[1st Edition] 9780128119174, 9780128119167

Table of contents :
Content:
Series PagePage ii
CopyrightPage iv
ContributorsPages ix-x
PrefacePages xi-xiiF. Toldrá
Chapter One - Nanotechnology Approaches for Increasing Nutrient BioavailabilityPages 1-30S.M. Jafari, D.J. McClements
Chapter Two - Food Processing AntioxidantsPages 31-64F.J. Hidalgo, R. Zamora
Chapter Three - Analysis of Nitrite and Nitrate in Foods: Overview of Chemical, Regulatory and Analytical AspectsPages 65-107L. Merino, U. Örnemark, F. Toldrá
Chapter Four - Protein Hydrolysates and Biopeptides: Production, Biological Activities, and Applications in Foods and Health Benefits. A ReviewPages 109-159M. Nasri
Chapter Five - Bioactive Properties of Maillard Reaction Products Generated From Food Protein-derived PeptidesPages 161-185K. Arihara, L. Zhou, M. Ohata
Chapter Six - Use of Foodomics for Control of Food Processing and Assessing of Food SafetyPages 187-229D. Josić, Ž. Peršurić, D. Rešetar, T. Martinović, L. Saftić, S. Kraljević Pavelić
Chapter Seven - Metabolic Phenotyping of Diet and Dietary IntakePages 231-270J. Brignardello, E. Holmes, I. Garcia-Perez
Chapter Eight - Nutritional Aspects of Dysphagia ManagementPages 271-318C. Gallegos, E. Brito-de la Fuente, P. Clavé, A. Costa, G. Assegehegn

Citation preview

ADVISORY BOARDS KEN BUCKLE University of New South Wales, Australia

MARY ELLEN CAMIRE University of Maine, USA

ROGER CLEMENS University of Southern California, USA

HILDEGARDE HEYMANN University of California, Davis, USA

ROBERT HUTKINS University of Nebraska, USA

RONALD JACKSON Brock University, Canada

HUUB LELIEVELD Global Harmonization Initiative, The Netherlands

DARYL B. LUND University of Wisconsin, USA

CONNIE WEAVER Purdue University, USA

RONALD WROLSTAD Oregon State University, USA

SERIES EDITORS GEORGE F. STEWART

(1948–1982)

EMIL M. MRAK

(1948–1987)

C. O. CHICHESTER

(1959–1988)

BERNARD S. SCHWEIGERT (1984–1988) JOHN E. KINSELLA

(1989–1993)

STEVE L. TAYLOR

(1995–2011)

JEYAKUMAR HENRY

(2011–2016)

FIDEL TOLDRÁ

(2016– )

Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 125 London Wall, London, EC2Y 5AS, United Kingdom First edition 2017 Copyright © 2017 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. ISBN: 978-0-12-811916-7 ISSN: 1043-4526 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Zoe Kruze Acquisition Editor: Alex White Senior Editorial Project Manager: Helene Kabes Production Project Manager: Surya Narayanan Jayachandran Senior Cover Designer: Christian J. Bilbow Typeset by SPi Global, India

CONTRIBUTORS K. Arihara School of Veterinary Medicine, Kitasato University, Towada, Japan G. Assegehegn I&D Centre Complex Formulations and Processing Technologies, Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany J. Brignardello Computational and Systems Medicine, Imperial College London, London, United Kingdom E. Brito-de la Fuente I&D Centre Complex Formulations and Processing Technologies, Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany P. Clav
e Centro de Investigacio´n Biom
edica en Red de Enfermedades Hepa´ticas y Digestivas (CIBERehd), Hospital de Mataro´, Universitat Auto`noma de Barcelona, Mataro´, Barcelona, Spain A. Costa Dysphagia Unit, Universitat de Barcelona, Hospital de Mataro´, Mataro´, Barcelona, Spain C. Gallegos I&D Centre Complex Formulations and Processing Technologies, Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany I. Garcia-Perez Nutrition and Dietetic Research Group, Imperial College London, London, United Kingdom F.J. Hidalgo Instituto de la Grasa, Consejo Superior de Investigaciones Cientı´ficas, Seville, Spain E. Holmes Computational and Systems Medicine, Imperial College London, London, United Kingdom S.M. Jafari Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran D. Josi
c University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcˇi
c 2, Rijeka, Croatia S. Kraljevi
c Paveli
c University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcˇi
c 2, Rijeka, Croatia

