related conditions like fibromyalgia or depression and there could have the additional, indirect impact on IBS course [45].

Fecal microbiota transplantation The fecal microbiota transplantation (FMT) is a novelty in IBS treatment. The substance of whole procedure is the insertion of fecal microbiota obtained from healthy donor to the GI tract of a patient. The most popular indication for this intervention is acute infection with Clostridium difficile, where its effectiveness

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is proved [48]. There are several administration ways used in FMT, including: oral capsules, enemas, administration via nasojejunal tube or during colonoscopy. FMT protocol may also include preparative operation like intestinal lavage or premedication with rifaximin, which is an antibiotic with proved beneficial influence on intestinal microbiota and can be used in IBS treatment independently [49]. The metanalysis published by Ianiro et al. [50] revealed some interesting data about FMT. Most importantly, FMT was not significantly more effective than placebo, in fact the percentage of positively responsive was similar in both cases with values close to the 50%. However, in the FMT there was less adverse effects than in placebo group, but this finding was also statistically insignificant. In fact, most of these adverse effects could be a result of administration procedure rather than the effect of interaction with microbes, e.g. intestinal perforation during colonoscopy or even death as a consequence of sedation [51, 52]. On the other hand, the comparison of colonoscopy with insertion of the donor’s stool was significantly more effective than this procedure with patient’s autologous stool [53, 54]. In the mentioned metanalysis, the orally administered capsules with FMT proved to be less effective than placebo. One of the most problematic issues with FMT treatment is the lack of standardization of this method. It reflects mainly the ways of FMT administration and screening of donors. To date, there is no screening protocol for donors, however Higgins et al. [55] used the higher butyrylo-CoA transferase gene level in the stool. The idea was based on a finding that the population of bacteria with this gene is lowered in IBS patients. Even though the metanalysis did not show superiority of FMT over placebo, it is still noteworthy that patients’ responsiveness was about 50%. This may fit to the psychosomatic character of IBS with significant involvement of brain-gut axis.

Conclusions Poor knowledge about irritable bowel syndrome requires further search for optimal therapeutic strategies. Taking into consideration that pharmacological treatment is linked to specific and often serious adverse effects, the non-pharmacological interventions should be regarded as particularly important and used as frequent as possible. Since they significantly pertain to patients’ life style, their effect is comprehensive and fits to the “intangible” character of IBS, which is a functional, but not organic disorder.

Chapter 12 Non-pharmacological approach in IBS therapy

Acknowledgments Supported by grant from the Polish Ministry of Science and Higher Education (Diamentowy Grant Program, #0064/DIA/2017/46 to AS). MS´ is the recipient of the grant from Medical University of Lodz “Granty UMEDu” (#564/1-00000/564-20-033).

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[14] Mansueto P, D’Alcamo A, Seidita A, Carroccio A. Food allergy in irritable bowel syndrome: the case of non-celiac wheat sensitivity. World J Gastroenterol 2015;21(23):7089–109. [15] Mansueto P, D’Alcamo A, Seidita A, Carroccio A. Food allergy in irritable bowel syndrome: the case of non-celiac wheat sensitivity. World J Gastroenterol 2015;21(23):7089–109. [16] Bischoff SC, Mayer J, Wedemeyer J, Meier PN, Zeck-Kapp G, Wedi B, et al. Colonoscopic allergen provocation (COLAP): a new diagnostic approach for gastrointestinal food allergy. Gut 1997;40(6):745–53. [Internet]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9245928. [17] Zar S, Benson MJ, Kumar D. Food-specific serum IgG4 and IgE titers to common food antigens in irritable bowel syndrome. Am J Gastroenterol 2005;100(7):1550–7. [18] McKenzie YA, Bowyer RK, Leach H, Gulia P, Horobin J, O’Sullivan NA, et al. British Dietetic Association systematic review and evidence-based practice guidelines for the dietary management of irritable bowel syndrome in adults (2016 update). J Hum Nutr Diet 2016;29(5):549–75. [19] Cozma-Petrut¸ A, Loghin F, Miere D, Dumitras¸ cu DL. Diet in irritable bowel syndrome: what to recommend, not what to forbid to patients! World J Gastroenterol 2017;23(21):3771–83. [Internet]. Available from: https:// www.ncbi.nlm.nih.gov/pubmed/28638217. [20] Akbar A, Yiangou Y, Facer P, Walters JRF, Anand P, Ghosh S. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut 2008;57(7):923–9. [21] Chan CLH, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, et al. Mechanisms of disease sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 2003;361:385–91. [22] Bortolotti M, Porta S. Effect of red pepper on symptoms of irritable bowel syndrome: preliminary study. Dig Dis Sci 2011;56(11):3288–95. [23] Serra J, Salvioli B, Azpiroz F, Malagelada J. Lipid-induced intestinal gas retention in irritable bowel syndrome. Gastroenterology 2002;123(3):700–6. [Internet]. Available from: http://www.sciencedirect.com/science/article/pii/ S0016508502001609. [24] Bagyanszki M, Krecsmarik M, De Winter BY, De Man JG, Fekete E, Pelckmans PA, et al. Chronic alcohol consumption affects gastrointestinal motility and reduces the proportion of neuronal NOS-immunoreactive myenteric neurons in the murine jejunum. Anat Rec (Hoboken) 2010;293(9): 1536–42. n M. The role of diet in irritable [25] Rej A, Aziz I, Tornblom H, Sanders DS, Simre bowel syndrome: implications for dietary advice. J Intern Med 2019;286(5): 490–502. https://doi.org/10.1111/joim.12966 [Internet]. [26] Reding KW, Cain KC, Jarrett ME, Eugenio MD, Heitkemper MM. Relationship between patterns of alcohol consumption and gastrointestinal symptoms among patients with irritable bowel syndrome. Am J Gastroenterol 2013; 108(2):270–6. [Internet]. 2013/01/08. Available from: https://www.ncbi.nlm. nih.gov/pubmed/23295280. [27] Spiller R. How do FODMAPs work? J Gastroenterol Hepatol 2017;32(S1):36–9. https://doi.org/10.1111/jgh.13694 [Internet]. [28] Gibson PR, Shepherd SJ. Evidence-based dietary management of functional gastrointestinal symptoms: the FODMAP approach. J Gastroenterol Hepatol 2010;25(2):252–8. https://doi.org/10.1111/j.1440-1746.2009.06149.x [Internet]. [29] Simren M, Tack J. New treatments and therapeutic targets for IBS and other functional bowel disorders. Nat Rev Gastroenterol Hepatol 2018;15(10): 589–605. https://doi.org/10.1038/s41575-018-0034-5 [Internet].

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[30] Ciampa BP, Reyes Ramos E, Borum M, Doman DB. The emerging therapeutic role of medical foods for gastrointestinal disorders. Gastroenterol Hepatol (N Y) 2017;13(2):104–15. [31] Whelan K, Martin LD, Staudacher HM, Lomer MCE. The low FODMAP diet in the management of irritable bowel syndrome: an evidence-based review of FODMAP restriction, reintroduction and personalisation in clinical practice. J Hum Nutr Diet 2018;31(2):239–55. [32] Staudacher HM, Whelan K. The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS. Gut 2017;66(8):1517–27. [33] van Tilburg MAL, Palsson OS, Whitehead WE. Which psychological factors exacerbate irritable bowel syndrome? Development of a comprehensive model. J Psychosom Res 2013;74(6):486–92. [34] Surdea-Blaga T, Baban A, Nedelcu L, Dumitrascu DL. Psychological interventions for irritable bowel syndrome. J Gastrointestin Liver Dis 2016;25(3): 359–66. [35] Radziwon CD, Lackner JM. Cognitive behavioral therapy for IBS: how useful, how often, and how does it work? Curr Gastroenterol Rep 2017;19(10):49. [36] Lackner JM, Jaccard J, Krasner SS, Katz LA, Gudleski GD, Holroyd K. Selfadministered cognitive behavior therapy for moderate to severe irritable bowel syndrome: clinical efficacy, tolerability, feasibility. Clin Gastroenterol Hepatol 2008;6(8):899–906. [Internet]. 2008/06/04. Available from: https:// www.ncbi.nlm.nih.gov/pubmed/18524691. [37] Ljotsson B, Hedman E, Andersson E, Hesser H, Lindfors P, Hursti T, et al. Internet-delivered exposure-based treatment vs. stress management for irritable bowel syndrome: a randomized trial. Am J Gastroenterol 2011;106(8): 1481–91. [38] Jang A, Hwang S-K, Padhye NS, Meininger JC. Effects of cognitive behavior therapy on heart rate variability in young females with constipationpredominant irritable bowel syndrome: a parallel-group trial. J Neurogastroenterol Motil 2017;23(3):435–45. [39] Fukudo S. IBS: autonomic dysregulation in IBS. Nat Rev Gastroenterol Hepatol 2013;10:569–71. [40] Palsson OS, Turner MJ, Johnson DA, Burnett CK, Whitehead WE. Hypnosis treatment for severe irritable bowel syndrome: investigation of mechanism and effects on symptoms. Dig Dis Sci 2002;47(11):2605–14. [41] National Collaborating Centre for Nursing and Supportive Care (UK). Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. NICE Clinical Guidelines; 2008 No. 61. [42] Naliboff BD, Lackner JM, Mayer EA. Psychosocial factors in the Care of Patients with functional gastrointestinal disorders [Internet]. In: Principles of clinical gastroenterology. Wiley Online Books; 2008. p. 20–37. https://doi. org/10.1002/9781444300758.ch3. [43] Hyphantis T, Guthrie E, Tomenson B, Creed F. Psychodynamic interpersonal therapy and improvement in interpersonal difficulties in people with severe irritable bowel syndrome. Pain 2009;145(1–2):196–203. https://doi.org/ 10.1016/j.pain.2009.07.005 [Internet]. [44] Creed F, Fernandes L, Guthrie E, Palmer S, Ratcliffe JOY, Read N, et al. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 2003;124(2):303–17. [45] Johannesson E, Simren M, Strid H, Bajor A, Sadik R. Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol 2011;106(5):915–22. [46] Hajizadeh Maleki B, Tartibian B, Mooren FC, FitzGerald LZ, Kruger K, Chehrazi M, et al. Low-to-moderate intensity aerobic exercise training modulates irritable bowel syndrome through antioxidative and inflammatory

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Diet in irritable bowel syndrome

13

Michał Sienkiewicz Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract The global prevalence of irritable bowel syndrome (IBS) is still increasing, particularly in highly developed countries. Currently, a wide range of studies have confirmed that conducting a proper diet can improve IBS symptoms, and also support pharmacological treatment. Available guidelines recommend proper diet and healthy lifestyle as the first-line dietary treatment in IBS. This approach is based on compliance of regular eating habits, good hydration, providing regular physical activity, and avoiding potential triggers in the case of exacerbation of the symptoms. Other effective possibilities in abating IBS symptoms include restricting foods with highly fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs). A low-FODMAP diet has been deemed as the second-line dietary approach, and should be applied under supervision of a healthcare professional (registered dietitian, gastroenterologist) if symptoms persist. Notwithstanding beneficial effects of this approach, some evaluations suggest that long-term follow-up of a low-FODMAP can cause nutritional deficiencies and potentially can decrease beneficial bacteria in the GI tract. Particular interest has also been given to other diets, probiotics and fecal microbiota transplantation, but available studies are highly fragmented, and the assessment of their effectiveness is a subject of ongoing debate.

Keywords Irritable bowel syndrome, Dietary therapy, Lifestyle, L-FODMAP, Microbiota, Probiotics

List of abbreviations BDA FMT FODMAPs GFD

British Dietetic Association fecal microbiota transplantation fermentable, oligo-, di-, monosaccharides and polyols gluten-free diet

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00013-7 # 2020 Elsevier Inc. All rights reserved.

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GI IBS IBS-C IBS-D L-FODMAP LHBT NCGS NICE PHGG QoL RCTs SCCs SCFAs TRPV1

gastrointestinal irritable bowel syndrome constipation-predominant IBS diarrhea-predominant IBS low-FODMAP diet lactose hydrogen breath test non-celiac gluten sensitivity National Institute for Health and Clinical Excellence partially hydrolyzed guar gum quality of life randomized controlled trials short-chain carbohydrates short-chain fatty acids transient receptor potential vanilloid type-1

Introduction Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder that affects approximately 9.8–12.8% of the global population [1–3]. The diagnosis is made up of review of a patient’s symptoms and medical history, estimation of prevalence of warning signs (e.g., unintentional weight loss, family history of inflammatory bowel disease or colorectal cancer, anemia), and also physical examination, and using well-established diagnostic criteria. According to recently published Rome IV criteria, IBS is classified into four subtypes: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed (IBS-M) or unspecified (IBS-U) [4]. The diagnosis of IBS should be based on the determination of recurrent abdominal pain associated with two or more of the following criteria: – related to defecation, – associated with a change in frequency of stool, – associated with a change in form (appearance) of stool. These ought to be fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis [4]. A proper diagnosis of IBS may be difficult, because symptoms can change over time, and may mimic other disorders (e.g., fructose or lactose intolerance). Furthermore, healthcare providers may not be well-versed of current knowledge and guidelines about IBS. Unfortunately, due to a lack of a precise biomarker for IBS, providers cannot surely confirm the final diagnosis [5]. The pathophysiology of IBS is complex and also not completely understood, but a number of factors can be taken into consideration, including visceral hypersensitivity, increased intestinal permeability, gut dysmotility, low-grade mucosal inflammation, disturbances of the brain-gut axis and altered microbiota [6, 7].

Chapter 13 Diet in irritable bowel syndrome

A variety of pharmacologic therapies are used to alleviate IBS symptoms, but many patients are focused on prospecting alternative paths rather than the use of medications. Moreover, a wide range of nutrients may be involved in the interplay between intestinal microbiota, and gut endocrine cells in different ways which can also trigger symptoms in the vast majority of individuals with IBS. Currently, there is no effective cure for IBS, and the clinical practice is directed to mitigate disease severity and symptomatic treatment [8, 9]. Therefore, a growing evidence refers to the crucial role of proper dietary management in IBS. Two-thirds of IBS patients initiate dietary limitations to improve symptoms [10], with up to 84% reporting food-related symptoms [10, 11]. The aim of this review is to summarize and clarify the evidence of dietary recommendations for patients with IBS.

The diet Consumption of food and nutrients affects GI motility, sensitivity, intestinal epithelial barrier function, and gut microbiota [12, 13]. Diet compounds are likewise stimulators of gut receptors, and hormones secretion, and this interrelatedness is not merely limited to the GI tract [12]. The impact of diet on IBS symptoms has been previously paired only with food hypersensitivity and food intolerance (or allergy), but now there is a dearth of quality evidence supporting a wider approach [14]. Visceral hypersensitivity to specific nutrients may be responsible for activation of the immune cells, which results in low-grade intestinal inflammation, augmented epithelial barrier permeability and disturbances of the brain-gut axis [12, 14]. Another significant aspect is luminal distension, which is caused by the ability of short-chain carbohydrates (SCCs) to enhance luminal water volume and gas production. These poorly absorbed components are also rapidly fermented in the large intestine, which results in the release of gases (e.g., methane, hydrogen, carbon dioxide). Short-chain fatty acids (SCFAs) are among other notable fermentation products which showed to increase motility, and water absorption [15, 16]. In IBS patients all the above can lead to abdominal pain, bloating, and visceral hypersensitivity [17, 18]. Overall, patients with IBS attribute their symptoms to intake of fat, dairy and wheat products, legumes, garlic, onion, cabbage, fried food, hot spices, caffeine, and carbonated or sugar beverages what makes them avoid these products [19]. Additionally, due to widespread recommendations IBS patients often attempt at eliminating fermentable, oligo-, di-, monosaccharides and polyols (FODMAPs) [19, 20]. Limiting consumption of certain foods

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promotes nutritional deficiencies [10, 19] and in consequence lower levels of calcium, magnesium, phosphorous, riboflavin, thiamine, β-carotene, retinol, and trans fatty acids are observed in IBS patients [19]. Moreover, some studies suggest that an unhealthy and irregular nutrition may affect colonic motility and trigger pro-inflammatory effects which strongly associate with IBS symptoms [21, 22]. For example, an analysis of a questionnaire in obese binge eaters found more frequent GI problems (e.g., vomiting, nausea, abdominal pain) compared to non-binge obese, and non-obese controls [23]. All the above should have implications in providing detailed nutrition guidelines by healthcare professional with expertise in dietary management (e.g., registered dietitian, gastroenterologist) to IBS patients. Moreover, some studies suggest that not only oneone appointments but also alternative pathways, e.g., education in groups are effective. Currently available recommendations in IBS dietary treatment have been established by the British Dietetic Association (BDA) and National Institute for Health and Clinical Excellence (NICE). Regarding the absence of randomized controlled studies (RCTs), these guidelines are mainly focused on clinical experience and commonly known physiological effects of nutrients in the GI tract [24]. The main points recommended by BDA and NICE are to follow a proper diet and healthy lifestyle provided by any healthcare professional with interest in IBS. The former has been deemed as the first-line approach [25, 26]. The low FODMAP (L-FODMAP) diet was stated as the second line-approach. Due to lack of substantial evidence, other specialized diets are not recommended [25, 26].

The first line therapy Even though there is currently insufficient evidence to unequivocally demonstrate that the effects of bad eating habits correlate with IBS, BDA and NICE presented their guidelines of healthy eating patterns in IBS patients [25, 26]. Primary recommendations include; regular eating habits (breakfast, lunch, and dinner), avoiding skipping meals and large portions, and likewise finding time for eating and chewing food efficiently. It also seems appropriate to monitor calorie and nutrient intake [27]. Moreover, the authors highlight the need to lower fat intake, and provide appropriate hydration. Equally important is to estimate alcohol and caffeine consumption, as well as assess the intake of dairy

Chapter 13 Diet in irritable bowel syndrome

products, and spicy food, which in the case of exacerbation of the symptoms shall be limited or withdrawn [25, 26].

Energy and macronutrients intake Diets usually differ in proportions of carbohydrates, proteins, and fat, or are related with exclusion of some nutrients. These changes may affect in many ways, e.g., gut hormones, intestinal microbiota, and homeostasis of the organism [8, 26, 28]. Currently, the most appropriate diet is based on compliance of healthy eating habits, providing appropriate energy and nutrients intake, which help maintain gut homeostasis and is responsible for the prevention of certain diseases [8, 19, 26]. Of note, in a recent analysis, Zhang et al. stated that dietary energy and macronutrients uptake are not key factors in the prevalence of IBS. The authors concomitantly pointed out that correlation between incidence of IBS and dietary intake may be biased and depend on misleading IBS diagnostic criteria [20]. Nevertheless, IBS patients often avoid eating fatty foods, associating this with alleviation of the accompanying symptoms [6, 29, 30]. However, there are still no RCTs that would clearly indicate the relationship between the amount of fat consumption and the severity of symptoms. Furthermore, polyunsaturated fatty acids and their metabolites have indicated potential beneficial effects on intestinal inflammation [31–33]. However, further investigations are needed to determine their possible supplementation in IBS patients. The current guidelines recommend that the fat supply in patients suffering from IBS should not exceed 40–50 g/24 h [34].

Fluid intake No high-quality evidence evaluating effects of fluid intake in IBS has been found. The present recommendations suggest daily intake of up to 1.5–3 L/24 h of fluids, especially water, non-caffeine and alcohol-free noncarbonated soft beverages [26]. In turn, carbonated beverages are not recommended due to worsening of the symptoms [29, 35]. It has been shown that relevant fluid intake can improve frequency and consistency of stool, and reduce the need of using laxatives in IBS-C [26].

Alcohol intake Although the effects of alcohol on GI tract are commonly connected with changes in absorption, motility, or intestinal permeability, the evidence relating with IBS is contradictory. Some findings showed that light (1 drink/day) and moderate

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(2–3 drinks/day) drinking are not associated with IBS symptoms, but binge drinking (more than 4 drinks/day) can trigger GI symptoms (e.g., abdominal pain, diarrhea). These results, due to the lack of high-quality evidence remain subject of further debate. Currently, BDA recommends for individual assessment of alcohol intake and reduction or withdrawal when required [26]. Recommended restrictions are described as no more than 2 drinks per day for men and no more than 1 drink per day for women. A standard drink equivalent is defined as 12 oz/355 g of regular beer (5%), 5 oz/148 g of wine, which is typically about 12% alcohol, and 1.5 oz/44 g of 40% alcohol [36, 37].

Caffeine intake In healthy people caffeine is associated with increase in gastric acid secretion and colonic motor functions. In susceptible individuals coffee intake can also stimulate rectosigmoid motor activity and may promote laxative effect. Some studies identified a connection of coffee and tea with IBS symptoms, especially in women [34, 36, 38]. In another study caffeine intake has been deemed as a factor which can result in a recurrence of symptoms in up to a third of individuals with IBS. Moreover, it has been confirmed that limiting caffeine intake can mitigate symptoms simultaneously in patients who suffer from IBS and reflux esophagitis [19]. Currently, there are no RCTs to prove the final conclusions. According to the BDA guidelines caffeine intake should be limited to 400 mg caffeine per day in healthy controls and 200 mg per day in pregnant women. If related with IBS symptoms, it shall be limited or withdrawn [26].

Fiber intake Dietary fiber is a wide term currently representing substances that are not broken down by enzymes in the small intestine, or remain poorly absorbed and metabolized [39]. The consumption of fiber is essential to maintain proper functioning of the GI tract [40]. The effects of fiber are different and depend on its physical and chemical properties, and its location in bowels. The current terminology and characteristics of fiber are still changing. Previously, fibers were assessed as soluble or insoluble type with recommendation to supply soluble fiber, and limiting water-insoluble form in IBS [26]. Nonetheless, this concept seems to be inadequate, because the majority of plantbased foods that are rich in fiber contain a mixture of soluble and insoluble form. Therefore, nowadays, it is more appropriate to classify fiber not only by its solubility and chemical structure,

Chapter 13 Diet in irritable bowel syndrome

but also other physico-chemical characteristics: viscosity, fermentability, gel formation, prebiotic properties, and the ability to absorb water and different substances [39, 41]. However, the bulk of hitherto research did not differentiate these features. The available data is thus inconsistent and include studies that found either no beneficial effect of fiber or showed positive results. A systematic review and meta-analysis assessing 12 RCTs (621 patients), and concerning soluble or insoluble fibers over placebo, has not demonstrated improvement on abdominal pain or significant influence on symptoms [42]. More recent meta-analysis based on 14 RCTs (906 patients) revealed benefits of intake of soluble fibers (e.g., ispaghula, psyllium) in IBS patients, especially in IBS-C. Insoluble forms, in turn, (e.g., bran) have been assessed as unusable, or which may even deteriorate the condition of disease [42]. These studies are in concordance with suggestion about efficiency and usability of soluble fibers with low rate of fermentation (e.g., ispaghula) in both IBS-C and IBS-D patients [43]. The current guidelines are not revealing optimal doses of fibers in IBS, although it is generally advised to begin with low doses (3–4 g/24 h), and gradually increase to a total dosage of 20–30 g/ 24 h [42, 44]. According to BDA, supplementation of linseeds (up to 2 tablespoons/24 h), consumed with fluid (150 mL/tablespoon) for a 3-month trial period is recommended to IBS patients, particularly in constipation-predominant subtype [26]. Studies concerning guar fiber supplementation have showed that supplementation of partially hydrolyzed guar gum (PHGG, guar fiber) can be effective for digestive health in both IBS-C and IBS-D subtype. Several reports confirmed that supplementation of 5 g/24 h PHGG can alleviate symptoms and improve the quality of life (QoL) in IBS patients [45, 46]. Overall, the linkage between fibers and IBS points out to the need for further investigations, especially RCTs.