ix

x

Contributors

T. Martinovi
c University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcˇi
c 2, Rijeka, Croatia D.J. McClements University of Massachusetts, Amherst, MA, United States L. Merino National Food Agency, Uppsala, Sweden M. Nasri Laboratory of Enzyme Engineering and Microbiology, University of Sfax, National Engineering School of Sfax, B.P. 1173-3038, Sfax, Tunisia M. Ohata Faculty of Education, Kyoto University of Education, Kyoto, Japan € U. Ornemark Emendo Dokumentgranskning, Ulricehamn, Sweden ˇ . Persˇuri
c Z University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcˇi
c 2, Rijeka, Croatia D. Resˇetar University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcˇi
c 2, Rijeka, Croatia L. Safti
c University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcˇi
c 2, Rijeka, Croatia F. Toldra´ Instituto de Agroquı´mica y Tecnologı´a de Alimentos (CSIC), Valencia, Spain R. Zamora Instituto de la Grasa, Consejo Superior de Investigaciones Cientı´ficas, Seville, Spain L. Zhou School of Veterinary Medicine, Kitasato University, Towada, Japan

PREFACE This volume of Advances in Food and Nutrition Research brings eight chapters reporting the latest developments in relevant and interesting aspects like nanotechnology for nutrients delivery, protein hydrolysates and bioactive peptides, new antioxidants, efficient nitrite and nitrate determination, use of foodomics, metabolic phenotyping of foods, or dysphagia management. So, the first chapter is focused on the use of nanotechnology to produce food-grade nanoparticles encapsulating bioactive substances in order to improve their bioavailability and expand their use in functional foods and beverages, aspect especially relevant when nutrients have poor solubility characteristics, impart undesirable flavor profiles, are chemically unstable, or have low bioavailability. The second chapter is bringing new insights on the chemical changes produced in foods during processing with special emphasis on the formation of antioxidants as a consequence of carbonyl-amine reactions produced by both carbohydrate- and lipid-derived reactive carbonyls. This type of carbonylamine reactions appears to be an effective method for the generation of efficient antioxidants that can be used in foods. The third chapter is revising the factors that should be considered for selecting and developing suitable analytical methods for the efficient determination of nitrite and nitrate which is a permanent request for regulatory aspects. In fact, a correct determination of nitrate and nitrite is a basic need in order to obtain reliable data of the real content of nitrite and nitrate in foods for law enforcement purposes, exposure estimates, and investigation of their physiological role in the human body. The fourth chapter is bringing novel views on the bioactive properties of Maillard reaction products generated from food protein-derived peptides. Although changes of amino acids or proteins and reduced sugars by the Maillard reaction are well known and have been extensively studied in the past, such changes of peptides by the Maillard reaction and their bioactive properties are not studied so much and further research is still needed. In fact, food protein-derived peptides are widely used in many processed foods, but not so much is known on the changes of peptides by the Maillard reaction during food processing and/or storage. The fifth chapter is dealing with the production, biological activities, and applications of protein hydrolysates and bioactive peptides that may be used as ingredients in functional foods and pharmaceuticals to improve human health and prevent diseases. The sixth chapter is focusing on the use of foodomics for the control of food processing and food safety xi

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assessment. There is a growing role of high-throughput foodomic methods based on genomic, transcriptomic, proteomic, and metabolomic techniques that bring better sensitivity and accuracy than those standard analytical procedures. So, foodomics will help to face new challenges due to the globalization of food chain and changes in the modern consumer preferences. The seventh chapter is discussing the metabolic phenotyping of foods that can be used to map the complex interaction between the diet and human metabolism and also to assess food quality and safety. This is due to the strong need to characterize such relationship diet/metabolism and its consequent impact on health. Some of the techniques currently used for metabolic phenotyping are described as well as some key applications in foods. The last chapter is related to swallowing and dysphagia, its rheological aspects, and its influence on the characteristics of the enteral nutrition for dysphagia management. Updated information is also given on the screening and diagnosis of oropharyngeal dysphagia, the consequences of dysphagia (aspiration pneumonia, malnutrition, and dehydration), and the nutritional management of dysphagic patients. This volume presents the combined efforts of 25 professionals from 8 countries (USA, Japan, UK, Germany, Sweden, Spain, Croatia, and Tunisia) with diverse expertise and background. The Editor wishes to thank the production staff and all the contributors for sharing their experience and for making this book possible. F. TOLDRA´ Editor

CHAPTER ONE

Nanotechnology Approaches for Increasing Nutrient Bioavailability S.M. Jafari*,1, D.J. McClements†,1 *Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran † University of Massachusetts, Amherst, MA, United States 1 Corresponding authors: e-mail address: [email protected]; [email protected]

Contents 1. 2. 3. 4.

Introduction Bioavailability of Nutraceuticals The Logic Behind the Development of Nanoparticles to Enhance Bioavailability Fabrication Methods for Production of Food-Grade Nanoparticles 4.1 Lipid-Formulation Nanoparticle Technologies 4.2 Nature-Inspired Nanoparticle Delivery Systems 4.3 Nanoparticles Made From Specialized Equipment 4.4 Biopolymer Nanoparticles 5. Safety and Toxicity of Nanostructures Applied in Food Systems 6. Conclusion and Perspectives References

2 3 6 8 13 16 19 20 23 24 24

Abstract Health-promoting ingredients such as phenolic compounds, vitamins, and minerals are being increasingly introduced into foods and beverages to produce “functional foods” specifically designed to improve human health, well-being, and performance. However, it is often challenging to incorporate these nutraceuticals into foods because they have poor solubility characteristics, impart undesirable flavor profiles, are chemically unstable, or have low bioavailability. This problem can often be overcome by encapsulating the bioactive components in nanoparticle-based delivery systems. The bioavailability of encapsulated bioactive agents often increases when the size of the particles containing them decreases, due to their faster digestion, ability to penetrate the mucus layer, or direct uptake by cells. Nanoparticles can be formulated to survive passage through specific regions of the gastrointestinal tract and then release their payload at a specified point, thus maximizing their potential health benefits. Nutraceutical-loaded nanoparticles can be fabricated through lipid formulations, natural nanocarriers, specialized equipment, biopolymer nanoparticles, and miscellaneous techniques. Classification into these five groups is based on the main mechanism or ingredient used to fabricate the nanoparticles. This chapter focuses on the utilization of food-grade nanoparticles for improving the performance of nutraceuticals in functional foods and beverages.

Advances in Food and Nutrition Research, Volume 81 ISSN 1043-4526 http://dx.doi.org/10.1016/bs.afnr.2016.12.008