Milk and dairy products Many patients with IBS associate their symptoms with consumption of dairy products (especially milk), mainly due to lactose intolerance [47]. The committed majority of dairy products contain lactose, which in the case of lack of specific enzyme (lactase) is transformed by gut microbiota into SCFAs and gases (e.g., methane, hydrogen), and cause side effects in the GI tract [34]. Most of the otherwise healthy people with lactase deficiency tolerate up to 20 g of lactose without negative signs [48, 49]. Certain examinations focused on lactose-free diet have confirmed an improvement in IBS symptoms [50, 51].

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However, these data were not performed with randomization, blinding, and placebo controlled groups [34, 51]. Moreover, there is no evidence that lactase supplementation can relieve the clinical symptoms of the disease. Finally, studies using the lactose hydrogen breath test (LHBT) confirmed that self-reported intolerance does not have to be always equal with diagnosis of lactose intolerance [34, 49, 51]. Therefore it may be hypothesized that other components of dairy products, such as casein (A1-β-casein) can trigger IBS symptoms [52]. Currently, patients should aim at limiting dairy and milk products only when the symptoms occur. Long-term restriction of dairy products and milk should be avoided as they usually cause nutritional deficiencies of calcium [48, 53]. It thus seems appropriate to recommend calcium intake from other calcium-rich foods or supplements in patients that cannot consume dairy products [48]. However, there is no available research evaluating the safety and effectiveness of calcium intake from these other, alternative sources.

Spicy food intake Ingestion of spicy food has been shown to elicit symptoms in patients with IBS, as well as to induce the onset of the disease [6, 11]. The major known component of chili peppers, capsaicin, accelerates GI transit via transient receptor potential vanilloid type-1 (TRPV1), hence causing sensation of burning and abdominal pain [54]. Additionally, enhanced TRPV1 expression has been correlated with visceral hypersensitivity, which occurs in IBS [55, 56]. Simultaneously, some studies suggest that chronic consumption of tangy food can decrease the IBS symptoms, like abdominal pain and discomfort [57]. In contrast, it has been noted that IBS patients from Asia, which consume 10–300  times higher doses of chili per day (2.5–8 g vs 0.05–0.5 g) than Western patients have fewer changes in bowel habits, and less abdominal pain [58]. This effect may be linked with desensitization of TRPV1 receptors. However, even if mitigation of the IBS symptoms occurred in some patients, it was correlated with earlier exacerbation of the disease in the first weeks of therapy [57]. Spicy food consumption should be individually customized, and if related with IBS symptoms, it shall be limited or withdrawn [26].

Physical activity Physical activity is an integral part of healthy lifestyle. Regarding their favorable influence on healthy subjects, systematic exercises have been confirmed to alleviate symptoms in IBS (e.g., to

Chapter 13 Diet in irritable bowel syndrome

mitigate constipation, sooth flatulence, and reduce bloating) [25, 59, 60]. It has been noted that the correlation between physical activity and improvement of psychological state may also be helpful in the treatment of IBS [25, 59]. Some findings revealed beneficial effects of increased physical exercises for the period of 12 weeks on QoL, fatigue, anxiety and depression in individuals with IBS [25, 60]. Interestingly, moderate physical activity (e.g., cycling, yoga, brisk walking) can be beneficial to IBS treatment, and particularly useful for patients who actually are not active [59–62]. In contrast, intensive and exhaustive exercise can induce or even worsen symptoms in IBS [59, 63]. Overall, making a decision about physical activity should be individually established, based on patient’s preferences and possibilities [25].

The second line approach—Low FODMAP diet When following proper diet is not effective, there is another suggested option to alleviate symptoms in IBS. According to BDA and NICE, a diet low in FODMAPs (L-FODMAP) is recommended as the second-line dietary treatment in all subtypes of IBS [25, 26]. Some authors presume that L-FODMAP can be even considered as the first-line therapy [24]. FODMAPs refer to shortchain fermentable carbohydrates (oligo-, di-, mono- saccharides and polyols) that are osmotically active and not easily absorbed, and also have the ability to trigger fermentation process in the gut, which induces luminal gas production, and can result in distension [64, 65]. FODMAPs intake can be also related to colonic hypersensitivity, dysmotility, and deterioration of the symptoms in IBS patients [18, 64]. Some findings demonstrate that FODMAPs metabolites can impact gut microbiota, and intestinal stem cells, which prompts to cells differentiation and results in abnormally heightened density of endocrine cells in the colon [8, 28]. While these cells have a crucial role in GI motility, secretion, absorption, and sensitivity, observed alternations in GI endocrine cells in susceptible individuals with IBS may be relevant factors for IBS development [8, 66]. Other trials comparing a L-FODMAP diet to baseline have revealed considerably lower levels of fecal Actinobacteria, Bifidobacterium, and Faecalibacterium prausnitzii (former Fusobacterium prausnitzii), total SCFAs, and serum levels of pro-inflammatory cytokines (IL-6, IL-8) [66]. Although a decrease in the levels of pro-inflammatory cytokines is beneficial for alleviation of IBS symptoms, further evaluations are still necessary to finally assess effects of low SCFAs levels, and the reduction of beneficial bacteria strains in IBS population.

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Table 1 Products with high and low FODMAP content [12, 67, 68]. Group of food products

High FODMAP content

Low FODMAP content

Bread and cereal products Dairy and alternatives

Sweet products, breakfast cereals, wheat/rye/ barley bread Cow’s milk and its preserves (custard, yoghurt), condensed milk, soy milk, ice cream

Fruits

Apple, pear, plum, watermelon, peach, dried fruit, canned fruit Legume (bean, lentil soybeans), some marinated/ processed meats Corn/agave syrup, glucose-fructose syrup, honey, sweeteners Asparagus, garlic, onion, brussel sprouts, cabbage, broccoli, green peas

Oats/quinoa/corn flakes/pasta, breads without wheat/rye/barley Almond/rice milk, camembert/brie cheese, butter, peanut butter, hard cheese, freelactose yoghurts Pineapple, strawberries, lemon, kiwi, orange, banana Egg, fish, tofu

Protein sources Sugars and confectionery Vegetables

Table sugar, stevia, maple/rice malt sugar, dark chocolate Corn, pumpkin, cucumber, eggplant, tomato, carrot, lettuce, potato

The products highlighted in Table 1 are divided into two groups depending on FODMAPs content [65, 69]. FODMAPs are naturally occurring in different types of food, especially vegetables and fruits, and can be divided into oligosaccharides, disaccharides (e.g., dairy products), such as fructans (e.g., onion, garlic), galacto-oligosaccharides (e.g., legumes), and monosaccharides including fructose in excess of glucose (e.g., honey), and polyols, such as sorbitol, mannitol and xylitol. The FODMAPs content in many products depends on their ripeness, and also varies from species to species. For example, banana initially has been entered to the L-FODMAP products, but further investigations have identified that unripe bananas have a lot of fructans and their intake shall be limited to 1 medium sized/per day (125 g), while ripe bananas have too high levels of fructose, and therefore can be eaten only in small portions (no more than half of 1 medium-sized banana). Additionally, less popular species of bananas, e.g., lady finger bananas have higher FODMAPs content compared to Cavendish bananas, which are the most popular [70]. The L-FODMAP diet should be implemented under the guidance of an expert (registered dietitian, gastroenterologist) and divided into three phases [24, 26, 65]. The first “elimination

Chapter 13 Diet in irritable bowel syndrome

phase” includes a strict restriction of products rich in FODMAPs for the period of 3–6 weeks; numerous patients will respond within just 1–2 weeks after the initiation of the therapy [65]. If there is a lack of improvement within the period set, this type of dietary intervention should be withdrawn and other available options (e.g., excluding certain nutrients) should be considered [24]. The second stage “reintroduction phase” is based on gradual enrichment of diet with FODMAPs-rich nutrients. Further extending of diet is related with the final step, “personalization phase,” which is individually customized, and applied into a long-term follow-up [26]. Currently, several high-quality RCTs have confirmed that consumption of high-FODMAP diet can trigger or exacerbate IBS symptoms, and following the L-FODMAP diet leads to a significant improvement of patient’s clinical condition [65, 71, 72]. Studies also proved that mitigation of both the short- and long-term symptoms of IBS may be observed in up to two-thirds of patients [26, 71, 72]. In an analysis conducted by Altobelli et al. comparing the L-FODMAP diet with control diet it has been shown that pain or bloating reduction was higher in patients on the L-FODMAP compared to traditional nutrition. Referring to stool texture, no meaningful differences have been observed [73]. Other evidence also corroborates to beneficial results of the L-FODMAP intake compared to control diet [67, 68] However, in a study conducted by Staudacher et al., the authors took into consideration that the change may have also occurred from particular components, such as lactose [67]. Noteworthy, in recent RCTs comparing the L-FODMAP diet with control diet it has been demonstrated that both strategies can improve symptoms in individuals with IBS with similar effectiveness [27], and these findings are consistent with earlier studies [26, 66, 71]. Moreover, patients on the L-FODMAP diet may have difficulties with proper fibers intake, resulting in altered intestinal microbiota and decreased SCFAs level, as well as reduced calcium level, particularly in a long-term follow-up [24, 26, 48]. Additionally, the beneficial effects of the L-FODMAP diet in IBS should be compared not only with evaluations assessing sham, or western diets, but primarily with the diet based on appropriate dietary recommendations (first line therapy) [26, 66, 74, 75]. A complementary nutrition support, such as dietary counseling is also indispensable for proper diet adjustment, and achieving the expected aims [25, 26]. Further high-quality evaluations are therefore needed to understand the effects of the L-FODMAP diet in individuals with IBS.

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Other possibilities Gluten free diet Gluten-free diet (GFD) refers to limiting the main structural protein complex (gliadin, glutenin) of wheat, barley, and rye. GFD is highly recommended for celiac disease, and some evidence suggests it may be beneficial for individuals with non-celiac gluten sensitivity (NCGS) [47, 76, 77]. However, current evidence is insufficient to recommend avoiding gluten products in regular diet, and following a GFD may also expose patients to nutritional deficiencies [26, 74]. The elimination of products consisting gluten is linked with a reduction of fructan intake, and some potentially harmful substances, such as wheat-germ lectin and α-amylase/trypsin inhibitors [78–80]. In some studies it has been shown that these substances can correlate with triggering of the innate immune response via Toll like receptor 4 [80]. It has also been demonstrated that lectin has the ability to impair intestinal permeability [81]. Proteins present in gluten diet may also alter the expression of zonulin, which is essential to modulating permeability of tight junctions in the gut, however these findings were conducted mainly in vulnerable individuals (celiac, NCGG, wheat allergy) [35, 82–84]. A recent systematic review showed some benefits of following GFD in patients with IBS, however in this case it may also be due to fructan limiting [72, 85]. Due to the lack of RCTs, GFD cannot be thus recommended to IBS patients and limiting gluten is unnecessary [82–85].

Probiotic supplementation Gut microbiota in healthy individuals may vary from the one occurring in patients with IBS, implying significant correlation between microbiota and the pathophysiology of IBS. Some findings confirmed a decline in the diversity of the microorganisms, as well as abundance of certain bacteria in both fecal and mucosal samples from IBS patients [66, 86, 87]. Available evidence shows reduction in Lactobacillus [88, 89] and Bifidobacterium strains [90, 91], and also correspondence between relative abundance of pro-inflammatory bacterial species (e.g., Enterobacteriaceae) and decrease of Lactobacillus and Bifidobacterium genera [92]. However, these reports are in conflict with other studies that demonstrated an increase of Lactobacillus species in fecal samples of individuals with IBS-D [93, 94].

Chapter 13 Diet in irritable bowel syndrome

Currently, there is also a growing concern with the impact of a changing lifestyle (high-fat, high-sugar diet, stress) on altered composition and modified activity of the human gut microbiome [75, 87]. In this context, novel treatment strategies for IBS have been applied in recent years. Available findings suggested favorable effects of supplementation of probiotics on alleviating global IBS symptoms [95–97]. Some other findings highlighted the benefits, including reduced flatulence, abdominal pain, and stabilization of intestinal motility [98–100]. A meta-analysis of 24 clinical trials proved that benefits from probiotic supplementation in IBS were higher than placebo [97]. Another trial evaluating supplementation of multi-strain probiotic, showed notable reduction in intestinal permeability in IBS-D patients [101]. An interesting study was performed by Douillard et al., analyzing 100 strains of Lactobacillus rhamnosus, of which 77 strains were isolated from various parts of the body, and 23 strains isolated from dairy products [102]. In this genomic and functional analysis it has been observed that these strains varied between the groups by their metabolism and also functional mucus binding pili (SpaCBA), which was higher in human isolates compared to strains acquired from dairy products. Further investigations are highly recommended to prove if the presence of human-mucus binding pili is an advantage linked to colonization in the GI tract, and whether strains from other ecological niches are adapted to human guts [102]. Regarding the linkage between the L-FODMAP diet and microbiota, it should be mentioned that the long-term ingestion of this diet results in a decrease of beneficial bacteria, such as Bifidobacterium spp. Therefore probiotic supplementation, particularly in long-term follow-up of the L-FODMAP diet seems to be relevant, however further investigations are highly needed. Consequently, one placebo-controlled study in patients on the L-FODMAP diet showed that the co-administration of a multistrain probiotic resulted in an increase of Bifidobacterium species compared with placebo [67]. It should be noted that the vast majority of the abovementioned RCTs were heterogenous or assessed only short-term effects. Additionally, inclusion of patients with different IBS subtypes and the supplementation of multiple probiotic strains and doses across studies labeled these studies as inappropriate to final conclusions [74, 103]. It is also extraordinarily important that many interactions between the human gut, gut microbiota, and pre- or probiotics remain unexplored.

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Fecal microbiota transplantation Fecal microbiota transplantation (FMT) is an approach which refers to the application of a solution of fecal material (colonoscopy infusion, or the delivery through the upper GI tract) from a healthy donor to a recipient with an aberrant composition of the gut microbiome. Available data confirmed the improvement of IBS condition after FMT, although the exact mechanism remains unknown. In a study accomplished by Halkjær et al. positive outcomes after FMT therapy have been observed in IBS patients, with no serious side effects [104]. In another evaluation, Mizuno et al. linked the improvement upon FMT not only with GI symptoms, particularly in stool consistency, but also with better psychological condition [105]. In this study, beneficial effects of FMT treatment have been combined with Bifidobacterium abundance in stool of donors which might have resulted from an increase in the diversity of microbiota. The effectiveness of FMT therapy has also been evaluated by Aroniadis et al., but at 12 weeks positive effects were not observed compared with placebo [106]. Another trial assessing the efficacy of FMT on recurrent Clostridium difficile infection showed the reduction of symptoms severity in patients with oral capsules similar to colonoscopy transplantation [107]. In a recent RCT performed by Johnsen et al. [108]. FMT has been demonstrated as an effective intervention in comparison to placebo, however, the authors pointed out that the alleviation of the symptoms disappeared within 12 months from beginning of the treatment. Apart from those, significant differences in fecal microbiota constitution after FMT have been observed only in one trial [109], and two other studies [104, 106] demonstrated no linkage between changes in gut microbiota, and relevant clinical responses. Furthermore, there are significant differences in species in the human microbiome pending its origin (luminal vs mucosal, lower vs upper GI tract) [110] which may be associated with some adverse events when an autologous FMT is applied [108, 109]. Due to known restrictions, such as small study groups, differences of placebo treatment, and using various routes of administration [104, 106–109], the right conclusions cannot be drawn currently, and further results should be supported by more high-quality RCTs.

Conclusions Available studies point out that proper diet and healthy lifestyle are the first-line dietary treatment. Also important is to assess potential triggers intake, and reduce or limit their

Chapter 13 Diet in irritable bowel syndrome

consumption, if related with IBS symptoms. Second-line approach is currently based on a L-FODMAP diet and should be considered in the case of persistent symptoms. It is worth noting that these recommendations should be supervised by a specialized dietitian. Further well-designed RCTs are still needed to approve final conclusions on the efficiency of L-FODMAP diet, particularly its long-term effects. Currently, the effects of L-FODMAP diet and traditional dietary advices are comparable, but following a stringent diet is considerably more challenging. Despite the pervasive interest on other diets, e.g., GFD, or any nonspecific food hypersensitivity interventions, there is a lack of evidence to recommend them for IBS treatment. More complicated, restrictive diets are—among others—difficult for patients, and may result in both incorrect application or lack of adherence to dietary recommendations. Another interesting set of accomplished studies refers to pre-, and probiotic supplementation, or fecal microbiota transplantation, but also due to incomprehensible mechanisms and gaps of knowledge in terms of microbiome-host relationships, these approaches cannot be yet recommended. Dietary management is undoubtedly indispensable for each IBS patient. However many of current investigations are limited by small sample sizes, comparing only with placebo, and no specific symptoms. Further trials should be focused on factors, which could be pivotal for IBS onset, and also responsible for IBS development. In the future, high-quality RCTs, on large groups of patients, validating not only short-term benefits, but also longterm effects are tremendously expected.

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[39] Jenkins DJA, Marchie A, Augustin LSA, Ros E, Kendall CWC. Viscous dietary fibre and metabolic effects. Clin Nutr Suppl 2004;1(2):39–49. [40] Holscher HD. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes. Taylor and Francis Inc.: 2017;8:172–84.  ska M. Podstawy [41] Sobotka L, Allison SP, Korta T, Kłęk S, Łyszkowska M, Brzezin zywienia klinicznego: edycja czwarta. Krakowskie Wydawnictwo Scientifica; 2013. p.169–78. [42] Moayyedi P, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol 2014;109:1367–74. [43] Capili B, Anastasi JK, Chang M. Addressing the role of food in irritable bowel syndrome symptom management. J Nurse Pract [Internet]. 2016 [cited 2019 Dec 27].12:324–9. Available from: www.npjournal.org. [44] Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109(Suppl 1):S2–26. [45] Niv E, Halak A, Tiommny E, Yanai H, Strul H, Naftali T, et al. Randomized clinical study: partially hydrolyzed guar gum (PHGG) versus placebo in the treatment of patients with irritable bowel syndrome. Nutr Metab 2016;13(1):10. [46] Rao TP, Quartarone G. Role of guar fiber in improving digestive health and function. Nutrition. Elsevier Inc.; 2019;59:158–69. [47] Cuomo R, Andreozzi P, Zito FP, Passananti V, De Carlo G, Sarnelli G. Irritable bowel syndrome and food interaction. World J Gastroenterol. WJG Press; 2014;20(27):8837–45. [48] Misselwitz B, Butter M, Verbeke K, Fox MR. Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management. Gut. BMJ Publishing Group; 2019;68:2080–91. [49] Yang JF, Fox M, Chu H, Zheng X, Long YQ, Pohl D, et al. Four-sample lactose hydrogen breath test for diagnosis of lactose malabsorption in irritable bowel syndrome patients with diarrhea. World J Gastroenterol 2015;21 (24):7563–70. €hmer CJM, Tuynman HARE. The effect of a lactose-restricted diet in [50] Bo patients with a positive lactose tolerance test, earlier diagnosed as irritable bowel syndrome: a 5-year follow-up study. Eur J Gastroenterol Hepatol 2001;13(8):941–4. [51] Vernia P, Marinaro V, Argnani F, Di Camillo M, Caprilli R. Self-reported milk intolerance in irritable bowel syndrome: what should we believe? Clin Nutr 2004;23(5):996–1000. [52] Jianqin S, Leiming X, Lu X, Yelland GW, Ni J, Clarke AJ. Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows’ milk. Nutr J 2016;15(1):45. [53] Deng Y, Misselwitz B, Dai N, Fox M. Lactose intolerance in adults: biological mechanism and dietary management. Nutrients. MDPI AG; 2015;7:8020–35. [54] Hammer J, Vogelsang H. Characterization of sensations induced by capsaicin in the upper gastrointestinal tract. Neurogastroenterol Motil 2007;19 (4):279–87. [55] Chan CLH, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, et al. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 2003;361(9355):385–91. 

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[56] Akbar A, Yiangou Y, Facer P, Walters JRF, Anand P, Ghosh S. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut 2008;57(7):923–9. [57] Bortolotti M, Porta S. Effect of red pepper on symptoms of irritable bowel syndrome: preliminary study. Dig Dis Sci 2011;56(11):3288–95. [58] Gonlachanvit S. Are rice and spicy diet good for functional gastrointestinal disorders? J Neurogastroenterol Motil 2010;16(2):131–8. [59] Johannesson E, Simren M, Strid H, Bajor A, Sadik R. Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol 2011;106(5):915–22. [60] Johannesson E. Intervention to increase physical activity in irritable bowel syndrome shows long-term positive effects. World J Gastroenterol 2015;21(2):600. [61] Van Tilburg MAL, Palsson OS, Levy RL, Feld AD, Turner MJ, Drossman DA, et al. Complementary and alternative medicine use and cost in functional bowel disorders: a six month prospective study in a large HMO. BMC Complement Altern Med 2008;24:8. [62] Kuttner L, Chambers CT, Hardial J, Israel DM, Jacobson K, Evans K. A randomized trial of yoga for adolescents with irritable bowel syndrome. Pain Res Manag 2006;11(4):217–23. [63] Peters HPF, De Vries WR, Vanberge-Henegouwen GP, Akkermans LMA. Potential benefits and hazards of physical activity and exercise on the gastrointestinal tract. Gut 2001;48:435–9. [64] Spiller R. How do FODMAPs work? J Gastroenterol Hepatol. Blackwell Publishing; 2017;32:36–9. [65] Mitchell H, Porter J, Gibson PR, Barrett J, Garg M. Review article: implementation of a diet low in FODMAPs for patients with irritable bowel syndromedirections for future research; Aliment Pharmacol Ther 2018;49(2):124–39. [66] Hustoft TN, Hausken T, Ystad SO, Valeur J, Brokstad K, Hatlebakk JG, et al. Effects of varying dietary content of fermentable short-chain carbohydrates on symptoms, fecal microenvironment, and cytokine profiles in patients with irritable bowel syndrome. Neurogastroenterol Motil 2017;29(4):1–9. [67] Staudacher HM, Lomer MCE, Farquharson FM, Louis P, Fava F, Franciosi E, et al. A diet low in FODMAPs reduces symptoms in patients with irritable bowel syndrome and a probiotic restores Bifidobacterium species: a randomized controlled trial. Gastroenterology 2017;153(4):936–47. [68] Piacentino D, Rossi S, Alvino V, Cantarini R, Badiali D, Pallotta N, et al. 374 Effects of low-fodmap and gluten-free diets in irritable bowel syndrome patients. A double-blind randomized controlled clinical study. Gastroenterology 2014;146(5). [69] Take online FODMAP training j Monash FODMAP—Monash Fodmap [Internet]. [cited 2019 Dec 28]. Available from: https://www.monashfodmap.com/ online-training/dietitian-course/; 2019. [70] Bananas and FODMAPs—a blog by Monash FODMAP j The experts in IBS— Monash Fodmap [Internet]. [cited 2019 Dec 29]. Available from: https:// www.monashfodmap.com/blog/update-bananas-re-tested/; 2019. [71] Whelan K, Martin LD, Staudacher HM, Lomer MCE. The low FODMAP diet in the management of irritable bowel syndrome: an evidence-based review of FODMAP restriction, reintroduction and personalisation in clinical practice, J Hum Nutr Diet [Internet] Apr [cited 2019 Dec 28]; 2018;31(2):239–55. Available from: http://doi.wiley.com/10.1111/jhn.12530. [72] Catassi C, Alaedini A, Bojarski C, Bonaz B, Bouma G, Carroccio A, et al. The overlapping area of non-celiac gluten sensitivity (NCGS) and wheat-sensitive irritable bowel syndrome (IBS): an update. Nutrients. MDPI AG; 2017;9, 1268.