#

2017 Elsevier Inc. All rights reserved.

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1. INTRODUCTION The demand for healthier foods by consumers has risen substantially over recent years due to an increasing awareness of the impact of diet on human health. Consequently, health-promoting ingredients (such as vitamins, minerals, and nutraceuticals) are being increasingly introduced into foods and beverages to produce “functional foods” specifically designed to improve human health, well-being, and performance (Aboalnaja, Yaghmoor, Kumosani, & McClements, 2016; Oehlke et al., 2014). On the other hand, as the population ages, there is increasing demand for food products with nutritional profiles specifically targeted to the elderly. By 2050, the number of people aged over 65 is expected to reach a total of about 1.5 billion, which is equivalent to 16% of the world’s population. It is notable that in 1950, this proportion was only 5% (Haub, 2011). A number of successful functional food products are already commercially available that contain nutraceuticals. Plant phytosterols and stanols have been incorporated into foods specifically designed to lower cholesterol levels (Chen, Ma, Liang, Peng, & Zuo, 2011). Omega-3 fatty acids have been added to foods designed to reduce the risk of cardiovascular illnesses (Kaushik, Dowling, Barrow, & Adhikari, 2015; Torres-Giner, Martinez-Abad, Ocio, & Lagaron, 2010). Vitamin D has been added to foods and beverages to reduce the risk of osteoporosis in certain populations (Heaney, 2007). Dietary fiber has been added to foods to reduce constipation and to improve gut health (Donini, Savina, & Cannella, 2009). Thus, there is a strong motivation to improve the potential health benefits of food and beverage products by fortifying them with nutraceuticals. Nutraceuticals are at the boundary between nutrition and medicine (McClements, Li, & Xiao, 2015; McClements & Xiao, 2014). This term was originally defined as “food or parts of food that provide medical or health benefits, including the prevention and treatment of disease.” Therefore, there has been considerable interest recently in the incorporation of different types of nutraceuticals into functional foods, such as essential fatty acids (omega-3, conjugated linoleic acid), carotenoids (β-carotene, lycopene, lutein, zeaxanthin), vitamins (D, E, thiamin, riboflavin), antioxidants (tocopherols, flavonoids, polyphenolic compounds), phytosterols (stigmasterol, β-sitosterol, campesterol), fibers (inulin), minerals (Fe2+, Mg2+), and bioactive peptides (casein hydrolysates) (McClements, 2013a, 2013b; Prasad, Tyagi, & Aggarwal, 2014; Sessa et al., 2014; Shaikh, Ankola,

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Beniwal, Singh, & Kumar, 2009; Ting, Zhao, Xia, & Huang, 2015; Tsai et al., 2011; Vachali et al., 2012; van Aken, de Hoog, McClements, & Decker, 2009; Yu & Huang, 2012; Zou, Liu, Liu, Xiao, & McClements, 2015). However, it is often challenging to incorporate these nutraceuticals into foods because they have poor solubility characteristics, impart undesirable flavor profiles, are chemically unstable, or have low bioavailability (McClements et al., 2015; van Aken et al., 2009). This problem can often be overcome by encapsulating the bioactive components in nanoparticle-based delivery systems. This chapter focuses on the utilization of food-grade nanoparticles for improving the performance of nutraceuticals in functional foods and beverages.

2. BIOAVAILABILITY OF NUTRACEUTICALS Several definitions of bioavailability exist, but broadly it refers to the proportion of an ingested bioactive substance that is absorbed from the diet and used for normal body functions (Aggett, 2010; Hurrell & Egli, 2010). Bioavailability captures two essential features: (i) the absorption rate—how fast the bioactive agent enters the systemic circulation and (ii) the absorption extent—how much of the bioactive reaches the systematic circulation (Borel, Preveraud, & Desmarchelier, 2013; Johnson et al., 2005). According to the FDA,a the bioavailability can be defined as the rate and extent to which the bioactive ingredient or active moiety is absorbed from a product and becomes available at the site of action (Pathak & Raghuvanshi, 2015). Poor bioavailability means failure of the ingredient to reach the minimum effective concentration in the blood to produce the desired biological results. Typically, a number of different steps determine the biological fate of bioactive agents after ingestion (Aggett, 2010; Katouzian & Jafari, 2016): • Release of the bioactive agent from the dietary matrix, • Digestion by enzymes within the intestine, • Adherence and uptake by the mucosal layer of the intestine, • Transfer across the gut wall (passing through and/or between the epithelium cells) to the lymphatic system or portal vein, • Systemic distribution, • Systemic deposition (storage), • Metabolic and functional use, • Excretion (via urine or feces). a

The US Food and Drug Administration.

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Various external and internal factors determine the overall bioavailability rate of an ingested bioactive agent. The external factors include the nature of the bioactive agent, and the composition and structure of the food matrix, while internal factors include gender, age, health, nutrient status, and life phase (e.g., pregnancy). Because factors such as nutrient status determine how much of a nutrient is actually used, stored, or excreted, some definitions of bioavailability restrict themselves to the fraction of a nutrient that is absorbed (Heaney, 2001). The bioavailability of macronutrients, carbohydrates, proteins, and fats is usually very high as more than 90% of the administered amount is ingested in the gut. On the other hand, the bioavailability of micronutrients (such as vitamins and minerals) and nutraceuticals (such as flavonoids and carotenoids) can vary greatly depending on their molecular and physicochemical characteristics. For example, the bioavailability of lipophilic bioactives is limited by their poor solubility, high melting point, chemical instability, poor bioavailability, and ingredient interactions (McClements, 2013b). Overall, several factors determine the bioavailability of nutrients and nutraceuticals as mentioned in Fig. 1.