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[73] Altobelli E, Del Negro V, Angeletti PM, Latella G. Low-FODMAP diet improves irritable bowel syndrome symptoms: a meta-analysis. Nutrients 2017;9:940 MDPI AG. [74] Cozma-Petrut A, Loghin F, Miere D, Dumitrascu DL. Diet in irritable bowel syndrome: what to recommend, not what to forbid to patients! World J Gastroenterol. Baishideng Publishing Group Co., Limited; 2017;23:3771–83. ˜ o-Janeiro BK, Vicario M, Alonso-Cotoner C, Pascua-Garcı´a R, Santos J. [75] Rodin A review of microbiota and irritable bowel syndrome: future in therapies. Adv Ther. Springer Healthcare; 2018;35:289–310. [76] Biesiekierski JR, Iven J. Non-coeliac gluten sensitivity: piecing the puzzle together. United Eur Gastroenterol J. [Internet] [cited 2019 Dec 28]; 2015;3 (2):160–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25922675. [77] Akhondi H, Ross AB. Gluten and associated medical problems. StatPearls, Treasure Island (FL): StatPearls Publishing. 2019. [Internet] [cited 2019 Dec 28]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30860740. [78] Catassi C, Bai J, Bonaz B, Bouma G, Calabro` A, Carroccio A, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 2013 [Internet] 26 [cited 2019 Dec 29];5(10):3839–53. Available from: http://www. mdpi.com/2072-6643/5/10/3839. [79] Volta U, Pinto-Sanchez MI, Boschetti E, Caio G, De Giorgio R, Verdu EF. Dietary triggers in irritable bowel syndrome: is there a role for gluten? J Neurogastroenterol Motil 2016;22(4):547–57. [80] Junker Y, Zeissig S, Kim SJ, Barisani D, Wieser H, Leffler DA, et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J Exp Med 2012;209(13):2395–408. [81] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci 2012;1258(1):25–33. [82] Vazquez-Roque MI, Camilleri M, Smyrk T, Murray JA, Marietta E, O’Neill J, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology 2013;144(5):903–11. e3. [83] Thabane M, Marshall JK. Post-infectious irritable bowel syndrome. World J Gastroenterol 2009;15(29):3591–6. [84] Roszkowska A, Pawlicka M, Mroczek A, Bałabuszek K, Nieradko-Iwanicka B. Non-celiac gluten sensitivity: a review. Medicina (Lithuania). MDPI AG; 2019;55, 222. [85] Dieterich W, Zopf Y. Gluten and FODMAPS-sense of a restriction/when is restriction necessary? Nutrients 2019;11(8):1957. [86] Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrateproducing bacteria from the human large intestine. FEMS Microbiol Lett 2009;294(1):1–8. [87] Duan R, Zhu S, Wang B, Duan L. Alterations of gut microbiota in patients with irritable bowel syndrome based on 16s rRNA-targeted sequencing: a systematic review. Clin Transl Gastroenterol. Lippincott Williams and Wilkins; 2019;10, 1–12. [88] Carroll IM, Chang YH, Park J, Sartor RB, Ringel Y. Luminal and mucosalassociated intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Gut Pathog 2010;2(1):19. € T, Kajander K, Ma €tto € J, Kassinen A, Krogius L, et al. Anal[89] Malinen E, Rinttila ysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol 2005;100(2):373–82. [90] Parkes GC, Rayment NB, Hudspith BN, Petrovska L, Lomer MC, Brostoff J, et al. Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome. Neurogastroenterol Motil 2012;24(1):31–9.

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[91] Duboc H, Rainteau D, Rajca S, Humbert L, Farabos D, Maubert M, et al. Increase in fecal primary bile acids and dysbiosis in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2012;24(6):513–20. [92] Zhuang X, Xiong L, Li L, Li M, Chen M. Alterations of gut microbiota in patients with irritable bowel syndrome: a systematic review and meta-analysis. J Gastroenterol Hepatol 2017;32(1):28–38. [93] Rigsbee L, Agans R, Shankar V, Kenche H, Khamis HJ, Michail S, et al. Quantitative profiling of gut microbiota of children with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2012;107(11):1740–51. [94] Labus JS, Hollister EB, Jacobs J, Kirbach K, Oezguen N, Gupta A, et al. Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome. Microbiome 2017;5(1):49. [95] Guglielmetti S, Mora D, Gschwender M, Popp K. Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life—a double-blind, placebo-controlled study. Aliment Pharmacol Ther 2011;33(10):1123–32. € ller-Lissner S, Martens U, [96] Enck P, Zimmermann K, Menke G, Mu Klosterhalfen S. A mixture of Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the irritable bowel syndrome—a randomized controlled trial with primary care physicians. Neurogastroenterol Motil 2008;20(10):1103–9. [97] Didari T, Mozaffari S, Nikfar S, Abdollahi M. Effectiveness of probiotics in irritable bowel syndrome: updated systematic review with meta-analysis. World J Gastroenterol. WJG Press; 2015;21:3072–84. [98] O’Mahony L, Mccarthy J, Kelly P, Hurley G, Luo F, Chen K, et al. Lactobacillus and Bifidobacterium in irritable bowel syndrome: Symptom responses and relationship to cytokine profiles. Gastroenterology 2005;128(3):541–51. [99] Kim HJ, Vazquez Roque MI, Camilleri M, Stephens D, Burton DD, Baxter K, et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil 2005;17(5):687–96. [100] Dolin BJ. Effects of a proprietary Bacillus coagulans preparation on symptoms of diarrhea-predominant irritable bowel syndrome. Methods Find Exp Clin Pharmacol 2009;31(10):655–9. [101] Zeng J, Li YQ, Zuo XL, Zhen YB, Yang J, Liu CH. Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoeapredominant irritable bowel syndrome. Aliment Pharmacol Ther 2008;28 (8):994–1002. € TE, Ja €rvinen HM, Messing M, et al. [102] Douillard FP, Ribbera A, Kant R, Pietila Comparative genomic and functional analysis of 100 Lactobacillus rhamnosus strains and their comparison with strain GG. PLoS Genet 2013;9(8):1–15. [103] Harper A, Naghibi MM, Garcha D. The role of bacteria, probiotics and diet in irritable bowel syndrome. Foods. MDPI Multidisciplinary Digital Publishing Institute; 2018;7, 13. € nther S, Hansen LH, et al. [104] Halkjær SI, Christensen AH, Lo BZS, Browne PD, Gu Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebocontrolled study. Gut 2018;67(12):2107–15. [105] Mizuno S, Masaoka T, Naganuma M, Kishimoto T, Kitazawa M, Kurokawa S, et al. Bifidobacterium-rich fecal donor may be a positive predictor for successful fecal microbiota transplantation in patients with irritable bowel syndrome. Digestion 2017;96(1):29–38.

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[106] Aroniadis OC, Brandt LJ, Oneto C, Feuerstadt P, Sherman A, Wolkoff AW, et al. Faecal microbiota transplantation for diarrhoea-predominant irritable bowel syndrome: a double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol Hepatol 2019;4(9):675–85. [107] Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial. JAMA 2017;318(20):1985–93. € sch F, Cavanagh JP, Leikanger IS, Kolstad C, Valle PC, et al. [108] Johnsen PH, Hilpu Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol 2018;3 (1):17–24. [109] Holvoet T, Joossens M, Wang J, Boelens J, Verhasselt B, Laukens D, et al. Assessment of faecal microbial transfer in irritable bowel syndrome with severe bloating. Gut. BMJ Publishing Group; 2016;66:980–2. [110] Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 2018;174(6):1388–405. e21.

Correlation of irritable bowel syndrome with psychiatric disorders

14

Miłosz Caban Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland

Abstract Irritable bowel syndrome (IBS) is a functional disorder of intestines. The detailed etiopathology of IBS is unknown, but it is evidenced that psychosocial stress is a contributing factor. The recent studies reported that there is relationship between IBS and psychiatric disorders; however molecular mechanisms of this correlation remain unclear. In this chapter, the relationship between IBS and individual psychiatric disorders with the assessment of their risk and the explanation of molecular causes will be discussed.

Keywords Anxiety, Bipolar disorder, Brain-gut axis, Depression, Eating disorders, Irritable bowel syndrome, Obsessive-compulsive disorder, Posttraumatic stress disorder, Psychiatric disorders, Sleep disorders

List of abbreviations 5-HT ACTH ALIC ANS AUD BD BDI-II CBT CNS CRD

5-hydroxytryptamine adrenocorticotropic hormone anterior limb of the internal capsule autonomic nervous system alcohol use disorder bipolar disorder Beck Depression Inventory-II cognitive behavioral therapy central nervous system colorectal distension

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00015-0 # 2020 Elsevier Inc. All rights reserved.

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CRH DBS ED ENS GABA HPA HR IBD IBS IBS-C IBS-D IBS-M IBS-U IRR MDD NMDA NREM OCD OED PED PLMS PRISM-RII PSQI PTSD QOL REM RLS RR SERT SF-36 SHAPS SNS SSRIs SNRIs STAI tau TCAs VAS VSI

corticotropin-releasing hormone deep brain stimulation erectile dysfunction enteric nervous system gamma-aminobutyric acid hypothalamic-pituitary-adrenal hazard ratio inflammatory bowel diseases irritable bowel syndrome irritable bowel syndrome-constipation predominant irritable bowel syndrome-diarrhea predominant irritable bowel syndrome-mixed irritable bowel syndrome-unsubtyped incidence rate ratio major depressive disorder N-methyl-D-aspartate non-rapid eye movement obsessive-compulsive disorder organic erectile dysfunction psychogenic erectile dysfunction periodic leg movements in sleep Pictorial Representation of Illness and Self Measure Revised II Pittsburgh Sleep Quality Index posttraumatic stress disorder quality of life rapid eye movement restless legs syndrome risk ratio serotonin transporter Short Form 36 Snaith-Hamilton Pleasure Scale sympathetic nervous system selective serotonin reuptake inhibitors serotonin norepinephrine reuptake inhibitors State-Trait Anxiety Inventory microtubule-associated protein tricyclic antidepressants visual analog scale visceral sensitivity index

Introduction Irritable bowel syndrome (IBS) is a functional disorder of small and large intestines. It is a chronic disease which is characterized by abdominal pain and defecation disorders which are not associated with organic or biochemical changes [1]. There are four subtypes of IBS: constipation-predominant (IBS-C), diarrheapredominant (IBS-D), mixed (IBS-M) and unsubtyped [2]. The etiopathology of IBS remains unknown, but altered gastrointestinal motility, visceral hypersensitivity, the brain-gut axis

Chapter 14 Correlation of irritable bowel syndrome

disorder, increased intestinal permeability, gut dysbiosis, improper diet, antibiotics or psychosocial distress were described as contributing factors [1]. There is strong evidence for a significant correlation between IBS and psychiatric disorders [3]. For example, a recent study reported that in approximately 50–80% of patients with IBS there is an association between stress and the occurrence and the severity of IBS symptoms [4]. The causes for this correlation and the underlying mechanisms are still unclear, yet significant to IBS pathogenesis, course and therapy [5]. “Classical” understanding of psychiatric diseases associates them with changes in the central nervous system (CNS) [6, 7]. However, CNS connects with the enteric nervous system (ENS) [8] and they form the brain-gut axis which was showed to function bidirectionally and which may modulate psychiatric disorders or cognitive process of the brain [9]. Furthermore, the brain-gut axis consists of gut microbiota and their changes are also known to affect the activity of CNS what may cause the disorders of behavior, mood and mental condition [10]. One of the possible communication routes between CNS and gut microbiota is the hypothalamic-pituitary-adrenal (HPA) axis [9]. The HPA axis consists of hypothalamus, pituitary gland and adrenal glands and each of these components secretes hormones which affect other elements of the axis: the hypothalamus secretes corticotropin-releasing hormone (CRH) that stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH), which in turn is responsible for the activation of adrenal glands and the increased levels of corticosteroids, mineralocorticoids and androgens [11]. Adrenal hormones inhibit the secretion of the hypothalamus and the pituitary gland in a mechanism of negative feedback [11]. In patients with IBS, hyperactivity of HPA axis is observed [12]. Consequently, an excessive amount of corticosteroids—among others cortisol which is a stress hormone—is observed in patients with IBS [12], similarly to patients with depression [13]. Moreover, the hyperactivity of the sympathetic nervous system (SNS) is also observed in IBS [14]. This system is a part of the autonomic nervous system (ANS) and its activation causes an increased secretion of other hormones such as adrenalin and noradrenalin which are responsible for the emotion-associated behaviors of the human organism or maintenance of the homeostasis in fight-or-flight situations [15]. Chronic activation of SNS is harmful and causes chronic stress in patients and emotional overactivity what was revealed in IBS patients [16]. The hyperactivity of SNS and HPA axis leads to several psychiatric disorders, inter alia anxiety or panic disorders [17].

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Visceral hypersensitivity, manifested by abdominal pain is another disorder observed in IBS and associated with the nervous system [18]. Both central and peripheral nervous systems take part in the course of visceral perception and its disorders may lead to visceral hypersensitivity. In visceral perception, the stimulus is induced in the peripheral nervous system and the nerve transmission is conducted by afferent tract to sensory areas in the brain. In consequence, emotional, cognitive and affective central mechanisms modulate the flow of information from the viscera. This causes that sensation and symptoms intensity are determined by cerebral mechanisms of neurotransmission [19, 20]. Disorders of neurotransmission may be responsible for visceral hypersensitivity. In an in vivo model, Chi and colleagues evidenced that disorders of serotonergic neurotransmission, presented by the reduced expression of serotonin transporter (SERT) and an increased expression of 5-HT4 receptor in the colon correlate with visceral hypersensitivity [21]. Serotonin (5-hydroxytryptamine; 5-HT) is one of the main neurotransmitters of CNS which modulates the brain-gut axis [9]. Its deficiency is responsible for several psychiatric diseases, primarily depressive syndrome [22, 23]. Of note, this signaling molecule also affects gut motility and takes part in the gastrointestinal sensation [24]. The neurotransmission of serotonin is associated with SERT which modulates the extracellular reuptake of serotonin. The gene of SERT is located on chromosome 17 and its rare variants are associated with the occurrence of psychiatric disorders in IBS patients [24]. Frequent concomitance of psychiatric disorders in IBS patients can be caused also by brain activity disorders what was revealed by brain imaging [25–27]. In these patients incorrect activity of insula, insular cortex, prefrontal cortex, thalamic cortex, cingulate cortex, parietal cortex was present [25–27] (Fig. 1), whereas in psychiatric disorders, e.g., in obsessive-compulsive disorder or bipolar disorder altered activation of orbitofrontal cortex and prefrontal cortex were showed [28, 29]. Furthermore, morphological and anatomical changes in the brains of IBS patients were noted compared with healthy people. For example, studies showed alterations in gray matter volume and cortical thickness [30, 31] as well as increased volume of gray matter of hypothalamus [32, 33]. Another team revealed the decreased quantity of gray matter in various regions of brain including striatum or thalamus [34] which are responsible for pain transmission [35]. Consequently, IBS patients with chronic pain had microstructural changes in cortical regions [36]. In the remainder of this chapter, the relationship between IBS and individual psychiatric disorders with the assessment of their risk and the explanation of molecular causes will be discussed.

Chapter 14 Correlation of irritable bowel syndrome

Fig. 1 Schematic image of the brain and its regions in which the activity is disturbed in the course of IBS.

Bipolar disorder Bipolar disorder (BD) is a psychiatric disorder whose frequency is approximately 2% of the global population [37]. This disease is an affective disorder and its course is characterized by depression, mania and hypomania episodes. The occurrence of two episodes of depression, mania or hypomania is necessary to the diagnosis of BD, but one of these episodes must be mania or hypomania. There are two basic types of BD: type 1 and type 2 [38]: BD-1 is characterized by the concomitance of depression and mania while the coexistence of depression and hypomania is typical for BD-2. Other types of BD include bipolar spectrum and rapid cycling [38]. Abnormally elevated mood, increased psychomotor drive, verbosity, reduced requirement of sleep, elevated self-assessment, intensive libido, foolhardy behavior, racing thoughts or lack of risk evaluation are typical manifestations of the mania episode [38]. These signs, but with lower severity also characterize the hypomania episode. The features of depression episode are the same for depression and they will be described in more detail in the next part of chapter. Lithium carbonate, antipsychotics, anticonvulsants or antidepressants are used in the treatment of BD [38]. Initially, studies did not reveal the interdependence between IBS and BD [39], however currently, the correlation between IBS

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and BD has been recognized. Lee et al. selected patients with IBS which were diagnosed by gastroenterologists and patients without IBS; the former did not have any diagnosis of psychiatric disorders before IBS identification. Consequently, the risk of BD occurrence in the course of IBS was evaluated and the results showed that patients with IBS had higher risk of BD (risk ratio, RR ¼ 2.44, 95% CI ¼ 1.25–4.61) compared to the control cohort. Also, this same team indicated that the risk was dependent on IBS duration. For patients who have suffered from IBS for over 5 years, the risk was significantly higher (RR ¼ 3.57, 95% CI ¼ 1.20–10.43) compared to the control group [40]. Noteworthy, it was revealed that the risk of BD was the lowest for patients with IBS duration between 1 and 5 years (RR ¼ 2.13, 95% CI ¼ 0.84–5.04) [40]. Liu et al. reported that the general risk of BD development was elevated for IBS patients compared to the patients from the control group (incidence rate ratio, IRR ¼ 2.63, 95% CI ¼ 2.10–3.31) [41]. Interestingly, the researchers also determined the exact risk values of BD formation depending on the duration of IBS and they revealed that the IBS duration shorter than 0.5 year was associated with the highest risk of BD occurrence (IRR ¼ 3.55, 95% CI ¼ 1.78–7.68) [41]. Moreover, male sex predisposed to the occurrence of BD in the course of IBS stronger than female sex [41]. Attempts to explain the potential mechanisms responsible for the association of IBS and BD and the elevated risk of BD in patients with IBS were made. The inflammatory process activated by IBS was presented as a possible reason of this relationship. In addition, peripheral inflammation was hypothesized to increase the risk of CNS inflammation what may contribute to the development of psychiatric disorder [42, 43]. A meta-analysis of the relationship between IBS and BD, performed in 2016 year by Tseng et al., confirmed the correlation of comorbidity. The BD prevalence ratio was higher for IBS patients than in the control group (odds ratio ¼ 2.48, 95% CI ¼ 2.35–2.61) [44]. Furthermore, no significant dependence between the risk of BD in IBS and age or prevalence of comorbid popular, somatic diseases such as diabetes mellitus or hypertension were observed [44]. The most recent study by Yeh et al. confirmed the abovementioned observations as the risk of developing BD was rated as increased in IBS patients and it was over threefold (adjusted hazard ratio, HR ¼ 3.273, 95% CI ¼ 2.984–3.892) [3]. It must be emphasized that the occurrence of BD in IBS patients might had been a consequence of genetic predisposition rather than IBS. Therefore, further studies aiming to analyze the relationship between BD and IBS are required.

Chapter 14 Correlation of irritable bowel syndrome

Also worthy of note is possible restriction in the treatment of IBS patients. Namely, antidepressants are currently indicated as drugs which may be used in IBS treatment [45]. It should be emphasized that these drugs inter alia selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) can induce mania episode in BD patients [38]. Therefore, a particular caution should be exercised in BD patients with IBS symptoms.