Physiological factors

Physicochemical/ nutraceutical factors

First-pass metabolism

Low apparent solubility

High gastric emptying rate

High molecular weight of nutraceuticals

Effect of food

Inappropriate partition coefficient

Restriction by the intestinal barrier Enzymatic degradation of bioactives in GT

Fig. 1 Factors determining the bioavailability of nutraceuticals and other bioactive components.

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Insights into how to formulate food-grade delivery systems with improved bioavailability characteristics can often be obtained from the pharmaceutical industry. Research has shown that the bioavailability of many poorly water-soluble drugs can be greatly improved by incorporating them within nanoparticle delivery systems (Aboalnaja et al., 2016; Thanki, Gangwal, Sangamwar, & Jain, 2013). The relatively high surface area of these systems can lead to rapid dissolution of drugs within the gastrointestinal tract (GIT) (Cui et al., 2009; Erfanian, Mirhosseini, Manap, Rasti, & Bejo, 2014). Consequently, there is a great interest in developing nanoscale delivery systems for nutraceuticals and other bioactive components intended for food use. To produce biologically effective functional foods, it is essential that the encapsulated nutraceuticals or nutrients have a sufficiently high bioavailability, i.e., the bioactives are absorbed into the blood stream at a level that is high enough to have a beneficial health effect. There are many examples where the potential health benefits of bioactive agents are not fully realized because of their low oral bioavailability. Vitamin D may be delivered in the form of supplements (tablets or capsules) or in food formulations such as fortified milk and fruit juices (Katouzian & Jafari, 2016). Human studies have shown that the fraction of vitamin D absorbed into the blood is typically relatively low for most oral formulations (Barakat, Shegokar, Dittgen, & M€ uller, 2013; Borel, Caillaud, & Cano, 2015). Considering the fact that the dose of nutraceuticals in functional foods is rather low (compared to pharmaceutical products), a biological effect is therefore questionable. The same applies to the various flavonoids, which are becoming increasingly popular as antioxidants, such as rutin, apigenin, hesperidin, hesperetin, and quercetin (Faridi & Jafari, 2016). In general, bioactive molecules are best absorbed when they are fully dissolved within the GIT fluids. Many highly hydrophobic bioactives (such as vitamin D, vitamin E, carotenoids, and curcumin) have poor water solubility but may still dissolve in aqueous GIT fluids because of the presence of colloidal particles that have hydrophobic regions that can solubilize them, i.e., mixed micelles and vesicles. In these cases, the bioavailability of the bioactive agent is highly dependent on the type and amount of coingested lipids. Another strategy utilized in the pharmaceutical industry is to produce nanocrystals of the bioactive substance that may be directly absorbed by the epithelium cells. In summary, technologies developed in the pharmaceutical industry to improve the performance of drugs may be utilized by the food industry to improve the performance of nutraceuticals. In this chapter, we focus

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on the utilization of nanotechnology-based approaches, which have been widely used in the pharmaceutical industry and are now finding increasing use in the food industry.

3. THE LOGIC BEHIND THE DEVELOPMENT OF NANOPARTICLES TO ENHANCE BIOAVAILABILITY Nanotechnology is an enabling technology that has the potential to revolutionize the development of functional food systems. Designing materials on the nanometer length scale (1–100 nm) can lead to food products with novel physicochemical, sensory, and nutritional properties, such as appearance, texture, flavor, stability, and gastrointestinal fate (Chaudhry et al., 2008; Duncan, 2011; Sozer & Kokini, 2009). The potential advantage of using nanomaterials as delivery systems is based on the fact that the physiochemical properties of materials change when they are reduced into the nanoscale (M€ uller & Keck, 2008). Nevertheless, there are still some inconsistencies among scientists and regulators working in this field about the critical cutoff size that determines the upper limit of the nanoscale. In the pharmaceutical sciences, “nanoparticles” are often defined as having dimensions below 1000 nm (1.7 mmol/L

Fasting HDL cholesterol

88 cm (women)

Blood pressure

130/85 mmHg

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(phosphatidylcholines diacyl), PCae (phosphatidylcholines acyl-alkyl), and medium-chain sphingomyelins that were associated with a deteriorated metabolic state, which was more related to an obese metabolic profile rather than a healthy metabolic profile (Allam-Ndoul et al., 2016). Other studies have explored the association between the urinary metabolome and BMI. In a unique cohort of samples from the INTERMAP epidemiologic study (Holmes, Loo, et al., 2008), 24-h urine collection samples were analyzed by NMR to derive an untargeted metabolic profile and a targeted ion exchange chromatography method was used to measure amino acid metabolites and related compounds. Urinary metabolites directly associated with BMI included trimethylamine, dimethylamine, 4-cresyl sulfate, phenylacetylglutamine and 2-hydroxyisobutyrate (gut microbial cometabolites), succinate and citrate (tricarboxylic acid cycle intermediates), ketoleucine and the ketoleucine/leucine ratio (linked to skeletal muscle mitochondria and branched-chain amino acid metabolism), 3-methylhistidine (skeletal muscle turnover and meat intake), and ethanolamine (skeletal muscle turnover; Elliott et al., 2015). These metabolites could be useful in clinical settings where obese urinary phenotypes detected in normal weight individuals may indicate a heightened risk of developing obesity or related metabolic diseases. Most obese individuals present with at least one altered characteristic for metabolic parameters, and this condition is termed metabolic unhealthy obesity (MUO). Interestingly, 10–30% of obese individuals present healthy metabolic parameters for insulin sensitivity, blood pressure, and lipid profiles (Wildman et al., 2008), referred to as metabolic healthy obesity (MHO; Ahima & Lazar, 2013; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001; Phillips, 2013). Currently, there is little knowledge about the role of abnormal metabolic phenotypes and factors that switch from MHO to MUO. Serum metabolic profiling of a paired group of 34 individuals with MUO and MHO was carried out using LC-MS for targeted analysis and GC-MS for both target and untargeted analysis. Metabolites that systematically differentiated between MUO and MHO individuals included L-kynurenine, glycerophosphocholine, glycerol 1-phosphate, glycolic acid, tagatose, methyl palmitate, and uric acid. In addition, these metabolites were related to several metabolic pathways, including fatty acid biosynthesis, phenylalanine metabolism, propanoate metabolism, and valine, leucine, and isoleucine degradation (Chen et al., 2015). Another similar study described distinct metabolic phenotypes for MUO, MHO, and lean healthy (LH) subjects after the consumption of a high-calorie meal challenge at breakfast. Plasma amino acid and fatty acid