Depression Major depressive disorder (MDD), also known popularly as depression is a syndrome which is one of the most frequent pathological conditions in medicine. The genetic predisposition, physical condition of the body and stress factors take part in the formation of MDD [46]. The decreased mood, anhedonia and energy reduction, feelings of guilt, pessimistic vision of future, suicidal thoughts, suicidal tendencies are the main symptoms of MDD [47]. The SSRIs and TCAs are the main treatment options which are used in MDD, however psychotherapy may also have significant impact on its course and development [48]. The depression frequency is many times higher in patients with somatic and neurological diseases and significantly higher morbidity is observed in chronic pain syndromes, thyroid diseases, diabetes mellitus and after myocardial infarction or stroke [49]. The relationship between depression and somatic diseases is complex, but the disorders of communication between the brain and digestive tract and modulation of endocrine and immune system are perceived as potential factors responsible for association of IBS and MDD [50]. Recently, a significant correlation between MDD and IBS was evidenced. Carpinelli et al. revealed that patients with IBS had higher level of anhedonia than the healthy group, independent of the severity of depressive symptoms [51]. Moreover, it was proved that greater intensification of anhedonia was responsible for a more intensive pain feeling, as evaluated using the visual analog scale (VAS) for abdominal pain and the Snaith-Hamilton Pleasure Scale (SHAPS) for anhedonia. Furthermore, the same group demonstrated an increased frequency and severity of subjective depressive symptoms in IBS patients [51] which were investigated using the Beck Depression Inventory-II (BDI-II) [51]. The psychiatric co-morbidity in IBS patients was confirmed by further studies. Kawoos et al. showed that the number of cases with major depressive episode was almost twofold higher in IBS patients group than in control group and patients cases with other

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depressive disorder such as mixed anxiety depression were fivefold more frequent than in control group [52]. Another evidence of the relationship between depression and IBS was given by a systematic review with meta-analysis which was published in 2019 by Zamani et al. The aim of this research was to evaluate the occurrence of depression in IBS. The meta-analysis revealed that compared to healthy group the likelihood of depression is threefold increased in patients with IBS [53]. Another study showed that the level of depression was higher in IBS patients and it was regardless of IBS subtype [54]. Furthermore, patients with IBS who complained of psychological distress had more severe gastrointestinal symptoms and gastrointestinal-specific anxiety what is associated with complex pathophysiology and clinical picture of IBS [55]. Also, these patients were characterized by visceral hypersensitivity, altered function of ANS and more frequent somatic non-gastrointestinal symptoms, for example pain in other localizations [55]. Recent studies underline a significant impact of IBS on the  ska quality of life (QOL) and mental health. For example, Kopczyn et al. revealed that QOL was reduced in patients with IBS [56] what was manifested by dysphoria, health worry, food avoidance body image disorders, social relation disorders, sexuality and relation ska et al. emphasized that the IBS sympship issues [56]. Kopczyn toms could be responsible for the low QOL and the reduction of lifestyle could lead to appearance of depression [56]. Interestingly, IBS is not the only gastrointestinal disorder which is associated with psychiatric disorders. Studies showed that inflammatory bowel diseases (IBD) such as ulcerative colitis or Crohn’s disease can coexist with psychiatric diseases [57]. In addition, Geng et al. revealed that the prevalence of comorbid depression with IBD and IBS was similar for these groups, but patients with IBS were characterized by more severe depressive symptoms than IBD patients [57]. The most recent study showed that IBD and IBS can coexist [58]. Furthermore, IBD patients with symptoms of IBS had higher risk of depression occurrence than IBD patients with no IBS diagnosis [58]. The health state of these patients requires intensive healthcare utilization what is caused by a more severe course of the disease [58]. Consequently, awareness of a high risk of psychiatric disorders not only in IBS patients, but also in IBD patients with IBS should associate with intensified health care—both psychiatric and gastroenterological [58]. The literature review reveals that depression may promote the initiation of IBS. For example, in an in vivo model of depression using 7-week-old male Wistar rats it was showed that dysbiosis was present [59]. Consequently, decreased quantity of Clostridiales

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species whereas the abundance of Lactobacillaceae, Turicibacteraceae, Peptostreptococcaceae, and Bifidobacteriaceae species were noted. Moreover, in the same model visceral hypersensitivity, as evaluated by the measure of colorectal distension (CRD) was observed [59]. On the other hand, a study by Tillisch and colleagues showed that the colon distention may cause an increase in the activity of the insula and the prefrontal cortex, what proved the role of these brain regions in the course of IBS [60]. Finally, the presence of abnormal levels of cytokines (IL-8, IL-10, and TNF-α) in both IBS and psychological distress, as evidenced by the assessment of their expression in the patients’ peripheral blood mononuclear cells, linked these two disorders. The increased levels of TNF-α, IL-8 and the decreased level of IL-10 in IBS patients with psychological distress were revealed compared to the control group [61]. The relationship between IBS and depression contributes to the purposefulness of the use of antidepressants in IBS [61]. However, as mentioned above it must be emphasized that the pharmacological treatment of gastrointestinal symptoms can mitigate significant depressive disorder. Finally, it needs to be underlined that the QOL should be verified in IBS patients during their visits in clinics as this may be an important tool for proper therapeutic management tailored to the patient’s individual situation.

Anxiety disorders Anxiety disorders are one of the most prevalent psychiatric diseases, with the frequency of approximately 18% of general population [62]. Anxiety, which is at the base of these disorders is a mood characterized by the presence of strong feeling of danger. Importantly, patients can experience this emotion in the absence of external stimulus or the emotions felt are inadequate to the stimulus [62]. Many chronic somatic diseases can be associated with the course of anxiety disorders such as tachycardia, chest pain, hypertension, asthma, rheumatoid arthritis, liver cirrhosis, multiple sclerosis, epilepsy, and cancer [63]. The most recent studies showed that also IBS was associated with elevated frequency of anxiety occurrence [63] and there is a threefold increased risk of anxiety disorder in patients with IBS [40, 53]. Moreover, the anxiety level was exacerbated in IBS patients [52, 54, 57, 64]. The highest level of anxiety was observed in patients with IBS-M subtype what could be the result of both diarrhea and constipation presence in its course [65].

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In 2015, Lee et al. published a detailed analysis through population-based cohort study and gauged risk coefficients dependent on the IBS duration. The risk ratio for anxiety disorder was the highest within 1 year of IBS diagnosis (RR ¼ 6.76, 95% CI ¼ 4.25–10.91) [40]. Longer IBS duration was associated with a lower frequency of anxiety disorder and its risk ratio was the lowest when the follow-up duration was longer than 5 years [40]. The level of anxiety can vary in patients, depending on several factors. One of them is perception of disease, as showed by Pletikosic Toncic and Tkalcic [66] who used the Pictorial Representation of Illness and Self Measure Revised II (PRISM-RII), the IBS-36 (measuring instrument of QOL for patients with IBS), the Short Form 36 (SF-36) Health Survey (assessment of physical and mental health related QOL), the State-Trait Anxiety Inventory (STAI), Visceral Sensitivity Index (VSI; gastrointestinal-specific anxiety) and a symptom diary in a group of IBS patients for 2 weeks of a study were used for measurements [66]. Patients who perceived IBS as weak, reported lower severity of symptoms and had higher quality of life [66]. The study concluded with the emphasis on the assessment of psychological functioning as a tool to improve the IBS course [66]. On the other hand, anxiety is a strong factor which may lead to IBS initiation. The findings suggest that the anxiety disorder increases twofold the risk for the onset of IBS [67]. There is also a strong correlation in duration time. In a study focused on the assessment of prevalence of IBS and its association with anxiety among medical students, the prevalence of IBS was the highest in students of the fifth year. Furthermore, the study proved that the higher year of their education was associated with the higher level of anxiety [68]. Phobia is a special anxiety disorder. The presence of anxiety in both specified situation or before its appearance and avoiding this event are the main features of phobia. Agoraphobia or specific phobias are the main groups of this disorder [69]. Data showed that phobic anxiety modulates the brain-gut axis in IBS [70]. On the other hand, the frequency of agoraphobia, panic disorder and panic disorder with agoraphobia in IBS subjects was higher than in non-IBS subjects [71]. IBS may induce the formation of agoraphobia [72] and higher prevalence of agoraphobia was revealed in panic disorder patients with IBS than panic disorder patients no IBS [73]. Antidepressants such as SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) are medicines which are used in the treatment of anxiety disorders [74]. Also, non-pharmacological approach, inter alia psychotherapy is adequate for their

Chapter 14 Correlation of irritable bowel syndrome

treatment. One of the forms of psychotherapy is cognitive behavioral therapy (CBT) [75], which is based on human behavior perceived as a natural response to stimuli. The CBT consists of training techniques which are habituated to therapeutic process [76]. Noteworthy, it is now scientifically proven that CBT reduces symptoms of both IBS and anxiety [77]. On the other hand, CBT with hypnosis was proven effective in the treatment of IBS-induced agoraphobia [72].

Obsessive-compulsive disorder Obsessive-compulsive disorder (OCD) belongs to the group of anxiety disorders. In OCD, characteristic symptoms are present: obsession and compulsive behavior. Recurring, obtrusive thoughts, ideas, perceptions, impulses (obsessions) and intrusive, repeatable actions (compulsive behavior) are its main features. Obsessions are often perceived as annoying and disagreeable. Patients with OCD try to refrain obtrusive actions, yet usually ineffectively what causes that the patients’ daily functioning is abnormal. The OCD is a chronic disease and its course is intensified in stressful situations [78]. Antidepressants are first-line drugs in OCD treatment, inter alia SNRIs and SSRIs [79]. It is now evidenced that patients with OCD have a significantly higher frequency of IBS. Masand et al. suggested over 14-fold frequency of IBS compared to the control group with the percentage of IBS patients in the OCD group of over 35% and 2.5% in the control group [80]. Moreover, more than 50% of OCD patients with IBS had the IBS-M subtype. The results of the study prove that clinicians should introduce special care for psychiatric patients taking into consideration gastrointestinal symptoms [80], for example by gathering their detailed history. This comes from the fact that SSRI are basic drugs in the OCD treatment; moreover, the doses used in the OCD therapy are very high, often maximal. Consequently, gastrointestinal disorders, among others diarrhea or nausea are one of the most frequent side effects, what may result from 5-HT receptors stimulation in the intestines [80]. High prevalence of IBS in OCD was confirmed in later studies [81]. Aside from pharmacological therapy, psychotherapy or brain stimulation are used in OCD. The deep brain stimulation (DBS) is used for the treatment of severe OCD which is treatmentresistant [82]. The literature review reveals an interesting case report which described co-morbidity of OCD and IBS. The female patient developed first compulsive symptoms at age of 14 and IBS

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symptoms after a few years [82]. At the age of 32 she developed full-blown OCD. In this case bilateral DBS of the posterior part of the anterior limb of the internal capsule (ALIC) was introduced [82]. After the DBS treatment, patient reported reduction of IBS symptoms. Noteworthy, the improvement of IBS course was not directly associated with weakening in OCD symptoms. This study indicates the possible involvement of ALIC in the IBS development [82].

Posttraumatic stress disorder Posttraumatic stress disorder (PTSD) is a psychiatric disorder which forms as a result of trauma which exceeds the ability of the patient to cope with this experience. War operations, catastrophes, natural disasters, traffic accidents, attacks, rapes, abductions, tortures, life-threatening diagnoses are accidents which can lead to PTSD [83]. The typical symptoms of PTSD are: anxiety, weakness, helplessness feeling, recurrent, involuntary memories, nightmares or avoidance of situations which are associated with traumatic experience [83]. The prevalence of PTSD is not accurately known and it differs in populations of various countries; however, PTSD is more frequent in female patients [83]. It was proven that trauma history increased the risk of IBS in women veterans [84–86], in which the most frequently reported traumatic incident was sexual assault. Other specific traumas were murder of family/friend by drunk driver, death of spouse/ partner/child or serious, life-threatening illness; in this case the prevalence of IBS was 33.5% [84]. The most recent meta-analysis revealed that PTSD increased the risk of IBS and PTSD patients had almost threefold increased risk of IBS (pooled odds ratio ¼ 2.80, 95% CI ¼ 2.06–3.54) [87]. In contrast, a study in African American population showed that PTSD was independently associated with IBS, but IBS exacerbated symptoms of PTSD [88]. Traumatic stress is related to altered autonomic function. The symptoms in PTSD patients with IBS can be thus caused by altered activity of sympathetic and parasympathetic nervous systems. On the other hand, traumatic stress or event can cause epigenetic changes in the neuroendocrine pathways and the gene expression of glucocorticoids, which may be responsible for dysregulations of serotonergic neurotransmission [87]. Furthermore, neuropeptide Y may be responsible for the relationship between IBS and PTSD, because the low level of this compound was detected in both IBS patients’ colons and PTSD patients plasma [89, 90].

Chapter 14 Correlation of irritable bowel syndrome

Schizophrenia Schizophrenia is a one of the most severe psychiatric disorders. It is estimated that 0.30–0.66% of general population suffers from schizophrenia [91]. In the clinical picture of schizophrenia, positive symptoms (delusions, hallucinations, thought disorders, distrust, hearing voices), negative symptoms (emotional stiffness, passivity, stereotypical thinking, difficult contact with people), depressive symptoms (sadness, despondence, anhedonia, suicidal thoughts) and cognitive disorders (impairment of attention, memory, learning ability) can be distinguished [91]. The primary treatment of schizophrenia is through antipsychotic medications [91]. The somatic condition of the patients is crucial in the treatment of schizophrenia because it may affect its efficiency. In consequence, detailed physical examination and diagnostic have an important role in the care of these patients. Schizophrenia increases the risk of somatic diseases, as these patients do not take a proper care of themselves [92, 93]. The literature review revealed only a limited number of studies in which the correlation of IBS with schizophrenia was examined, which may only be due to psychotic symptomatology in the subjects. Nevertheless, an increased prevalence of IBS in schizophrenia patients was determined, with the frequency of IBS estimated at 17% [94] and 19% [95]. On the other hand, Lee and colleagues proved that IBS increased general risk of schizophrenia (RR ¼ 1.80, 95% CI ¼ 0.86–3.57), but this result did not become statistically significant [40]. Further studies are clearly needed to understand the relationship between schizophrenia and IBS.

Sleep disorders Sleep is a condition of the organism which is characterized by abolition of consciousness, reduction in motor activity, depletion of responsiveness to stimuli and loss of contact with environment [96]. There are two phases of sleep: non-rapid eye movement (NREM) and rapid eye movement (REM) [97]. Many factors affect sleep, but age, circadian rhythm and homeostatic process have the strongest impact [98]. The sleep disorders are present in many somatic diseases such as hypertension [99], diabetes mellitus [100] and gastrointestinal disorders [101], and manifest in: insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, parasomnias, sleep-related movement disorders and other [102]. Concurrently, somatic symptoms of various diseases such as pain, burning, itching etc. can be responsible for sleep disorders [103].

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The symptoms of IBS such as abdominal pain, flatulence, constipation, diarrhea, and nausea may cause sleep disorders and the studies proved that the association between IBS and sleep disturbances is common [40, 104]. Lee et al. showed that there is a twofold increase in the risk of sleep disorder in IBS patients compared to controls (RR ¼ 2.01, 95% CI ¼ 1.73–2.34) [40]. Moreover, there is an association between IBS duration and sleep disturbances: the highest risk rate of sleep disturbances was up to 1 year since the first symptoms of IBS occur (RR ¼ 4.01, 95% CI ¼ 2.21–7.28). For IBS duration of over 1 year, the rate was decreased and it was slightly more than 2, which may be due to the adaptation to IBS symptoms. However, it must emphasized that the risk rate was still statistically significant for IBS patients with more than 5 years since diagnosis [40]. In 2018 year, a systematic review with meta-analysis was performed which confirmed high prevalence of sleep disorders in IBS. Based on this meta-analysis, the frequency of sleep disorders in IBS was established at 37.6% [105]. Moreover, this review revealed distinctiveness according to different areas, age, gender or occupation. For example, the prevalence of sleep disorders in IBS patients in Asia, North America, South America and Europe was 36.9%, 37.3%, 67.1% and 35.9% respectively [105], however it must be emphasized that individual regions were characterized by various numbers of studies what might have affected the results [105]. The sleep disorders were more widespread among females with IBS (43.6 vs 34.4% in males with IBS) [105]. Of note, there were 11 studies regarding occupation in IBS patients: eight studies were performed among students, two among nurses and one among veterans [105] and sleep disorders observed in 51%, 32.2%, and 7.1%, respectively [105]. The prevalence of sleep disorders were more frequent among children (42.4%) than adults (36.4%) [105]. One of the most frequent disturbances of sleep was a change in its quality. Sleep fragmentation, prolonged sleep latency, dissatisfaction of sleep quality and daytime sleepiness were all reported in IBS patients [106–108], resulting in poor sleep quality [104, 109–112]. Furthermore, the literature review revealed increased percentage share of REM and NREM sleep [113–116], REM time [114], REM latency [106] and sleep onset latency [108] in IBS patients. Noteworthy, the co-occurrence of IBS with other gastrointestinal disorders elevates the risk of sleep disorders [110]. For example, the concomitance of IBS and functional dyspepsia intensified sleep impairment compared to IBS alone. Patients with comorbidity had increased Pittsburgh Sleep Quality Index

Chapter 14 Correlation of irritable bowel syndrome

(PSQI; a measure of sleep quality) [109] and suffered from insomnia more frequently than IBS patients. On the other hand, sleep disturbances elevate the risk of IBS. For example, gastrointestinal symptoms were more intensified when IBS patients had poorer sleep quality the prior night [112]. Curiously, in a study by Patel et al. who examined the effects of restless sleep on gastrointestinal symptoms, IBS patients slept more hours per day. However, longer sleep duration was not connected with better feeling and rest [111]. In addition, the studied patients often demonstrated waking episodes which predisposed to aggravated abdominal pain and gastrointestinal distress, which were the reason of reduced QOL and worse mood [111]. Motor disorders of sleep is a particular group of sleep disturbances. The restless legs syndrome (RLS), also known as Willis-Ekbom disease is one of the most frequent movement sleep disorders concerning approximately 3% of general population [117]. Its symptoms which occur exclusively or mostly in the evening or night (when patients fall asleep)—what is associated with lying position—include the need for movements of patient’s legs, feeling discomfort or tingling, creeping, aching, stretching, crawling in legs [117]. Movement mitigates these symptoms, therefore these patients may get out of bed and move what leads to the reduction of symptoms [117]. Most patients with RLS experience periodic limbs movements which may occur in sleep or wakefulness. Periodic leg movements in sleep (PLMS) may lead to arousals and in consequence sleep fragmentation and daytime sleepiness [117]. In severe RLS, the symptoms may occur earlier in the day during rest period in sitting or lying position [117]. Some disorders such as iron deficiency, renal failure or rheumatologic disorders have an increased prevalence of RLS [117]. Moreover, a possible association between RLS and other diseases such as diabetes mellitus, cardiovascular diseases or migraine was revealed [118]. Studies showed that RLS was associated with higher prevalence in IBS patients and vice versa [104, 119–122]. Furthermore, RLS was many more frequent in patients with IBS-D subtype [119]. The IBS patients with co-morbid RLS had exacerbated IBS symptoms and they significantly suffered more from vomiting, stomach pain, and nausea [120]. Compared to RLS patients without IBS, RLS patients with IBS were older, mainly female, more depressive, had more frequent insomnia symptoms and they perceived more often sleep insufficiency [122]. The mechanisms underlying the relationship between IBS and sleep disorders remain unclear. The hyperactivity of CNS, ANS, ENS and HPA axis can be involved in the formation of sleep disorders in IBS patients [105]. For example, it was showed that

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symptoms of IBS can lead to the activation of ANS and a decrease in the efficiency of sleep [123]. Also, changed gut microbiota may have an impact on the sleep disorders in IBS patients. Degradation products or metabolites of microbiota can activate immune response, induce inflammatory reaction, triggering sleep disorders [124, 125] and changing circadian rhythm [126].

Use disorders Alcohol use disorder (AUD) is a problematic pattern of alcohol use what is manifested by among others excessive amount alcohol, long period of alcohol use, the presence of persistent desire or disorders in the fulfilling of social, occupational, recreational activities [127]. Alcohol has a comprehensive action, primarily acting as a CNS depressant, affecting gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors [128]. Patients with AUD are characterized by—among others—strong need of alcohol intake and difficulties in controlling behavior which is related to alcohol intake; withdrawal symptoms, tolerance presence, dereliction of interests and daily chores or harmful medical consequences can also be seen [127]. Initial studies investigating the correlation of IBS with AUD revealed inconsistent results. The symptoms of IBS were the cause of alcohol avoidance and therefore earlier studies did not confirm the relationship between AUD and IBS [129, 130]. However, recent reports pointed to association between the diseases. Alcohol dependence syndrome increased 5.51-fold risk of IBS (adjusted HR ¼ 5.51, 95%CI ¼ 4.36–6.96) [131]. Moreover, a family history of alcohol abuse was showed to predispose to IBS [132]. Further studies are now necessary to determine detailed interdependence between IBS and AUD. In addition, they could contribute to the identification of dependence mechanisms. Another popular use disorder which is associated with IBS is cannabis use disorder [133]. It was proved that patients who suffer from cannabis use disorder have higher odds for hospitalization caused by IBS [133].

Erectile dysfunction Erectile dysfunction (ED) is a type of sexual dysfunction defined by difficulties or inability to achieve or maintain erection of the penis [134]. This disorder is a cause of unsatisfactory sexual intercourse [134]. The three types of ED can be identified: organic erectile dysfunction (OED) psychogenic erectile dysfunction

Chapter 14 Correlation of irritable bowel syndrome

(PED) and mixed type [134]. OED is caused by organic reasons and can be associated with neurogenic, vasculogenic, endocrinological factors, systemic diseases and drugs [134]. It is evidenced that IBS increases the risk of developing OED [135, 136]. In contrast to OED, psychiatric disorders mainly anxiety and depression are responsible for PED. These disturbances have significant role in IBS course. A study by Hsu et al. showed that IBS promoted the development of PED. IBS patients had 2.38 times likelihood to suffer from PED than control group (adjusted HR ¼ 2.38, 95% CI ¼ 1.47–3.85) and they had higher risk of PED than OED [136].

Dementia Dementia is characterized by problems of mental functioning which is a result of extensive, irreversible brain damage and the vast majority of cases occur among elderly subjects [137]. Consequently, the limitations in domestic, social and occupational functioning is common in dementia [137]. Furthermore, the decrease of independence and changes of personality occur in the course of this disorder. Genetic, vascular and age are the main factors which implicate as risk factors of dementia [137]. The literature revealed that the prevalence of dementia was more frequent in IBS patients, however this effect was observed only in patients older than 50 years [138]. Of note, an increased risk of dementia was 1.26 (adjusted HR ¼ 1.26, 95% CI ¼ 1.17–1.35) after adjustment for age, sex, hypertension, stroke, diabetes, coronary artery disease, head injury, depression, and epilepsy [138]. The mechanisms of this correlation may be advanced. In another study, Daulatzai described a potential relationship between dementia and IBS [139]. Gut dysbiosis, gut inflammation, the dysfunction of gut barrier occur in IBS and they lead to the enhanced production of pro-inflammatory cytokines and the induction of neuroinflammation [139]. In consequence, gut-brain axis afferent dysfunction, efferent gut-brain pathway deregulation and CNS structure dysfunction can contribute to the amyloid deposition, a microtubule-associated protein (tau) phosphorylation and neurocognitive impairment which promote the dementia [139].

Eating disorders Eating disorders are a group of psychiatric disorders which are characterized by inadequate behavior associated with food intake. Anorexia nervosa and bulimia nervosa are two main eating

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Fig. 2 Schematic representation of the potential changes in the course of IBS which may lead to the formation of psychiatric disorders.

disorders, however they have various clinical image [140]. The reduction of body mass, occurrence of patient’s activities which lead to a decline of body weight (inter alia inducible vomiting), and the perception of one’s body as obese are crucial features of anorexia nervosa [140]. Bulimia nervosa is primarily characterized by chronic, excessive focus on food and an uncontrolled need of food intake with coexisting episodes of ridding of excessive food intake [140]. Initially, the relationship between eating disorders and IBS was doubtful [141]. Tang and colleagues tried to address this issue by evaluating common characteristics in mental sphere [141]. They revealed that patients with IBS (and women in particular) were unsatisfied with their bodies. Moreover, IBS patients who had severe bouts of vomiting and nausea in the past, also had bulimic-type characteristics [141], as evaluated using the Bulimia subscale of Eating Disorder Inventory. Moreover, these patients reported the presence of thoughts about vomiting as a method of body weight reduction [141]. Subsequent studies clarified the correlation between IBS an eating disorders. In a study with 234 subjects, in 87% patients with IBS eating disorders occurred before the IBS onset and the average period between IBS and eating disorder onset was 10 years. These results revealed that eating disorders may increase the risk of IBS development in future [142]. Another study indicated high frequency of IBS in patients with bulimia nervosa; however, exact correlation remained unknown, since in this examination no

Chapter 14 Correlation of irritable bowel syndrome

comparison to the healthy group was made [143]. The most recent study revealed the relationship between eating disorders and IBS in French students [144]. In this group, the research team examined the prevalence of IBS, eating disorders and eating disorder co-existing with IBS. In a group of 731 students, the frequency of these disorders was 7.8%, 16.7% and 2.7%, respectively [144]. Of note, the mean risk of IBS was elevated in patients with eating disorder (adjusted odds ratio ¼ 2.42, 95% CI ¼ 1.30–4.51) and the mean risk of eating disorder was high in patients with IBS (adjusted odds ratio ¼ 2.46, 95% CI ¼ 1.32–4.55). Moreover, the occurrence of these disorders was more frequent in female students and third year or above students [144].

Summary The data show a strong relationship between IBS and psychiatric disorders. Currently, the exact mechanisms responsible for this correlation are not known; however, several potential underlying factors have already been identified (Fig. 2). The clinical implications for this associations thus follow: there is a need for psychiatric assessment and screening in IBS patients [145, 146]; however, on the other hand drugs used to treat psychiatric diseases or psychological treatment options can be used in the IBS therapy. Further research aimed at exploring and determining the links between IBS and psychiatric disorders may contribute to knowledge on IBS pathophysiology and the development of new therapeutic options.

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[128] Costardi JV, Nampo RA, Silva GL, Ribeiro MA, Stella HJ, Stella MB, Malheiros SV. A review on alcohol: from the central action mechanism to chemical dependency. Rev Assoc Med Bras 2015;61(4):381–7. [129] Halpert A, Halpert A, Dalton CB, Palsson O, Morris C, Hu Y, Bangdiwala S, Hankins J, Norton N, Drossman D. What patients know about irritable bowel syndrome (IBS) and what they would like to know nationalsurvey on patient educational needs in ibs and development and validation of the patient educational needs questionnaire (PEQ). Am J Gastroenterol 2007;102:1972–82. [130] Masand PS, Sousou AJ, Gupta S, Kaplan DS. Irritable bowel syndrome (IBS) and alcohol abuse or dependence. Am J Drug Alcohol Abuse 1998;24:513–21. [131] Hsu TY, He GY, Wang YC, Chen CY, Wang SH, Chen WK, Kao CH. Alcohol use disorder increases the risk of irritable bowel disease: a nationwide retrospective cohort study. Medicine 2015;94(51). [132] Knight JR, Locke GR, Zinsmeister AR, Schleck CD, Talley NJ. Family history of mental illness or alcohol abuse and the irritable bowel syndrome. J Psychosom Res 2015;78(3):237–41. [133] Patel RS, Goyal H, Satodiya R, Tankersley WE. Relationship of cannabis use disorder and irritable bowel syndrome (IBS): an analysis of 6.8 million hospitalizations in the United States. Subst Use Misuse 2020;55(2):281–90. [134] Shamloul R, Ghanem H. Erectile dysfunction. Lancet 2013;381(9861):153–65. [135] Chao CH, Lin CL, Wang HY, Sung FC, Chang YJ, Kao CH. Increased subsequent risk of erectile dysfunction in patients with irritable bowel syndrome: a nationwide population-based cohort study. Andrology 2013;1(5):793–8. [136] Hsu CY, Lin CL, Kao CH. Irritable bowel syndrome is associated not only with organic but also psychogenic erectile dysfunction. Int J Impot Res 2015;27(6): 233–8. [137] Gale SA, Acar D, Daffner KR. Dementia. Am J Med 2018;131(10):1161–9. [138] Chen CH, Lin CL, Kao CH. Irritable bowel syndrome is associated with an increased risk of dementia: a nationwide population-based study. PLoS One 2016;11(1). [139] Daulatzai MA. Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia. Neurochem Res 2014;39(4):624–44. [140] Polivy J, Herman CP. Causes of eating disorders. Annu Rev Psychol 2002;53:187–213. [141] Tang TN, Toner BB, Stuckless N, Dion KL, Kaplan AS, Ali A. Features of eating disorders in patients with irritable bowel syndrome. J Psychosom Res 1998; 45(2):171–8. [142] Perkins SJ, Keville S, Schmidt U, Chalder T. Eating disorders and irritable bowel syndrome: is there a link? J Psychosom Res 2005;59(2):57–64. [143] Dejong H, Perkins S, Grover M, Schmidt U. The prevalence of irritable bowel syndrome in outpatients with bulimia nervosa. Int J Eat Disord 2011;44(7):661–4. [144] Spillebout A, Dechelotte P, Ladner J, Tavolacci MP. Mental health among university students with eating disorders and irritable bowel syndrome in France. Rev Epidemiol Sante Publique 2019;67(5):295–301. [145] Fond G, Loundou A, Hamdani N, Boukouaci W, Dargel A, Oliveira J, Roger M, Tamouza R, Leboyer M, Boyer L. Anxiety and depression comorbidities in irritable bowel syndrome (IBS): a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci 2014;264(8):651–60. [146] Stasi C, Caserta A, Nisita C, Cortopassi S, Fani B, Salvadori S, Pancetti A, Bertani L, Gambaccini D, de Bortoli N, Dell’Osso L, Blandizzi C, Marchi S, Bellini M. The complex interplay between gastrointestinal and psychiatric symptoms in irritable bowel syndrome: a longitudinal assessment. J Gastroenterol Hepatol 2019;34(4):713–9.

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15

Laura Lo´pez-Go´meza,b∗, Ana Bag€ u esa,c,d∗, a,b Jos e Antonio Uranga , and Raquel Abaloa,b,d a

Department of Basic Health Sciences, University Rey Juan Carlos (URJC), Alcorco´n, Spain. bHigh Performance Research Group in Physiopathology and Pharmacology of the digestive system (NeuGut), URJC, Alcorco´n, Spain. cHigh Performance Research Group in Experimental Pharmacology (PHARMAKOM), URJC, Alcorco´n, Spain. dR+D+i Unit Associated to Medical Chemistry Institute (IQM, CSIC), Madrid, Spain

Abstract Irritable bowel syndrome (IBS) is a disorder of the gut-brain interaction, highly prevalent and impactful. Visceral hypersensitivity and alterations of colonic motility and defecation are definitory, but other features (increased intestinal permeability, anxiety, depression) also occur throughout the life of IBS patients. In this chapter, we will first review the different animal models that have been developed in an attempt to mimic IBS and its symptoms, which may vary according to the different underlying etiology. Thereafter, we will review the techniques and models that are used in vitro. Whereas in vivo models constitute the final preclinical step in the search of new effective and safe treatments, in vitro studies offer essential information on molecular mechanisms underlying the disease, which may open the gate to finding new treatment targets. Both approaches are therefore complementary and need to be considered for successful preclinical research on IBS.

Keywords Constipation, Diarrhea, Gastrointestinal transit, Gut-on-a-chip, Irritable bowel syndrome, Leaky gut, Stress, TNBS, Visceral hypersensitivity



Same contribution.

A Comprehensive Overview of Irritable Bowel Syndrome. https://doi.org/10.1016/B978-0-12-821324-7.00012-5 # 2020 Elsevier Inc. All rights reserved.

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List of abbreviations 5-HT ATP AWR CCK CRD CRH CUMS DRG DSS EAL EMG FITC FPO FS FUST GABA GFAP GI GIP GLP-1 HIO HPA i.c. i.p. IBD IBS IBS-C IBS-D IL Isc JAM LPS MS nNOS ORL-1 PI-IBS PND RT SP TEER TEM TNBS UGIT VMR WAS WGIT ZO

serotonin adenosine triphosphate abdominal withdrawal reflex cholecystokinin colorectal distension corticotropin-releasing hormone chronic unpredictable mild stress dorsal root ganglia dextran sulfate sodium early adverse life electromyography fluorescein isothiocyanate fecal pellet output forced swim female estrous urine sniffing test gamma-aminobutyric acid anti-glial fibrillary acidic protein gastrointestinal gastric inhibitory polypeptide glucagon-like-peptide-1 human intestinal organoids hypothalamic-pituitary-adrenal intracolonically intraperitoneal inflammatory bowel disease irritable bowel syndrome irritable bowel syndrome—constipation irritable bowel syndrome—diarrhea interleukins short-circuit current junctional adhesion molecule lipopolysaccharide maternal separation neuronal nitric oxide synthase opioid receptor like-1 postinflammatory irritable bowel syndrome postnatal day room temperature substance P transepithelial resistance transmission electron microscopy trinitrobenzene sulphonic acid upper GI transit visceromotor response water avoidance stress whole GI transit zonula occludens

Introduction Irritable bowel syndrome (IBS) is a common digestive functional disorder, nowadays more precisely defined as “a disorder of the gut-brain interaction”, that seriously affects the quality of

Chapter 15 Preclinical models of irritable bowel syndrome

life of up to 20% of the population worldwide [1]. Patients suffering from IBS present biological alterations that result in symptoms such as alterations of colonic motility and visceral hypersensitivity. These problems occur throughout the life of IBS patients, who are also affected by psychological factors such as stress or depression. Nowadays, there are no specific markers to make a diagnosis of IBS, that is the reason why symptom-based criteria, known as Rome IV, are currently used. Accordingly, IBS has been classified into four subtypes: IBS-C, in which constipation predominates; IBS-D, in which diarrhea predominates; IBS-M, with alternating periods of constipation and diarrhea; and, finally, a type of IBS without a defined pattern [2]. In this chapter, we will first review the different animal models that have been developed in an attempt to mimic the human disease and its symptoms, which may vary according to the different underlying etiology. Thereafter, we will review the techniques and models that are used in vitro. Whereas in vivo models constitute the final preclinical step in the search of new effective and safe treatments, in vitro studies offer essential information on molecular mechanisms underlying the disease, which may open the gate to finding new treatment targets. Both approaches are therefore complementary and need to be considered for successful preclinical research on IBS.

Animal models of irritable bowel syndrome Due to the complex etiology of IBS in humans, different approaches need to be used to mimic it in experimental animals. Two main strategies are used: direct irritation/ inflammation/infection of the colonic mucosa, with symptom evaluation after colitis resolution and indirect induction of symptoms through application of stress during adulthood or early life (generally postnatally). Combinations of stimuli are also sometimes used. Whatever the chosen model, it should display the main IBS symptoms, i.e., visceral pain (hypersensitivity) and altered motility/defecation/feces consistency (diarrhea/constipation). Whereas visceral sensitivity is generally evaluated, gastrointestinal (GI) motility and defecation are more scarcely assessed in the same study. Other symptoms, like altered permeability of the intestinal mucosa or altered behavior (anxiety/depression-like symptoms) are even less frequently evaluated in these models. To evaluate visceral hypersensitivity, the most frequently used method is colorectal distension (CRD), where a latex/polyethylene balloon is introduced in the distal colon of the anesthetized animal to a certain depth proximal to the anus. After recovery

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from anesthesia, the balloon is inflated to a defined pressure (usually in the interval of 0–80 mmHg) or volume (depending on the size of the animal), which will mechanically stimulate the colon. The methods used to produce this stimulation are different among the studies: some use phasic stimulation, which consists in the repetition of the same short (10–20 s) stimulus two to three times within a time period (generally 5 min), with a 60–90 s rest between individual stimuli [3–5]; others use tonic stimulation, in which the same stimulus is maintained for the whole time period (3–5 min), and the responses may be more prone to habituation [6–8]. Accordingly, important differences can be observed between both types of stimulation [9]. As a nociceptive index, some authors record the total number and duration of abdominal contractions caused by the mechanical stimulation [7, 8]. Another method is to apply the abdominal withdrawal reflex (AWR) score, which grades as follows: 0—the rats are emotionally stable and move freely; 1—the rats are emotionally unstable and occasionally twist their heads; 2—the abdominal muscles contract slightly, but the abdomen touches the floor; 3—the abdominal and back muscles contract strongly, and the abdomen is lifted off the ground; and 4—the abdominal and back muscles contract strongly, the back arches, and the abdomen, pelvis and perineum are lifted off the ground [10–12]. An alternative manner to evaluate visceral sensitivity is through the recording of the visceromotor response (VMR) to CRD. For this, animals need to undergo surgery a few days before the trial, so that the recording electrodes are implanted in the abdominal muscles for electromyography (EMG). Afterwards, the motor activity of the abdominal muscles caused by CRD can be analyzed [13, 14]. A classical method to evaluate visceral sensitivity is through the writhing test, it differs from CRD in the nature of the stimulus, which is chemical in this case. Diluted acetic acid is injected intraperitoneally, and the number of writhes is counted over a 10-min period. This test is mainly performed in mice [15]. To study GI motility in experimental animals, different approaches can be used [16]. Thus, a marker (charcoal, Evan’s blue, phenol red, 51Cr …) can be administered by gavage, and the whole GI transit (WGIT) is recorded, as the time that takes for the marker to appear in the feces [17]. Alternatively, the animals are sacrificed at 20–30 min after marker administration, the GI organs are removed, the length the marker has traveled along the small intestine is measured, and the upper GI transit (UGIT) or the geometric center may be calculated [8, 18, 19]. Another option to study GI motor function is to take serial short (20–60 ms) X-rays after the intragastric administration of barium

Chapter 15 Preclinical models of irritable bowel syndrome

sulfate, which is a non-invasive method that does not require anesthesia and allows for the evaluation of macroscopic changes of the GI organs along the course of the radiographic session or throughout the development of the model [16, 20–22]. Also, a simple method to study colonic transit is by counting the total number of fecal pellets expelled in an interval of time, termed as fecal pellet output (FPO) [7], but the bead expulsion test may be also used, in which a small bead is inserted in the colon at a particular depth proximal to the anus and, after sedation/anesthesia recovery, the time taken for the bead to be expelled is recorded [22, 23]. Lastly, alterations in colonic contractility may be detected in organ bath studies (see later), either using the whole organ [22] or strips cut longitudinally or transversely (keeping or not mucosa and submucosa), hung under tension and bathed in physiological solution. Once in this bath, colonic strips can be stimulated electrically or chemically, and the involvement of different receptors or the effect of different drugs can be assessed [24]. To study the occurrence of diarrhea or diarrhea-like patterns, some authors use the Bristol fecal score, typically applied in patients to classify the consistency of the stool [10]. However, this clinical score is more difficult to apply in rodents, due to the fact that the “normal” appearance of stools in these animals is much dryer than in humans. Thus, other, more simple, scores are more frequently used in rodents, i.e. 0: normal; 1: loose/moist; 2: amorphous/sticky; and 3: diarrhea [25], or the amount of water of the stools can also be analyzed [26]. IBS has been shown to induce alterations in permeability of the intestinal mucosa, and this has been studied in different in vivo IBS models through different methods (Table 1). For example, fluorescein isothiocyanate (FITC) may be orally administered, and the amount of this compound is analyzed in blood samples taken after a specific time [27]. Similarly, urine concentration of different sugars can be analyzed at certain time points after their oral administration [28]. These markers are non-absorbable under normal mucosal permeability conditions; thus, their occurrence in blood or urine samples suggest the presence of altered (increased) permeability (“leaky gut”). Finally, because anxiety and depression are frequently associated with IBS, in an effort for basic research to be more translational, anxiety- and depression-like behavioral studies are being increasingly performed in the last few years. Anxiety-related behavior can be studied using the elevated plus maze, open field or hole board tests. In all these tests, the exploratory behavior of the animal is studied in an aversive/non aversive situation (elevated plus maze test: open arms vs closed arms; open field test and hole board test: thigmotaxis vs exploratory behavior) [25].

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Table 1 Main features of preclinical in vivo models of irritable bowel syndrome (IBS). Visceral pain

GI motor function

Stool consistency

IBS models induced by irritants and inflammatory substances

Irritant enemas (acetic acid, mustard oil)/CRD in pups

Visceral hyperalgesia in adulthood

Decreased FPO in acetic acid model

Administration of irritants (TNBS, DSS …) during adulthood and evaluation after colitis resolution PI-IBS models

Visceral hypersensitivity

Increased GI motility

Increased watery and amorphous stool in pups submitted to CRD but reduced FPO and water content in rats treated with i.c. acetic acid before weaning N.D.

Visceral hypersensitivity

Controversial

Softer and wetter feces

Increased colon and small intestine motility Gastric emptying remains unaffected

N.D.

Increased colon motility Delayed gastric emptying Often habituation

Increased water content

Reduced colonic motility (FPO) 24 h after being exposed to an acute stressor Reduced during adolescence Increased during adulthood Control animals habituate to chronic restraint stress, whilst animals previously subjected to MS do not habituate

N.D.

IBS models induced by stress

WAS test

Restraint stress

Overcrowding/social defeat Maternal separation (MS)

Acute and chronic exposure induce long-lasting visceral hyperalgesia Acute and subchronic restraint stress induces visceral hyperalgesia Visceral hypersensitivity Most laboratories have found visceral hypersensitivity A second stressor during adulthood might be needed

Increased water content in male adult mice

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Table 1 Main features of preclinical in vivo models of irritable bowel syndrome (IBS)—cont’d

Limited nesting

Heterotopic stress in pregnant dams

Visceral pain

GI motor function

Stool consistency

Visceral hypersensitivity Very few studies using this model Visceral hypersensitivity in the pups at adult age

N.D.

N.D.

N.D.

N.D.

See text for details. ACh, acetylcholine; CRD, colorectal distension; DSS, dextran sulfate sodium; FPO, fecal pellet output; GI, gastrointestinal; i.c., intracolonic; IBS, irritant bowel syndrome; MS, maternal separation; N.D., not determined; PI-IBS, post infectious IBS; TNBS, trinitrobenzene sulphonic acid acid; WAS, water avoidance stress.

Depression-like behaviors can be studied by analyzing the occurrence of anhedonia, which can be assessed through the sucrose preference test (animals are given the choice to drink from bottles containing either sweet or normal water: a reduced intake of sweet water is associated with anhedonia), or analyzing the time male animals spend sniffing female estrous urine (FUST test [29]: a reduced amount of time performing this behavior is considered as an index of anhedonia). Fig. 1 shows a summary of the methods used to measure, in experimental animals, the different symptoms of IBS described in this section. We overview next the main in vivo IBS models in which these symptoms can be evaluated.

IBS induction through the direct stimulation of the colonic mucosa Chemically-induced IBS models Enemas containing chemical substances such as mustard oil [3], zymosan [25], deoxycholic acid [11] or trinitrobenzene sulphonic acid (TNBS) [30], or dextran sulfate sodium (DSS) in drinking water [31] are commonly used to induce colitis models. Systemically administered lipopolysaccharide (LPS) may also be used to alter the integrity of colonic mucosa, in an indirect manner, but with similar consequences [32]. Irritants, which are intracolonically (i.c.) administered, are usually applied with a cannula and the animals are left tail up

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Fig. 1 Methods to study the symptoms associated with irritable bowel syndrome in experimental animals in vivo. See text for descriptions. AWR, abdominal withdrawal reflex; CRD, colorectal distension; EMG, electromyography: FITC, fluorescein isothiocyanate; FPO, fecal pellet output; FUST, female urine sniffing test; IBS, irritable bowel syndrome; UGIT, gastrointestinal transit; VMR, visceromotor response; WGIT, whole gastrointestinal transit.

for approximately 1 min so that the irritant does not leak out. In some of these studies, visceral hyperalgesia is tested shortly after the administration of the irritant [33–35], but findings could reflect more closely what happens in other clinical conditions (including the active phase of inflammatory bowel diseases, IBD). However, irritant-induced visceral hypersensitivity and increased colonic permeability have shown to last long after the resolution of inflammation [11, 25, 36], and the results of experiments testing the presence of these symptoms at this non-inflammatory stage more closely reproduce the IBS clinical situation. Interestingly, when compared with control animals, prior i.c. acetic acid administration is associated with an increase in FPO when animals are exposed to an acute stressor, and mustard oil increases UGIT after inflammation has resolved [37, 38]. Of the chemically-induced IBS models, i.c. administration of TNBS has been the most extensively used [39] and has recently been considered worthy for screening novel therapeutics by the visceral pain subgroup in the 2019 workshop “Critical Evaluation of Animal Pain Models for Therapeutics Development”. The reasons leading to this decision were that the “TNBS model has

Chapter 15 Preclinical models of irritable bowel syndrome

shown reliability and reproducibility across multiple laboratories with high construct validity and translational relevance, is relatively simple, can be used for high throughput studies and is applicable to a large segment of patients that develop IBS following an episode of enteritis” [40]. The visceral pain subgroup highlights that this model is recommended for discovery of new therapeutics, not for the discovery of the etiology behind IBS, and that more disease specific models should be tested before clinical trials. As a drawback, little is known on the effects of TNBS on GI motility once inflammation has subsided. In a study performed in guinea pigs, colonic propulsive motility was reduced when measured in organ bath (see in vitro methods below) [41].

Parasite infection-induced animal models Following infective gastroenteritis, more than 10% of the patients develop post-infectious IBS (PI-IBS), and the risk seems greater after bacterial than after viral infections [42]. Parasite infection models have been stablished to study PI-IBS models. The most commonly used parasites are Cryptosporidium parvum and Trichinella spiralis. Infections with these parasites induce long-term visceral hypersensitivity, and tissue damage [28, 43, 44]. Other parasites used to induce reliable PI-IBS are Giardia duodenalis [45] and Citrobacter rodentium [46]. Using fluoroscopy and spatiotemporal maps to evaluate small intestinal peristaltic activity in mice, it was found that gastric and intestinal contractions were increased during infection, resulting in loose stools. After infection, gastric contractions were normalized but intestinal contractions were reduced and slower propagation of contractions was recorded, together with an increased occurrence of retroperistalsis in this model [47]. However, Yang et al., also using T. spiralis infection in mice, found an increased intestinal transit after infection, and the water content of feces and their consistency score was higher in the PI-IBS group than in control animals [48]. These contradictory results may be due to the different experimental conditions, including the different strains and ages of the mice used, as well as the particular methods to evaluate intestinal motor function. In both cases, visceral hypersensitivity to CRD was demonstrated [47, 48].

Stress-induced IBS Stress during adult life Stress, anxiety and depression are main risk factors associated with IBS [49]. Thus, paradigms using different stressors have been used in experimental animals.

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The most frequently used models to induce visceral hypersensitivity are the water avoidance stress (WAS) and restraint stress models, which differ in the nature of the stressor: whilst WAS uses a psychological stressor, restraint stress is more physical in nature. WAS has been reproduced in different strains of rats [32] and mice [50] of both sexes [7, 51] and is probably the most widely reproduced stress-induced IBS-D model. The WAS model was first proposed by Bradesi et al. [52]. In this model of psychological stress, animals are placed on a small platform in the middle of a tank filled with water, up to approximately 1 cm below the platform. Studies have shown that just 1 h of WAS is sufficient to increase visceral hypersensitivity. When applied during 7–10 consecutive days, animals do not develop habituation, but perpetuate the hypersensitized state, which has been shown to last for up to a month after discontinuing the stressor, whilst somatic hypersensitization is transient [13, 52, 53]. Also, WAS increases GI transit (with increased FPO), though the effect in all organs is not the same: whilst there is an increase in the contractions of the stomach and colon, as well as an increase in the emptying of the colon, WAS does not significantly modify gastric emptying. In any case, most studies focus on visceral hypersensitivity [54, 55]. Both visceral hypersensitivity and increased motility remain after chronic WAS test in most studies [56], although in some, tolerance has been developed and after 10 days of WAS no visceral hyperalgesia was observed [51]. Because IBS has been associated with alterations in sleeping patterns [57], the WAS test has been adapted to reproduce these altered sleeping patterns, by increasing the time the animals spend in the tank. After 3 days of submitting mice to WAS test for 20 h per day, mice increase the number of writhes after intraperitoneal (i.p.) administration of acetic acid and also increase the GI transit, measured as the intestinal length traveled by a charcoal meal after 20 min of feeding [58]. Restraint stress was initially introduced in 1988, as a model to mimic IBS [59]. This model is performed by wrapping the upper forelimbs, shoulder and trunk of rats in cloth tape to induce mild restraint stress. Usually, it is performed in a single session, and symptoms similar as those in IBS-D are seen: increased intestinal transit, and stimulated large intestinal transit with increased FPO and visceral pain [59–62]. Similar to what happens in the WAS test, colonic motility is increased, with higher FPO and increased colonic contractility, although gastric emptying is delayed [63–65]. When animals are restrained at a cold temperature, both stressors have an additive effect, increasing the number of fecal pellets, as well

Chapter 15 Preclinical models of irritable bowel syndrome

as the water content of the stool [65], though the effect over GI transit is modest [21, 65]. Different modalities of this model have been developed, with the use of small adjustable cylinders, and increasing the time of application of the stressor, also causing visceral hypersensitivity and increased gut permeability and mucosal inflammation [27, 66]. However, habituation to repeated psychological stressors is an adaptative mechanism which can limit the occurrence of stressrelated symptoms, including stress-induced alterations of GI motility [63, 67]. In an attempt to model chronic daily stressors in rodents, the chronic unpredictable mild stress (CUMS) paradigm was developed, which could be useful when studying the mechanisms of chronic visceral pain comorbid with depressionlike symptoms. This paradigm consists in submitting the animals to different stress procedures each day for 7–10 days (or once each week for a longer-lasting paradigm), so that habituation does not occur. Different situations can be used, i.e. forced swim (FS), 24 h of food or water deprivation or cold restraint [68–70]. Other models such as social defeat model or overcrowding, both models of chronic social stress, induce anxiety- and depression-like behaviors [71] as well as visceral hypersensitivity but, curiously, decreased FPO [72].

Stress during early life In the past years, early adverse life (EAL) events in the form of sexual, physical, or emotional abuse or trauma have been identified as risk factors for the development of adult IBS. Also, a greater perceived severity of the traumatic events and the type of trauma increased the odds of developing IBS [73, 74]. Although the exact mechanisms by which EAL events can predispose to IBS and other health problems are yet unknown, it is thought that there is a final dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and an altered regulation of GI function by the autonomic nervous system [75]. Because animal models are a necessary tool to examine the neurobiological mechanisms underlying the association between EAL events and visceral hypersensitivity, the use of animal models of EAL events have recently increased drastically. Numerous different models have been used and with multiple methodologies, including maternal separation, maternal deprivation, or neonatal limited bedding (for review see [76]). Maternal separation (MS) is the most frequently used model to study the mechanisms of early life stress in IBS induction. It consists in removing the pups from the dams for 3 h each day at

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postnatal day (PND) 2–14th. The pups are placed in a warm room or on an electric blanket to maintain body temperature; afterwards, the pups are returned to the dam’s cage [29, 77]. However, differences in the experimental procedures can be found across the different studies, i.e. in the particular days in which the pups are removed from the dams [27, 78, 79] or in the portion of the litter that is separated [61]. Most studies have found that MS induces a series of cognitive, anxiety- and depression-related alterations during the adult life, observed in different paradigms as in the light box, and reduced FUST and sucrose intake [80]. Also, most studies have found an increase in visceral sensitivity during the adult age, measured as an increase in the visualized AWR in male and female rats [7, 61, 77] and EMG activity in response to CRD at different pressures in rats [77, 80] and mice [26, 78]. Nevertheless, in some studies it has been necessary to add a second stressor to develop this hypersensitivity [79, 81]. In fact, the application of a second stressor during adult life has been shown to increase corticosterone levels in plasma at higher concentrations in MS animals than in control ones [29]. Authors explain the differences observed across studies as related with the different strains and methodologies used [79]; i.e., BALB/c mice (a higher anxiety strain than C57Bl/6 mice), and Wistar Kyoto rats have been shown to be stress-sensitive strains, exhibiting a high anxiety phenotype [6, 82]. But also the different methodologies used during CRD (tonic vs phasic stimuli) [9], as well as the nature and number of the second stressor [81, 83] can account for these differences. Fewer studies have evaluated FPO in MS animals. Interestingly, Yi et al. [80] found that, during adolescence (PND 35), MS rats showed a reduced FPO when compared to controls, whilst on PND 56 (young adult age) FPO was significantly increased when compared to controls. The authors suggested that MS rats show alternating constipation and diarrhea changes from the prepuberal to the adult age. In line with these findings, the percentage of water present in feces increases in MS male (but not female) mice from the 6th to the 12th week of age, whilst in control animals the percentage of fecal water content tends to decrease over time; also GI transit increases in MS mice at 12 weeks of age [26], and intestinal permeability is likewise increased when compared to controls [29, 78]. Other less frequently used models of early life stress include the limited nesting model, in which dams and their pups are placed in a wire-bottomed cage and supplied with a single paper towel as nesting material from PND 2 till PND 9–10; this paradigm

Chapter 15 Preclinical models of irritable bowel syndrome

has also been shown to induce visceral hypersensitivity [84, 85]. An additional neonatal stress-based model is the odorattachment learning paradigm, which consists in submitting the pups to peppermint odor and subsequent 0.5 mA shocks to the base of the tail 2 min after odor presentation during PND 8–12; each day, pups received eleven 30 s-trials with a 4-min intertrial interval; as a result, animals which have suffered this type of stress display visceral hypersensitivity and increased permeability in adulthood [86]. Additionally, other forms of physical stress, including direct irritation of the colon, have been applied before weaning and its consequences evaluated in adulthood. Thus, i.c. administered irritant compounds such as acetic acid or mustard oil, or mechanical irritation through CRD have been applied in pups at different times. This provokes a visceral sensitized state during adult age, in the absence of inflammation or disrupted growth of the colonic tissue [87–89]. Still, the consequences on stool formation are different: whilst CRD seems to induce an IBS-D-like syndrome, with softer and amorphous stool during adulthood [90], acetic acid induces a reduction in FPO and feces with less content of water [91]. Finally, very few studies have assessed the effect of gestational stress on the offspring. In two previous studies, in which the pregnant dams were submitted to heterotypic intermittent stress (WAS 60 min, cold restraint stress at 4 °C for 45 min and FS for 20 min) until delivery, the adult offspring presented visceral hypersensitivity in response to CRD, measured through EMG recording [92, 93]. A recent study performed in mice has shown that pregnant dams submitted to restraint stress deliver offspring with important damage of the intestinal wall but the functional consequences in adulthood were not described [94].

Models of IBS with constipation IBS-C is the most often diagnosed and reported form of IBS [95]. For these patients, most bothersome symptoms are constipation, abdominal pain or discomfort, bloating and other side effects like headache or flatulence [95–97]. Furthermore, although considered a benign condition, IBS-C can lead to serious complications such as fecal impaction, incontinence, hemorrhoids, anal fissure and bleeding and even bowel perforation [95, 98]. Conventional treatment targets a single symptom, altered bowel movement, rather than the whole pathophysiology of IBS-C, and it is not always successful [95, 99]. Thus, preclinical studies are required for the identification of novel targets to treat IBS-C as a whole.

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Unfortunately, preclinical models of IBS-C in which the presence of both colonic hypersensitivity and constipation are demonstrated, are scarce. Interestingly, constipation (reduced intestinal transit, colonic propulsion and FPO) may occur at some phases during the development of some models, as described above [95, 99], but it is more often induced to study disorders different from IBS-C, namely chronic constipation, like that associated with opioid administration for chronic pain treatment [100]. Obviously, in this case, no attempt is generally made to evaluate visceral sensitivity because mimicking IBS-C is not the aim of these studies. Still, opioids, atropine or even fibreless or high-fat diets are used to induce models displaying constipation [101–103] in which the laxative or anti-constipating effects are tested for drugs that also reduce visceral hypersensitivity in more classical IBS models [104], like those described above (more often associated with diarrhea). Thus, even if positive, in most preclinical studies on IBS-C results are separately obtained from models displaying either constipation or visceral hypersensitivity. One model in which both constipation and visceral hypersensitivity have been shown to occur concurrently is induced by intragastric administration of cold saline (0–4 °C, 10 mL/kg) for 14 consecutive days. After an additional period of 14 days, rats subjected to this stimulation display an increase in abdominal contractions in response to CRD (using either EMG recording of VMR or AWR behavioral scoring) and reduced production of feces, with a dryer (less moistened) consistency compared with controls (that received saline at room temperature, RT). This model also reproduces some of the characteristics found in humans, including an increased number of inhibitory neurons immunoreactive for neuronal nitric oxide synthase (nNOS) in the myenteric plexus [105–107]. Therefore, the intragastric administration of cold saline may represent a kind of physical stressor leading to IBS-C-like symptoms at that particular time point. As discussed above, constipation was found to occur short after stimulus application in some IBS models, but diarrhea occurred at longer times [80]. Thus, it would be necessary to ascertain if alternation also occurs in this model, with a constipation phase being followed by a diarrhea phase. Although this model does not seem to represent a physiopathological situation, we have confirmed the development of IBS-Clike symptoms in our own laboratory (Fig. 2). Thus, as shown by radiographic techniques and the bead expulsion test, colonic transit was delayed, and CRD induced by phasic stimuli elicited an increased number of abdominal contractions at low intracolonic pressure in conscious rats treated with cold saline, compared

Fig. 2 Summary of results obtained in rat models of IBS-C (based on experiments obtained at URJC laboratory). Model 1: Animals were exposed to standard diet (CTRL) or a purified diet (AIN93G) enriched in evening primrose oil (EP), but were otherwise undisturbed. Model 2: Animals were exposed to standard diet but received a daily intragastric administration of saline at room temperature (RT) or at 0–4 °C (cold saline, C-S) for 14 days. Different parameters were evaluated 28 days after the beginning of exposure to diet or to intragastric saline. Visceral sensitivity was evaluated using phasic (3  20 s long stimuli in a period of 5 min) or tonic (1  5 min long stimulus) colorectal distension (CRD). Gastrointestinal motor function was non-invasively evaluated using radiographic methods (X-rays); in brief, rats received a load of contrast medium (barium) and X-rays were taken at different time points thereafter (representative X-rays taken 2 and 6 h after barium for each experimental group are shown above the table; scale bar: 3 cm; S, stomach; SI, small intestine; C, caecum; FP, fecal pellets within the colorectum). Both sexes were used in model 1 (except for visceral sensitivity to tonic stimulation, where only males were used), whereas only males were used in model 2. For CTRL, differences of females vs males are specified. For EP, differences with the correspondent CTRL sex are specified. For RT-S, differences with CTRL males are specified. For C-S, differences with RT-S are specified. F, females; M, males; N.D., not determined. *Published results [22].

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with controls. However, both groups of rats (treated with cold and RT saline) showed an increased number of mast cells in colon submucosa compared with undisturbed rats (see below for a deeper description of IBS-derived biopsy studies). Furthermore, the model was used as positive control to study the possibility that diets with different composition in fiber and fatty acids might also induce IBS-C-like symptoms in the rat. In this case, a purified AIN93G diet was used to feed adult male rats. This diet was developed in the 90s to feed developing animals [108]. All the fat in this diet is from soy oil (SOY), but half of it was replaced by coconut (COCO) or evening primrose (EP) oil in two additional experimental groups. These diets also have a lower proportion of fiber compared with the standard laboratory chow. As a result of a 4-week exposure to these diets, animals displayed a reduced colonic propulsion in the bead expulsion test (but not in the X-ray study), a reduced and less organized motor in vitro activity of the colon, an increased visceral nociception in response to CRD induced by phasic stimulation (data not shown), and an increase in colonic mast cell density [22]. More recently, female rats appeared to be more sensitive to these diets regarding intestinal transit, which was reduced in the X-ray study, but no difference was found to occur between diets in the CRD study. Finally, behavior was evaluated both using the open field test (to assess exploratory behavior), and the splash test (to evaluate anhedonia). In these tests, regardless of the sex of the animal, behavioral alterations were more common when exposed to EP diet (these results have been accepted as a poster to be presented at the next conference of the Federation of Neurogastroenterology and Motility, FNM, that will take place in Adelaide, Australia, in March 2020). In summary, IBS-C-like models are difficult to develop and may be dependent on the particular time point after stress induction. Alternatively, some diets that induce constipation might represent more physiological models of IBS-C and other functional disorders of the GI tract, like functional constipation, depending on sex. In addition to GI motor function studies, visceral sensitivity, mucosal permeability and behavioral evaluations are needed in order to fully characterize the usefulness of the IBS-C (and IBS-D) models to closely mimic the different clinical situations.

In vitro methods to study irritable bowel syndrome The pathogenesis of IBS is scarcely understood. In fact, the lack of animal models displaying all the symptoms represents a main challenge that compromise the development of effective

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therapeutic approaches. However, a series of in vitro methods have been developed in the last two decades trying to deal with this problem (Table 2). These methods have shown that altered mucosal and immune function, altered enteric microbiota and altered nervous communication between gut and brain play a central role in the symptoms described by patients. Two main approaches have been assayed: biopsies from IBS patients and IBS models; and cultured cells, organoids or even the whole organ exposed to extracts from human biopsies or fecal supernatants from IBS patients. In these models, aspects like mucosa permeability, soluble protein expression and neuronal sensitization have been addressed by a series of methods such as immunohistochemistry, transmission electron microscopy, spectrophotometry,

Table 2 Advantages and disadvantages of in vitro techniques used to study irritable bowel syndrome (IBS). Technique

Advantages

Disadvantages

Biopsies

Allows the study of ultrastructure and protein expression in mucosa of human and animal samples

Ussing chambers

It permits to study mucosal permeability of isolated human and animal samples in detail

Cell/organ cultures

Reproducibility It permits to study in detail the effect of IBS soluble factors and microorganisms on human cell lines and small organ-like structures Allows the study of large preparations of isolated nervous plexuses of animal samples

Scarce availability of human biopsies Intrinsic variability of human samples It does not allow to study the whole organ It does not allow to study the whole organ and the interaction with gut wall layers other than mucosa Scarce availability of human biopsies It does not allow to study the whole organ Cell lines only partially mimic normal adult digestive cells

Whole mount preparations Organ bath

It permits the study of changes in contractility or neuronal electrical activity of whole samples exposed to IBS soluble factors

Gut-ona-chip

Reproducibility It allows to partially model the structure of the mucosa

See text for details.

It does not allow to study the whole organ or human samples Sample thickness may complicate immunostaining It is not possible to use human samples from IBS patients or healthy volunteers Samples can be maintained only for a limited time It does not allow to study the whole organ Cell lines only partially mimic normal adult digestive cells

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transepithelial electrical resistance, protein and RNA quantification, patch clamp, and voltage or calcium sensitive dyes among others. These models and methods will be discussed next.

Studies in biopsies from IBS patients and animal models Protein expression and immunohistochemical studies The mucosal barrier is the main responsible agent protecting the body’s internal milieu from the external digestive environment. It acts as a semipermeable barrier allowing the absorption of nutrients but limiting the transport of potentially harmful antigens and microorganisms. Epithelial permeability is controlled by tight junctions, protein complexes at the apical side of the cells composed by transmembrane claudins, occludin, and the junctional adhesion molecule (JAM) among others, which interact with zonula occludens (ZO) proteins that bind actin cytoskeleton and its associated proteins [109, 110]. Immunohistochemical labeling techniques have been widely used to study the expression of these proteins since this technique allows the characterization of protein location and the quantification of their variations by means of software packages or western blotting. A number of studies using biopsies from IBS patients have suggested that an increase in intestinal permeability could be a key factor of IBS progression. For example, it has been shown that there is a relationship between alterations in intestinal permeability in IBS-D and a decrease in ZO-1 expression. The location of this protein varies, moving from the cell membrane to the cytoplasm, suggesting its internalization [111]. Similarly, Boyer and coworkers [112] also detected a decrease in ZO-1 protein that correlated with an increase in intestinal permeability. Modifications in the expression and immunohistochemical labeling of claudin 1 have also been observed in patients with IBS-D [113]. A decrease in the expression of other proteins of the tight junctions such as claudin-2 and occludin and an increase in the phosphorylated myosin light chain has been detected in biopsies of IBS-D patients as well as, again, internalization of components of the tight junctions to the cytoplasm [111]. Interestingly, dietary changes have also been found to affect mucosa permeability in IBS-D patients, since they may increase myosin light chain phosphorylation and therefore permeability [114]. Some studies relate these changes to an increase in degradative activity by proteasomes, the protein complexes with protease activity responsible for the destruction of proteins in the cytoplasm [115]. Using tissues from animal

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models and human biopsies, a decrease in proteins such as occludins, ZO-1, ZO-2 or claudins has been quantified by PCR or Western blotting [116–118], although in some studies using IBS-C biopsies no variations were found [119]. Immunohistochemical labeling has also been used to study variations in the number of mast cells, T lymphocytes, enteroendocrine cells and in stem cell populations in the intestinal epithelium. Mast cells are part of the innate immune system and are commonly found in the intestine, contributing to the modulation of a wide variety of gastrointestinal processes. Mediators released by these cells are directly related to the generation of visceral hypersensitivity and abdominal pain and have also been shown to be greatly involved in the modulation of paracellular permeability [120]. Among these mediators, tryptase seems particularly relevant since it can activate the protease-activated receptors of epithelial cells, which allows modulation of tight junction proteins [121, 122]. Mast cells can be studied and quantified using routine histological staining, such as toluidine blue, or using antibodies against CD117 or tryptase. In general, these methods have revealed an increase in mast cell populations in the IBS samples [111, 112, 123–129] and in some cases they have allowed to determine the proportion of these cells located near the nerves of the mucosa, labeling these nerves with antibodies against PGP 9.5, or calcitonin gene-related peptide (CGRP) [124, 130]. T cells are involved in adaptive immunity, the activation of other cell types, such as B lymphocytes and macrophages, and the destruction of infected host cells [121]. Proinflammatory interleukins (IL) derived from T cells and cytokines have been implicated in the alteration of the intestinal epithelial barrier. Among them, it has been shown that tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ) are key effector molecules in the deregulation of the transcellular and paracellular pathways. Several authors have analyzed the presence of intraepithelial lymphocytes in patient biopsies, previously labeled with anti-CD3 antibodies. In this case, cell counting did not provide relevant results, except in situations of PI-IBS [111, 112, 123, 126, 128, 131]. Immunohistochemical labeling of endocrine cell populations in the gastrointestinal tract using antibodies against secretin, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP), somatostatin or serotonin (5-HT) antibodies have shown a decrease in duodenal biopsies of patients with IBS and even differences between IBS subtypes [132, 133]. The hormones secreted by intestinal endocrine cells regulate intestinal motility, visceral sensitivity, and secretion. Abnormalities in intestinal endocrine cells may then explain intestinal dysmotility, visceral hypersensitivity and

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abnormal secretion observed in patients with IBS. Among these cell populations, enterochromaffin cells synthesize, store and secrete 5-HT. Enterochromaffin cells are located by labeling with antibodies against chromogranin A and 5-HT and an increase in their number has been detected in biopsies from IBS patients and animal models [126, 127, 134, 135]. Finally, some investigations in stem cell populations of the intestinal epithelium have been carried out using antibodies anti-mushashi-1 or anti-neurogenin-3 showing a decrease of these markers in IBS. These changes may reveal problems in the renewal of cellular populations of intestinal epithelium [133, 136].

Transmission electron microscopy studies Transmission electron microscopy (TEM) allows the study of ultrastructure of cells and cellular components. It has been used to analyze structural alterations related to intestinal permeability and changes in populations of the intestinal epithelium and immune system. Thus, it has been shown that the intestinal mucosa of patients with IBS-D shows alterations such as exfoliation of the microvilli, increased extracellular vesicles in the intestinal lumen, presence of numerous multivesicular bodies in the epithelial cells, presence of necrotic cells, dilated intercellular junctions and an increase of intercellular distance [137]. Similarly, an increase in mucus secretion has been detected to occur in goblet cells, indicating mucositis in intestinal cells of the ileum and colon of patients with IBS-D and IBS-C. On the other side, the neuroendocrine cells of these patients presented a large number of endocrine granules and vacuoles in their cytoplasm [113]. Ultrastructure of the tight junctions has been analyzed in detail, revealing morphological changes in the samples of biopsies from IBS patients, related with changes in permeability [122]. Differences between IBS subtypes have also been detected. Thus, Cheng and co-workers found, in biopsies from IBS-D patients, open spaces between tight junctions that did not occur in patients with IBS-C or controls [113]. Furthermore, TEM has also allowed to study the passage of normal bacteria such as E. coli and pathogens such as Salmonella through the intestinal epithelium in biopsies from IBS patients, showing an increase of transcellular passage of Salmonella through endocytosis mechanisms [138]. Transmission electron microscopy also provides information about the changes that occur in mast cells during the development of the disease. Specifically, it has been used to count the number of mast cells per area and detect those with signs of

Chapter 15 Preclinical models of irritable bowel syndrome

degranulation. In activated mast cells, events like the solubilization of the content of granules and the fusion of granules with the plasma membrane have been observed. This technique has also been useful for determining the relative position of the mast cells to the mucosal nerves [124]. Biopsies from IBS patients have revealed to have a larger area occupied by mast cells, a greater number of activated mast cells and a greater number of mast cells located near the nerves. It is thought that the action of the substances released by the mast cells sensitizes the nerve endings, offering a possible explanation to visceral hypersensitivity [113, 124, 125, 139]. TEM has also revealed alterations in the general structure of mucosal nerve fibers in IBS biopsies [140]. Finally, studies performed in normal human colonic biopsies exposed to the stress-related corticotropin-releasing hormone (CRH), also revealed changes in the number of mast cells and increased signs of degranulation [141].

Ussing chambers to study mucosa permeability of IBS patients and animal models Ussing chambers, designed by the zoologist Hans Ussing in 1950, are used to study tissue permeability. In these devices, the studied tissue is located separating two halves of a chamber, with initially identical electrolyte concentrations in each half [142]. In the case of IBS, Ussing chambers are widely used to study the epithelia that covers the gastrointestinal tract. This device allows different types of measurements to study the permeability of the tissue located in the central area of the chamber. (1) Transepithelial resistance (TEER) analyzes the electrical resistance of cells to the passage of an ion flow. It is a very sensitive and reliable method to study tissue integrity and permeability, with low TEER values indicating a greater permeability. This type of technique is also suitable to continuously monitor the integrity of the epithelial barrier. Active and passive transport contributes to total ion flow that crosses epithelial tissues. Once mounted in the Ussing chamber, an external current is passed through the tissue obtaining a measurement of ionic flow. Transepithelial resistance has been used to assess mucosal permeability in biopsies from IBS patients and animal models [119, 141, 143–145]. The general pattern observed in the samples is an increased mucosal permeability. (2) Paracellular flow measurements can be performed in these chambers using a colorimetric or fluorescent probe such as horseradish peroxidase, FITC-dextran or fluorescein 5.6 to

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quantify the passage across the epithelium. Studies performed using human IBS biopsies or biopsies from laboratory animals after adding fecal supernatants from IBS-D patients [146] have confirmed an increase in paracellular flow related to the alterations observed in the tight junctions by immunohistochemistry and electron microscopy [118, 119, 129, 143, 145–150]. However, it is important to note that measurements of TEER and paracellular flow are indicators of epithelial and tight junction’s integrity but determine different experimental parameters. Whereas TEER is mainly due to the plasma membrane, the paracellular resistance is due to the junctions between adjacent cells [151]. Thus, TEER reflects the ionic conductance of the transcellular pathway in the epithelium, while the flow of non-electrolytic tracers indicates the macromolecular paracellular flow, as well as the pore size of the tight junctions [152]. (3) The short-circuit current (Isc) has also been used in electrophysiological measurements made with Ussing chambers. Isc refers to the current that is required to cancel the potential difference of the tissue and is the sum of all ionic currents through the epithelium [142]. Isc allows to determine the active transport of substances through epithelial cells and this parameter has been used to study the influence of stress, soluble mediators and leptin in IBS pathology but no significative changes have been detected [144, 147, 153, 154]. (4) In some experiments, the passage through the epithelium of fluorescently labeled bacteria such as E. coli and Salmonella has been analyzed in the Ussing chamber, and these experiments have shown an increase in the passage of these bacteria in IBS conditions. In addition, Salmonella produced a decrease in TEER values [138]. Altogether, the studies performed with Ussing chambers have allowed to determine the effects on permeability of various factors such as the involvement of pathogenic bacteria [138], stress-related hormones that increase permeability [141, 143, 147, 154], the effect of the intake of some antibiotics [145], the beneficial effect on permeability of guanylate cyclase agonists such as linaclotide [86], plecanatide or dolcanatide [150] or the increase in permeability produced by soluble mediators extracted from the tissues of patients with IBS applied to healthy tissues [146, 148, 153]. However, the limited availability of biopsies is an important limitation for this kind of studies, and the reason why using other methods like cell cultures has become popular to test alterations

Chapter 15 Preclinical models of irritable bowel syndrome

in the gut physiology. In addition, it must be taken into account that these techniques are expensive and require specialized and trained personnel to be performed and to interpret results properly.

Cell and organ cultures and organ bath studies Cell and organoid cultures Two human epithelial colon adenocarcinoma cell lines are commonly used, Caco-2 and T84. However, they are not fully equivalent, Caco-2 being more similar to enterocytes of the small intestine than to colonocytes [155]. These cells are seeded onto porous filters in Transwell chambers where they form an epithelial polarized monolayer separating two spaces after 2–3 weeks. Similar to experiments performed with the Ussing chambers, permeability may be measured by means of changes in TEER between the upper and the basolateral chamber and/or the passage of fluorescence molecules across them. In this way, increased permeability has been found after exposing the cells to supernatants obtained after incubation of human IBS biopsies [118, 156, 157] or fecal supernatants from IBS patients [158]. In all cases the soluble mediators released from biopsies or feces of IBS patients evoked an increase in epithelial permeability that might be reverted by probiotics [118, 156]. Several soluble factors may play a role in this epithelial dysfunction. Luminal proteases obtained from feces have been shown to affect tight junction proteins. Specifically, serine protease levels are elevated in diarrhea-subtype IBS patients and alter ZO-1 distribution [146]. On the contrary, cysteine proteases are predominant in the feces of the constipation subtype and degrade occludins [158]. Another important protein that has been implicated in IBS is tryptase, released by mast cells. As mentioned above, the mast cell population is significantly increased in many IBS biopsies and correlates with IBS symptoms [120, 159, 160]. Release of tryptase increases permeability measured with Transwell inserts [161]. When Caco-2 cells are co-cultivated with a human mast cell line (HMC-1), degranulated tryptase increases permeability to fluorescence dextrans, decreases TEER and opens tight junctions by decreasing JAMs, which are also reduced in IBS biopsies [162]. Cell culture has also been used to study PI-IBS, a form of IBS that affect an important percentage of patients after an inflammatory process, mainly bacterial gastroenteritis [163]. The effect of Chlamydia trachomatis infection has been studied in inoculated

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LCC-18 cells, derived from a neuroendocrine colon tumor and CNDT-2 cells, derived from small intestinal carcinoid. In both cases a down-regulation of genes related with vesicular transport has been found [164]. Similarly, giardiasis, induced by Giardia duodenalis, is a risk factor of PI-IBS that generates dysbiosis, enterobacterial invasion, tight junctional disruption and apoptosis, as shown in co-cultures of bacteria and Caco-2 cells [165]. The effect of probiotics and their postbiotic mediators has also been studied in vitro. In this case, colonic mucosal biopsies from PI-IBS patients of the diarrhea subtype were cultured on Netwell inserts, a kind of Transwell chamber with larger pore size specially adapted for tissue slices, with Lactobacillus casei. Proinflammatory factors, significantly elevated in PI-IBS, were reduced both at the RNA and protein level by exposure to the probiotic [166]. Overall, these studies clearly suggest that barrier function breakdown, with the possibility of bacterial invasion and immune system activation, plays an important role in the pathogenesis of IBS, including pain hypersensitivity. Indeed, supernatants obtained from biopsies of IBS patients have been shown to be able to activate neurons from the enteric plexuses and from dorsal root ganglia (DRG). Neuron activation has been shown by means of calcium sensitive dyes in mice DRG neurons cultured with serine proteases or mast cell mediators released by human colonic IBS-D biopsies [125, 167]. Similarly, isolated murine DRG neurons have been used to address their excitability after overnight incubation with supernatants of biopsies from IBS patients. Patch clamp recordings showed a marked increase in neuronal excitability after exposure to IBS-D mediators but not with the constipation subtype [168]. Regarding enteric plexuses activation, human samples obtained after colectomy have been used to isolate the inner submucosal plexus by removing the mucosa and the muscular layers. Individual ganglia were then stained with voltage-sensitive dyes, exposed to supernatants from human IBS biopsies and the changes in fluorescence intensity corresponding to changes in membrane potential were thereafter optically recorded. The neuronal activation was mediated by 5-HT, histamine and tryptase, whose levels were increased and correlated with activation [169]. Mast cell mediators and 5-HT levels have also been observed to correlate with severity of symptoms in mesenteric afferent nerve recordings of isolated rat jejunum previously perfused with human IBS supernatants [125, 127]. Finally, enteric glial cells have also been studied given their importance in neuronal physiology. Embryonic rat glial cells have been isolated, cultured and exposed to human biopsies supernatants and their protein expression and ATP-induced calcium

Chapter 15 Preclinical models of irritable bowel syndrome

response, important for gap junction signaling, have been analyzed. Less glial cells were found after exposure to IBS-C supernatants, and calcium response to ATP was reduced in cells cultured with IBS-D and IBS-M supernatants [170]. One problem of using cell cultures is that cells in a monolayer can hardly recapitulate the original structures where they come from. In fact, cells in the body are in close relationship one with another, building 3D structures and growing under the conditions of a certain environment. On the other hand, the cell lines more commonly used are originated from cancerous tissues and unable to mimic normal cell behavior, in particular considering that one of the characteristics of malignant tumors is to stop forming an epithelial monolayer, whereas the integrity of the mucosa is an important point in IBS. Looking for more physiological models, three-dimensional structures of human epithelium have been generated from human small intestinal crypts (enteroids) or from colonic crypts (colonoids). These structures were exposed to fecal supernatants from IBS patients of undefined subtype, the permeability tested with FITC-dextrans, and tight junction protein expression evaluated by biomolecular techniques. Barrier function was altered, with increased permeability, but this was prevented by the addition of Lactobacillus rhamnosus GG [171]. Enteroids and colonoids are, however, a partial solution since they contain all major epithelial but lack other cell types, like smooth muscle, fibroblasts, vascular cells or nerves. A more complex approximation has been the development of human intestinal organoids (HIO) containing most intestinal cell types, generated from pluripotent stem cells. These HIO are composed of epithelial and mesenchymal cells with the epithelial surface facing the interior of the structure. Furthermore, the epithelium contains functional enterocytes, goblet, Paneth, and enteroendocrine cells retaining basic intestinal function. However, these organoids were absent of vascular and nervous cells [172]. It is then necessary to develop more functional human organoid systems comprising more cell types and extracellular scaffolds to mimic the intestines 3D geometry as a screening system to study the complex relationship between luminal factors, mucosa permeability, immune system and enteric neurons, as occurring in IBS [173–175].

Whole-mount preparations Some of the problems cited above may be solved studying some of the digestive structures as a whole. Whole mount preparations of whole tissues in combination with immunohistochemical analysis are very useful for the study of organs with a large

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surface area and diversity of regions, i.e. nervous plexuses. The greatest limitation of the use of whole mount preparations lies in the difficulties antibodies may have to penetrate the tissue, which makes necessary a previous preparation of the sample. Consequently, the mucosa and muscle layers are removed to expose the submucosal plexus, or both mucosa and submucosal layers are removed in order to expose the myenteric plexus. In this way, several analyses have been performed. Firstly, changes in the populations of excitatory and inhibitory neurons within the enteric plexuses have been evaluated. In this case, a pan-neuronal marker (anti Hu-D) was used to label all enteric neurons and a double labeling was performed with antibodies to excitatory (anti-choline acetyltransferase (ChAT), anti-calbidin, anti-calretinin) or inhibitory neurons (anti-nNOS), anti-vasoactive intestinal peptide (VIP)) to quantify the neuronal subtypes present in the enteric ganglia. A decrease in the number of nNOS-labeled inhibitory neurons in the myenteric plexus or an increase in ChAT- and VIP-labeled neurons was detected in the submucosal plexus of patients with IBS-D [176], although in other cases no significant differences were detected [177]. As mentioned earlier, numbers of nNOS neurons were decreased in the IBS-C model induced by intragastric administration of cold saline [105]. Secondly, analysis of changes in populations of glial cells and their interrelation with the neurons of the plexus, as well as the morphology presented by glial processes labeled using anti-S100β or anti-glial fibrillary acidic protein (GFAP) antibodies. Using this methodology, hyperplasia of glial cells has been detected in animal models of IBS together with an increased number of glial processes surrounding enteric neurons with distinct morphology [178]. These morphological changes seem to be accentuated by stress [177, 179]. Finally, the integrity of the enteric nerves has been studied by means of intermediate filaments distribution using antibodies against peripherine and beta-tubulin III. In this case, IBS caused structural alterations in animal models such as reduced peripherin expression [178]. In addition, whole mount preparations can be used to perform ratiometric calcium imaging recordings, which allows measuring changes in intracellular calcium as a marker of neuronal excitability. These studies have been used to determine the effects of plasma obtained from IBS patients on healthy animal tissues. The soluble mediators in this plasma stimulated a robust increase in Ca2+ intracellular concentration in submucosal neurons [153]. On the other hand, the use of the whole mount preparations can be extended to intracelullar evaluation of electrical behavior

Chapter 15 Preclinical models of irritable bowel syndrome

of neurons of submucous and myenteric plexuses. Thus, it is possible to study the excitability of enteric neurons using micropressure techniques. Neuronal excitability is reflected as a depolarization of membrane potential and the discharge of action potentials. In these experiments, an intracellular electrode is inserted in the neuron, allowing to record the membrane potential [180]. Moreover, different cells mediators could be applied over those specific neurons with a puff allowing to analyze changes in excitability. For example, exposure of enteric neurons to mast cells mediators such as histamine, tryptase or prostaglandins in normal guinea pig samples results in an elevated neuronal excitability [181–188]. Considering this, this kind of studies might also be applied to study the electrical activity of neurons in whole mount preparations obtained from IBS models and (ideally) patients.

Organ bath studies Organ bathing uses isolated organs such as colon (segments or whole organ) or smooth muscle strips (with or without mucosa), keeping them in conditions as similar as possible to physiological conditions through the supply of electrolytes and essential nutrients, as well as maintaining temperature, oxygen concentration and pH conditions. Organ bathing is a classic pharmacological tool for assessing the concentration-response relationship in contractile tissues and it has been used to evaluate the basal contractile activity of tissues from animal models [189, 190], as well as the effects induced by antibiotics [145], hormones such as leptin, substance P (SP) or neurotrophic factors [144, 189, 191–194], or the implication of certain cellular receptors in the modulation of colon smooth muscle contractions, such as receptors for glucagon-like-peptide-1 (GLP-1) [24, 106], gamma-aminobutyric acid (GABA) [195], 5-HT [191, 196], TREK-1 subfamily of mechano-gated potassium channels [197] and opioid receptor like-1 (ORL-1) [198], and the action of their agonists or antagonists as possible therapeutic options. Organ bath has also allowed to study the implication of glial cells in the smooth muscle contraction in animal models of IBS, revealing their implication in the regulation of gastrointestinal function [177]. Similarly, organ bath techniques have been used to test the effect of supernatants obtained from biopsies of IBS patients on healthy tissues derived from patients undergoing colonoscopy for colorectal cancer screening [199], which caused a reduction in basal contractions on a concentration-dependent way, or to analyze in animal models hypercontractility produced by stress conditions

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[177, 194, 200], the therapeutic action of plant-derived products [193], and the modulation exerted by trimebutine maleate on Ca2+ and K+ ionic channels in PI-IBS [189]. Finally, the effect of gases produced by intestinal bacteria has also been studied in organ baths. For example, methane provoked an increase of the smooth muscle contraction, establishing a relationship between contractility and alterations in the microbiome of methane producing bacteria [201, 202].

Gut-on-a-chip In recent years, it has been proposed that the microbiota plays a fundamental role in the regulation of endocrine activity in the gastrointestinal tract. Since the intestinal epithelium acts as an interface between the microbiota and the immune system of the intestinal mucosa, the study of the interaction between these three elements can provide information about different intestinal pathologies, including IBS. In fact, many endocrine alterations suffered by patients with IBS could be related to changes in the composition of the microbiota and its metabolic activity [202]. One approach to study the microbiome is to perform co-cultures of the intestinal epithelium with microbiota for periods of 1 day or more using conventional or organoid culture models. However, in this type of co-culture, intestinal bacteria finally proliferate, damaging epithelial cultures. In addition, in this type of models it is not possible to reproduce the real physiological conditions of the intestine such as the morphology of the intestinal epithelium, mucus production or the presence of microvilli [203]. To facilitate the resolution of these problems, in vitro models of the human intestine have been developed to allow the study of the GI tract, combining microfluidics technology with organoid culture. These devices, called gut-on-a-chip, allow the study of factors such as intestinal permeability, pharmacokinetics or pharmacodynamics, creating structures that reproduce the real conditions of the GI tract. In general terms, they consist of two chambers with constant circulation of culture medium. A porous membrane is located between both chambers and serves as a scaffold for the culture of epithelial cells (cell lines or cells obtained from biopsies), usually coated with extracellular matrix proteins to favor cell anchoring and proliferation [203]. These devices can be used to perform permeability measurements using fluorescent probes, as well as to analyze the response to drugs or pathogens that are added to the luminal part of the chip [204]. Kim and coworkers have used these systems to study the relationship between the microbiome and the cells of the immune

Chapter 15 Preclinical models of irritable bowel syndrome

system with the intestinal epithelium. They seeded the apical chamber with a typical intestinal bacterium, Lactobacillus rhamnosus, and immune system cells were added in the lower chamber. Both chambers were separated by Caco-2 cell line cultured on the porous membrane. The use of this system allowed to prolong the culture for more than a week [205, 206]. In another study, a pathogenic strain of the intestinal bacterium, E. coli, that causes intestinal cell destruction and extreme diarrhea in humans and peripheral blood mononuclear cells were added in the upper and lower chambers, respectively, and it was observed that epithelial cells grown in the central support produced cytokines that altered the intestinal barrier function of the epithelium and its normal morphology [207]. By creating a personalized gut-ona-chip for selected IBS patients, valuable understanding on the efficacy of new drugs on individual patients could be gained, with the aim to reduce the exposure of patients to needless possible side effects [208]. Finally, it is important to note that although the in vitro procedures described above have shown that soluble mediators released by infectious agents, mast cells and/or enteroendocrine cells affect mucosa permeability and may sensitize nociceptive neurons, certain differences do exist in the results comparing not only the different IBS subtypes but also within the same subtype. This lack of consistency in the results is not strange since there is not a standardized method, and discrepancies do exist, for example, in the way the supernatants are obtained, the exposure time of cells or tissues to them and, finally, the intrinsic patients’ variability [120].

Conclusions This chapter offers an overview of the great variety of preclinical models and methods to evaluate the symptoms and pathogenic mechanisms of IBS. The immense complexity of this gut-brain interaction disorder justifies the need to adapt the model to the particular IBS type and underlying etiology and makes also results from preclinical evaluations very difficult to be reproduced in different laboratories. Most in vivo models have focused on evaluating the presence of visceral hypersensitivity, with those induced by i.c. TNBS, intestinal infection, chronic WAS and MS standing out for reproducibility and clinical translatability. Although these models tend to elicit diarrhea-like symptoms (increased GI transit, increased colonic propulsion, wetter stool), a more thorough evaluation of

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changes in GI (colonic) motor function and feces consistency, as well as intestinal permeability and associated behavioral changes is warranted in order to identify those models that more closely mimic the clinical situations and find more targeted treatment strategies. Moreover, in spite of the high clinical prevalence of IBS-C, models concurrently displaying visceral hypersensitivity and constipation (reduced GI transit, reduced colonic propulsion, dryer stool) are impressively scarce, and most researchers generally study the antinociceptive and anticonstipating effects of new drugs in separate models of visceral hypersensitivity, on the one hand, and constipation (which may be induced by drugs or diets), on the other. Studies of changes in intestinal permeability or behavior are practically inexistent in IBS-C preclinical models. The in vitro models have addressed the molecular changes in mucosal barrier integrity damage, immune system activation or enteroendocrine involvement underlying the development of IBS. Mucosal biopsies are relatively easy to be obtained for direct study of their cellular components or for extraction of soluble factors that may induce changes in neuronal activity (isolated or in whole-mount preparations), suggestive of hypersensitization or leading to changes in colonic contractility under IBS conditions. More sophisticated systems, like Ussing chamber techniques, cultures of enteroids, colonoids or HIO, as well as gut-on-chip are increasingly being employed to more precisely define particular aspects of cell-cell homotypic or heterotypic interactions occurring in the intestinal tissues and how IBS conditions may influence these interactions. Although more consistent results might be obtained with standardized protocols, a variety of models and methods will always be required to address IBS complexity. Thus, both in vivo and in vitro approaches are complementary and essential to advance knowledge on this complex GI disorder. Combined efforts from different laboratories using different models and methods are expected to lead to new more effective and safe treatments for IBS patients based on a better understanding of the underlying pathogenic mechanisms.

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[207] Kim HJ, Li H, Collins JJ, Ingber DE. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc Natl Acad Sci U S A 2016;113(1):E7–15. [208] Chong PP, Chin VK, Looi CY, Wong WF, Madhavan P, Yong VC. The microbiome and irritable bowel syndrome—a review on the pathophysiology, current research and future therapy. Front Microbiol 2019;10:1136 Frontiers Media S.A.

Index Note: Page numbers followed by f indicate figures and t indicate tables.

A Abdominal pain, 10, 146. See also Pain management Abdominal withdrawal reflex (AWR) score, 236, 240f Abincol®, 63 Acetaminophen, 161 Acetylcholine-induced CCA, 77 Acetylocholinesterase, 117 Adherens junctions (AJs), 45f, 46 Adipokines, 114 Adrenocorticotropic hormone (ACTH), 29, 207 Agoraphobia, 214 AIN93G diet, 246–248, 247f Alcohol intake, 187–188 Alcohol use disorder (AUD), 220 Allodynia, 11 Alosetron, 159 for IBS-D, 130t, 134 α-defensins, 44–45 Alverine, 131, 156 Amitriptyline, 154 Androgen receptor (AR), 73–75, 74t Androgens, 73 colonic motility modulation, 75–76 in visceral pain regulation, 78 Anhedonia, 211, 237–239 Animal models, 234–235 chemically-induced IBS models, 239–241 colorectal distension (CRD), 235–236 fecal pellet output (FPO), 236–237 in vivo models, 237, 238–239t limited nesting model, 238–239t, 244–245

maternal separation, 238–239t, 243–244 methods to study symptoms association, 239, 240f parasite infection-induced, 241 PI-IBS, 238–239t, 241 restraint stress, 238–239t, 242 social defeat model/ overcrowding, 238–239t, 243 stress-induced IBS during adult life, 241–243 with constipation, 245–248, 247f during early life, 243–245 WAS test, 238–239t, 242 writhing test, 236 Anorexia nervosa, 221–222 Antibiotic treatment, 155–156 Anti-CdtB, 113–114 Antidepressants, 153–155 for anxiety disorders, 214–215 for bipolar disorder, 211 Antidiarrheals, 158–160 Antigen-presenting cells, 49–50 Antispasmodics, 131, 156 Anti-vinculin antibodies, 113–114 Anxiety disorders, 213–215 Asimadoline, 135 ASP-7147, 139 AST-120, 136–137 Autonomic nervous system (ANS), 30, 175, 207

B Bacteroides spp., 15, 110, 168 B cells, activation of, 48t, 50

Beck Depression Inventory-II (BDI-II), 211 Benzodiazepines, 36, 155 17β-estradiol, 73, 74t, 75–76 Bifidobacterium spp., 110, 136, 195 B. animalis, 47–48, 136 B. bifidum, 63–64 B. infantis, 63, 151 B. lactis, 63–64 Bile acid, 115, 136–137 Bile acid malabsorption (BAM) syndrome, 111–112 Biomarkers, 108–109 adipokines, 114 genetic testing, 119–120 immune cell-derived, 116–117 inflammation-related, 109 intercellular interactions related, 113–114 intestinal permeability related, 112–113 leukocyte proteins, 115–116 lipid related, 115 microbiome-related, 109–112 neuropetides, 114 in panels, 117–119 Biopsies, mucosal transmission electron microscopy, 252–253 Ussing chambers, 253–255 ZO-1 expression and immunohistochemical labeling, 250–252 Bipolar disorder (BD) IBS association with, 209–210 occurrence, 209 treatment, 211 types, 209 Bloating, 63, 71, 103

277

278

Index

Bombesin receptors subtype 2 (BB-2), 139 Brain activity disorders, 208, 209f Brain-gut axis (BGA), 207–208. See also Microbiotabrain-gut axis (MBGA) central nervous system, 32 components of, 28, 29f enteric nervous system, 30–31 HPA axis, 29–30 IBS pathology, 11–12 immune system, 31 Brain gut-microbiota axis (BGMA), 60 Bristol fecal score, 237 Bristol Scale of stool, 103 British Dietetic Association (BDA), 173–174, 186 Bulimia nervosa, 221–222 Bulimia subscale of Eating Disorder Inventory, 222 Butyrate, 47, 111 Butyrylcholinesterase, 117 Butyrylo-CoA transferase, 178

C Caco-2 cells, 255 Caffeine, 170–171, 188 Calcitonin gene-related peptide (CGRP), 52, 251 Calgranulin C, 115–116 Calprotectin, 115 Campylobacter jejuni, 113 Cannabinoid receptor genes, 90–91 Cannabis use disorder, 220 Capsaicin, 152, 171 Casein, 190 Catastrophizing, 175 Catechol-O-methyltransferase (COMT) gene, 91–92 Central nervous system (CNS) brain-gut axis and, 28, 29f, 32 and mucosal immune system activation, 51 Chemically-induced IBS models, 239–241 Chlamydia trachomatis infection, 255–256

Chromogranins, 116 Chronic unpredictable mild stress (CUMS), 243 Cilansetron, 134 Citalopram, 154 Citrobacter rodentium, 241 Clinical diagnosis, 100–105 Clostridium difficile infection, 64, 177–178, 196 CNR1 gene, 90 Cognitive behavioral therapy (CBT), 147, 175–176 Cold saline (C-S), 246, 247f, 258 Colonic contractile activity (CCA), 75–77 Colonic motility, 76 Colonoids, 257, 262 Colorectal distension (CRD), 235–236, 240f Commensal bacteria, 47–48 Complete spontaneous bowel movement (CSBM), 131 COMT gene. See Catechol-Omethyltransferase (COMT) gene Constipation-predominant IBS (IBS-C), 3 FDA approved therapeutics, 130, 130t linaclotide, 132–133 lubiprostone, 132 rat models, 245–248, 247f SCN5A mutation, 87 serotonin level, 12 tenapanor, 133 Corticosteroids, 207 Corticotrophin-releasing hormone (CRH), 29–30, 207 Corticotropin releasing factor (CRF), 50–51 Cryptosporidium parvum, 241 Cytoskeletal distending toxin B (CdtB), 113

D Deep brain stimulation (DBS), 215–216 Defensins, 116–117

Dehydroepiandrosterone sulfate, 78 Dementia, 221 Desipramine, 154 Desmosomes, 46 Diagnostic questionnaire, Rome IV criteria, 101, 102–103t Diarrhea-predominant IBS (IBS-D), 3 adipokines in, 114 alosetron, 134 antispasmodic drug therapy, 156 asimadoline, 135 Bifidobacterium, 110 cilansetron, 134 eluxadoline, 135, 160 FDA approved therapeutics, 130, 130t gut microbiota and, 15 Lactobacillus, 110 loperamide, 135 ondansetron and granisetron, 159 probiotics, 136 ramosetron, 134 restless legs syndrome, 219 rifaximin, 136 SCN5A mutation, 87 serotonin level, 12 small intestine bacterial overgrowth, 61–62 synbiotic treatment, 63–64 tricyclic antidepressants, 153–154 Diet, 169 first line therapy alcohol, 171, 187–188 caffeine, 170–171, 188 energy and macronutrients intake, 187 fiber intake, 188–189 fluid intake, 187 milk and dairy products, limiting, 189–190 physical activity, 190–191 primary recommendations, 186–187

Index

spicy food consumption, 190 FODMAPs, 172 gluten-free, 194 and immune response, 170 impact on IBS symptoms, 185 limits, 185–186 low-FODMAP, 174, 174t, 191–193 medical food, 173, 173t probiotic supplementation, 194–195 role of, 18 traditional dietary advice, 173–174 Dietary fiber, 150, 188 Dietary modifications fiber based diet, 150 FODMAP-diet, 149–150 probiotics, 151–152 red pepper-capsaicin, 152 Diet-microbiome-metabolome axis, 111–112 Disaccharides, 18, 149, 172t Dorsal root ganglia (DRG), 256 Doxepin, 154 Drospirenone, 71–72 Dysbiosis, 15, 60

E Early adverse life (EAL) events, 243 Eating disorders, 221–223 Educational programs, 148 Elastase, polymorphonuclear neutrophil, 116 Eluxadoline, 135, 160 Empirical treatment, 131 Endocannabinoid (ECB) system, 90–91 Enteric glial cells, 77, 256–257 Enteric nervous system (ENS), 28, 29f, 30–31 Enterochromaffin cells (ECs), 12, 30–31 Enteroids, 257 Eosinophils, activation of, 48t, 50 Erectile dysfunction (ED), 220–221

Estrogen receptors (ERs), 73–75, 74t colonic motility modulation, 77 Estrogens, 75–76 Eubacterium spp., 168 Evening primrose (EP) oil, 246–248, 247f

F FAAH gene, 90–91, 93t Faecalibacterium prausnitzii, 168 Fat hypersensitivity, 171 FDA approved therapeutics, 130, 130t Fecal markers, 109 Fecal microbiota transplantation (FMT), 64–65, 177–178, 196 Fecal M2-PK, 116 Fecal pellet output (FPO), 236–237, 240f Federation of Neurogastroenterology and Motility (FNM), 248 Female urine sniffing test (FUST), 239, 240f Fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs), 18, 191, 192t features, 172 in food products, 172, 172t Fermented fiber, 150 Fibers, 188–189 Fibroblast growth factor 19 (FGF19), 115 Fluid intake, 187 Fluorescein isothiocyanate (FITC), 237, 240f Fluoxetine, 154 FODMAP-diet, 149–150 Free testosterone, 72 Fructans, 172, 172t Fulvestrant, 74t, 78–79

279

Functional bowel disorders (FBD), 100 Functional gastrointestinal diseases (FGID), 108–109, 118

G GABA. See Gamma aminobutyric acid (GABA) Gabapentin, 155 GA-mapTM Dysbiosis Test, 112 Gamma aminobutyric acid (GABA), 34f, 36 Gasogenic food, 171–172 Gastrocolonic reflex, 171 Gastrointestinal infections, 51 Gender-related differences, 70–71 Genetic predisposition, 86 SCN5A mutation, 87 single nucleotide polymorphism (SNP), 88 association with IBS, 92–93, 93t cannabinoid receptor genes, 90–91 COMT gene, 91–92 GNβ3 gene, 91 interleukin genes, 92 serotonin receptor genes, 89–90 serotonin transporter gene, 88–89 Genetics, IBS pathogenesis, 16–17 Genetic testing, 119–120 Gestational stress, 245 Giardia duodenalis, 241, 255–256 Glucocorticoids, 29 Gluten, 18 Gluten-free diet (GFD), 149, 194 GNβ3 gene, 91 Goblet cells, 44–46, 257 Gonadal hormones in colonic motility modulation, 75–77 in irritable bowel syndrome, 71–73

280

Index

Gonadal hormones (Continued) in visceral pain regulation, 78–79 G protein coupled estrogen receptor (GPER), 73, 74t, 78–79 Granins, 116 Granisetron, 159–160 G-1 treatment, 77 Guanylyl cyclase C (GC-C), 132 Guar fiber supplementation, 189 Gut-directed hypnosis (GDH), 176 Gut microbiota, 14, 28, 29f, 33, 44, 47–48, 194 alteration, in IBS patients, 60–61 density of, 58 fecal microbiota transplantation (FMT), 64–65 IBS pathogenesis, 14–16 mouse model, 59 post-infectious IBS, 59 role of, 58–59 small intestine bacterial overgrowth (SIBO), 61–62 Gut-on-a-chip, 260–261 Gut wall, 28, 29f

H Herbal supplements, 153 High-FODMAP diet, 192t, 193 Histamine, IBS pathogenesis, 13–14 5-HT. See 5-Hydroxytryptamine (5-HT) HTR3A gene, 88–89, 93t 5-HT receptor type 2A (HTR2A) gene, 89–90, 93t 5-HT receptor type 4 (HTR4) gene, 90 HTR3E gene, 89, 93t HTR4 gene, 90, 93t 5-HTTLPR gene, 88–89 Human β-defensin-2 (HBD-2), 116–117 Human intestinal organoids (HIO), 257, 262

Human mast cell line (HMC-1), 255 5-Hydroxyindoloacetic acid (5-HIAA), 119 5-Hydroxytryptamine (5-HT), 12, 88 MBGA pathways, 34f, 35 platelet-depleted plasma, 77 Hyperalgesia, 11 Hypnotherapy, 148 Hypothalamic-pituitary-adrenal (HPA) axis, 28–30, 29f, 207

I Ibodutant, 137 IgE-dependent inflammation, 170 IL-10 G1082A polymorphism, 92, 93t Immune cell-derived biomarkers, 116–117 Immune system activation of, 48, 48t B cells, 50 eosinophils, 50 in IBS, 50–51 macrophages, 49–50 mast cells, 49 T cells, 49 brain-gut axis and, 29f, 31 Immunoglobulin E (IgE), 170 Immunohistochemical labeling, 250–252 Inflammation-related biomarkers, 109 Insoluble fibers, 189 Intercellular interactions related biomarkers, 113–114 Internet delivered CBT (ICBT), 175–176 Interstitial cells of Cajal (ICC), 113 Intestinal barrier, 44, 45f Intestinal epithelium (mechanical barrier), 44, 45f, 58 goblet cells, 45–46 intracellular connections, 46 nervous system and, 51–52

paneth cells, 44–45 proteasome and, 46–47 Intestinal microbiota. See Gut microbiota Intestinal permeability related biomarkers, 112–113 In vitro methods, 248–250 advantages, 249t biopsies, mucosal transmission electron microscopy, 252–253 Ussing chambers, 253–255 ZO-1 expression and immunohistochemical labeling, 250–252 cell and organoid cultures, 255–257 disadvantages, 249t gut-on-a-chip, 260–261 organ bathing, 259–260 whole-mount preparations, 257–259 In vivo models, 237, 238–239t Irritable bowel syndrome (IBS) diagnosis, 2 diagnosis of, 184 epidemiology, 2 incidence, 2 lifestyle factors, 4 mortality rates, 4 prevalence, 2–3 socioeconomic status and, 4 subtypes, 3 symptoms, 1–2 Irritants, 238–239t, 239–240 Isoflavone treatment, 79

L Lactase, 189 Lactobacillus, 110 L. paracasei, 151–152 L. reuteri, 151–152 L. rhamnosus, 257, 260–261 L. salivarius, 151 Lactobacillus acidophilus NCFM, 151–152 Lactoferrin, 116 Lactose, 172, 172t Lactose-free diet, 189

Index

Lactose hydrogen breath test (LHBT), 190 Lamina propria, 44, 45f Laxatives, pain management, 157–158 Leaky gut, 237 Leukocyte proteins, 115–116 Limited nesting model, 238–239t, 244–245 Linaclotide, 157–158 adverse effects, 158 for IBS-C, 132–133 Loperamide, 160 for IBS-D, 135 Low FODMAP (L-FODMAP) diet, 173, 186, 191, 197 vs. control diet, 193 food products with, 192t implementation, 192–193 phases of, 174, 174t trials, 191 Low-grade mucosal inflammation, 17–18 Lubiprostone, 157 adverse effects, 157 for IBS-C, 132 Luminal distension, 185 Luminal proteases, 255 LX1031, 137 Lysozyme, 44–45

M Macrophages, activation of, 48t, 49–50 Major depressive disorder (MDD), 211–213 Manning criteria, 2 Markov clustering algorithm (MCL), 119–120 Mast cells (MCs), 251 activation of, 48t, 49 IBS pathogenesis, 13–14 infiltration, 109 up-regulation of, 75 Maternal separation (MS) model, 238–239t, 243–244 Matrix-metalloproteinase 9 (MMP-9), 117 Medical foods, 173, 173t

Melatonin, 60, 139 Microbiome-related markers, 109–112 Microbiota, 58. See also Gut microbiota Microbiota-brain-gut axis (MBGA), 29f communication routes, 33, 34f in IBS treatment, 36 pathways, 33–36 5-HT, 35 GABA, 36 SCFAs, 35 Minimal contact CBT (MC-CBT), 175–176 Mixed IBS (IBS-M), 3, 10 Monosaccharides, 172, 172t Motor disorders, of sleep, 219 M2-pyruvate kinase (M2-PK), 116 Mucosal barrier, 250–251 Mucosal biopsies, 250–255, 262 Mucosal inflammation, lowgrade, 17–18 Mucosal layer, 44, 45f Mucosal microbiota, 110

N National Institute for Health and Care Excellence (NICE), 173–174, 186 Neonatal stress-based model, 244–245 Netwell inserts, 255–256 Neuronal excitability, 258–259 Neuronal nitric oxide synthase (nNOS), 246 Neuropeptide Y (NPY), 13 Neuropetides, 114 Nociceptive index, 236 Non-celiac gluten sensitivity (NCGS), 18, 194 Non-celiac hypersensitivity, 171–172 Non-pharmacological treatment diet, 169 alcohol, 171 caffeine, 170–171 FODMAPs, 172

281

and immune response, 170 low-FODMAP, 174, 174t medical food, 173, 173t traditional dietary advice, 173–174 directions in, 169, 169f fecal microbiota transplantation, 177–178 physical activity, 177 psychological interventions, 175 cognitive behavioral therapy, 175–176 gut-directed hypnosis, 176 psychodynamic interpersonal therapy, 176–177 Non-rapid eye movement (NREM) sleep, 217–218 Non-steroidal antiinflammatory drugs (NSAIDs), 161 Norepinephrine, 75–76

O Obsessive-compulsive disorder (OCD), 215–216 Oligosaccharides, 172, 172t Ondansetron, 159–160 Open field/hole board tests, 237–239 Opioids, pain management, 160 Organ bathing, 259–260 Organic erectile dysfunction (OED), 220–221 Otilonium, 131, 156

P Pain management non-pharmacological treatment dietary fiber, 150 education, 148 FODMAP-diet, 149–150 herbal supplements, 153 hypnotherapy, 148 patient-doctor relationship, 149

282

Index

Pain management (Continued) peppermint oil, 152 probiotics, 151–152 psychological therapies, 147 red pepper-capsaicin, 152 self-management, 148 pharmacological treatment antibiotics, 155–156 antidepressants, 153–155 antidiarrheals, 158–160 antispasmodics, 156 benzodiazepines, 155 laxatives, 157–158 non-steroidal antiinflammatory drugs, 161 opioids, 160 pregabalin and gabapentin, 155 Pain neuroscience education, 148 Panel of biomarkers, 117–119 Paneth cells, 44–45, 257 Paracellular flow measurements, 253 Parasite infection-induced animal models, 241 Paroxetine, 154 Pathogenesis factors and mechanisms brain-gut axis, 11–12 dietary influence, 18 genetics, 16–17 gut microbiota, 14–16 histamine, 13–14 immune activation, 17–18 low-grade mucosal inflammation, 17–18 mast cells, 13–14 peptide YY, 13 serotonin, 12–13 impaired gut motility, 10 visceral hypersensitivity, 11 Patient-doctor relationship, 149 Patient health questionnaire 12 (PHQ-12), 119 Peppermint oil, 152 Peptide YY (PYY), 13 Periodic leg movements in sleep (PLMS), 219

Peripheral blood mononuclear cells (PBMCs), 17–18 Pharmacotherapy, 130, 147, 153–161 Phasic stimulation, 235–236 Phobia, 214 Physical activity, 177, 190–191 Physical stress, 245 Pictorial Representation of Illness and Self Measure Revised II (PRISM-RII), 214 Pittsburgh Sleep Quality Index (PSQI), 218–219 Platelet-depleted plasma 5-HT, 77 Plecanatide, 133, 254 Polymorphonuclear neutrophil elastase, 116 Polyols, 172, 172t Post-infectious IBS (PI-IBS), 17, 59 models, 238–239t, 241 Posttraumatic stress disorder (PTSD), 216 Prebiotics, 62–64 Preclinical models in vitro, 248–261 in vivo, 237, 238–239t Pregabalin, 155 Prevotella, 15 in IBS-D patients with SIBO, 62 P. copri, 60–61 Probiotics, 62–64, 136, 151–152, 194–195 Propionate, 47, 111 Prostaglandin derivative, 132 Proteasome, 46–47, 250–251 Proteinase-activated receptor 2 (PAR-2), 112 Prucalopride, 138 Psychiatric disorders, IBS correlation with, 207 anxiety, 213–215 bipolar disorder, 209–211 dementia, 221 depression, 211–213 eating disorders, 221–223

erectile dysfunction, 220–221 factors, 222f, 223 obsessive-compulsive disorder, 215–216 posttraumatic stress disorder, 216 schizophrenia, 217 sleep disorders, 217–220 use disorders, 220 Psychodynamic interpersonal therapy, 176–177 Psychodynamic therapy, 147–148 Psychogenic erectile dysfunction (PED), 220–221 Psychological interventions, 147, 175 cognitive behavioral therapy, 175–176 gut-directed hypnosis, 176 psychodynamic interpersonal therapy, 176–177 Psychosocial therapies, 147 Psyllium, 150

R Ramosetron, 159 for IBS-D, 134 Rapid eye movement (REM) sleep, 217–218 Recurrent abdominal pain (RAP), 86, 101 Red flag symptoms, 103 Red pepper-capsaicin, 152 Renzapride, 138 Restless legs syndrome (RLS), 219 Restraint stress model, 238–239t, 242 Rifaximin, 155–156, 177–178 for IBS-D, 136 Rome criteria, 2, 100–101 Rome IV criteria, 100, 234–235 diagnostic questionnaire, 101, 102–103t goal of, 105 IBS subgroups, 101 recurrent abdominal pain, 101 step I, 101–103

Index

step II, 103–104 step III, 104 step IV additional laboratory tests, 104–105 basic laboratory tests, 104 ROSE-010, 138

S Salmonella, 59, 252, 254 SCFAs, Short chain fatty acids (SCFAs) Schizophrenia, 217 IBS association with, 217 SCN11A gene, 87 SCN5A mutation, 87 Selective serotonin reuptake inhibitors (SSRIs), 153–154, 214–215 Self-management (SM), 148 Serotonin metabolism, 12–13 Serotonin/noradrenalin reuptake inhibitors (SNRIs), 153, 155, 214–215 Serotonin transporter (SERT), 16–17, 208 Serotonin transporter linked polymorphic region (5HTTLPR), 88–89 SERT gene, 88–89 Short chain fatty acids (SCFAs) fermented fiber, 150 gut microbiota, 15–16, 47 as markers, 110–111 MBGA pathways, 34f, 35 Short-circuit current (Isc), 254 Short Form 36 (SF-36) Health Survey, 214 Single nucleotide polymorphism (SNP), 88 association with IBS, 92–93, 93t cannabinoid receptor genes, 90–91 COMT gene, 91–92 GNβ3 gene, 91 interleukin genes, 92 serotonin receptor genes, 89–90

serotonin transporter gene, 88–89 Sleep, 217 disturbances, 218 motor disorders, 219 phases of, 217 Sleep disorders, 217–220 IBS association with, 219–220 periodic leg movements in sleep (PLMS), 219 prevalence of, 218 restless legs syndrome (RLS), 219 Small intestine bacterial overgrowth (SIBO), 61–62 Snaith-Hamilton Pleasure Scale (SHAPS), 211 Social defeat model/ overcrowding, 238–239t, 243 Solifenacin, 138 Soluble TREM-1, 117 Solute carrier family 6 member 4 (SLC6A4), 88 Somatization, 175 Sorbitol, 172, 172t Soy germ treatment, 79 Spastic colon, 10 Spicy food intake, 190 Sporadic IBS, 59 Standard CBT (S-CBT), 175–176 Standard drink equivalent, 188 State-Trait Anxiety Inventory (STAI), 214 Stress, IBS and, 30 Stress-induced IBS model during adult life, 241–243 with constipation, 245–248, 247f during early life, 243–245 Synbiotics, 63–64

T Tachykinins, 137 T cells, 251 activation of, 48t, 49 TEER. See Transepithelial resistance (TEER)

283

Tegaserod, 88–89, 137–138, 158 Tenapanor, 133 Testosterone, 72, 74t Therapeutics, FDA approved, 130, 130t Tight junctions (TJs), 45f, 46 Tiropramide, 139 TNF-α G308A polymorphism, 92, 93t TNFSF15 gene polymorphism, 92, 93t Tonic stimulation, 235–236 Traditional dietary advice, 173–174 Transepithelial resistance (TEER), 253–254 Transient receptor potential vanilloid type-1 (TRPV1), 171, 190 Transmission electron microscopy (TEM), 252–253 Traumatic stress, 216 Trichinella spiralis, 241 Tricyclic antidepressants (TCAs), 153–154 Triggering receptor expressed on myeloid cells 1 (TREM-1), 117 Trinitrobenzene sulphonic acid (TNBS), 239–241 Tryptase, 14, 251, 255 Tryptophan hydroxylase (TPH), 12 Tryptophan 5-hydroxylase 1 (TPH1), 137

U Unspecified IBS (IBS-U), 101, 184 Upper GI transit (UGIT), 236–237, 240f Urine metabolome, 111–112 Ussing chambers, mucosa permeability study, 253–254 advantages and disadvantages, 249t

284

Index

Ussing chambers, mucosa permeability study (Continued) fluorescently labeled bacteria, 254 paracellular flow measurements, 253 short-circuit current, 254 transepithelial resistance (TEER) analyzes, 253

V Venlafaxine, 155 Vinculin, 113 Visceral hypersensitivity (VH), 32, 185, 208 biomarkers and, 119 definition, 11

in vivo models, 235–236, 238–239t, 261–262 prevalence of, 11 Visceral pain, 146 GPER and, 78–79 regulation of, gonadal hormones in, 78–79 Visceral Sensitivity Index (VSI), 214 Visceromotor response (VMR), 236, 240f Visual analog scale (VAS), 139, 211 Volatile organicmetabolites (VOMs), 119 Voltage-gated sodium channel, mutations within genes, 87

W Water avoidance stress (WAS) test, 238–239t, 242 Whole GI transit (WGIT), 236–237, 238–239t Whole-mount preparations, 257–259 Willis-Ekbom disease. See Restless legs syndrome (RLS) Writhing test, 236

Z Zonula occludens (ZO), 46, 250–251 Zonulin, 112, 194