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profiles were analyzed by CE-MS and GC, respectively. MHO subjects were capable to easily adapt to the caloric challenge compared to MUO, showing a preserved insulin sensitivity. The metabolic profile presented some significant differences in amino acid levels between fasting and postprandial states for asparagine (LH vs MUO), cysteine (LH vs MUO and LH vs MHO), glutamine (LH vs MUO and MUO vs MHO), and serine (LH vs MUO and LH vs MHO). Lipid metabolic profiles were significantly different between fasting and postprandial for palmitoleic acid (LH vs MUO and LH vs MHO), linoleic acid (MUO vs MHO), γ-linolenic acid (LH vs MUO and MUO vs MHO), and arachidonic acid levels (MUO vs MHO). Additionally, positive correlations were found between fasting levels of isoleucine, fasting insulin, and insulin area under curve. Also, a positive association of leucine with both HOMA-IR and fasting insulin was described, confirming the role of branched amino acids to identify possible obese people at cardiometabolic risk (Badoud et al., 2015). These fasting metabolites and associations should be considered as potential predictive indicators of postprandial response, independently of the BMI or metabolic disease diagnosis in patients. A recent study proposed a regression model of prediction for successful weight loss for patients with OW, obesity, and morbid obesity based on metabolic signatures at baseline before the consumption of caloric restriction diet for 8 weeks. Participants received a liquid diet of approximately 800 kcal during 8 weeks. Metabolic profile changes in plasma were measured before and after weight loss period using NMR for low-weight molecular metabolites and LC-MS for lipidomics. By looking at baseline parameters, a maximum of 57% of participants’ weight loss could be predicted. However, the best predictions were obtained with the morbid obesity participants in comparison with obese participants (Stroeve et al., 2016). Weight loss prediction was based on metabolites related to energy metabolism such as acetoacetate, triacylglycerols, phosphatidylcholines, amino acids, creatine, and creatinine. Hence, it is suggested that a successful weight loss in morbid obesity is modulated by a high energy metabolism status prior to a calorie restriction diet period allowing a personalized advice in this type of patients in near future.

2.4 Feeding the Gut Microbiome No nutrition-associated metabolic phenotyping chapter would be complete without mentioning the gut microbiome and its role in metabolism of nutrients and foods, with consequent impact on metabolic signaling between host and bacterial community. The microbiome is key to the status of the

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immune system with capacity to affect a diverse range of tissues and organs including the liver and intestinal tract and is implicated in the etiology or development of many diseases including inflammatory bowel disease, fatty liver diseases, and several cancers. Given the close relationship between the gut and liver (the “gut–liver axis”), the intestinal microbiome has been widely recognized for playing a key role in the maintenance of gut–liver health. Ingested foods and nutrients processed by the gut bacteria are transformed into metabolically active chemicals, some of which act directly as signaling molecules in gut–brain axis communication. At the broadest level, high-calorie diets and obesity have been shown to be associated with distinct microbiomes with an increased ratio of Firmicutes to Bacteroidetes identified as being modulated by a weight reduction diet (Jumpertz et al., 2011) However, other research groups have failed to reproduce consistent differences in the Firmicutes to Bacteroidetes in the microbiota of obese and nonobese individuals (Schwiertz et al., 2010), suggesting a more complex relationship between nutrition and the microbiota with regard to its role in MS and obesity. Nevertheless, the weight of evidence heavily favors a strong relationship between obesity and the microbiome based on both metagenomic data (Serino et al., 2012) and metabolic phenotyping data showing clear differences in gut microbial metabolites of dietary aromatic amino acids, phenolics, and SCFAs (Holmes, Li, Marchesi, & Nicholson, 2012). One of the strongest modulators of the intestinal microbes and their activity is caloric restriction. Low-fat diets and other diets aiming to achieve weight loss result in a robust panel of metabolic changes, mirrored by an alteration in the gut microbiome. Higher urinary concentrations of hippurate, phenylacetylglutamine and 4-cresyl sulfate, all gut microbial metabolites, or bacterial–host cometabolites have been associated with lean body mass and with weight loss (Holmes, Loo, et al., 2008; Zhang et al., 2012). Microbial modulation of dietary choline, specifically phosphatidylcholine to trimethylamine-N-oxide (TMAO), has been implicated in CVD (Wang, Klipfell, et al., 2011) and yet high levels of TMAO are found in urine samples obtained from Japanese populations originating from a diet rich in fish containing high levels of TMAO (Holmes, Loo, et al., 2008). Clearly heart disease is not overtly high in the Japanese, in fact quite the contrary, again pointing to the extreme complexity surrounding the microbe–host relationship in processing of foods and nutrients and pointing to conditional relationships of gene–environmental interactions in disease etiology. One of the most credible pieces of evidence highlighting the interaction of diet and the microbiome in disease is that there are three distinct

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metabolic phenotypes of individuals found with respect to gut bacterial metabolism of the dietary soy component daidzein: individuals who metabolize daidzein to O-desmethylangolensin (ODMA), equol, or both (Reverri, Slupsky, Mishchuk, & Steinberg, 2016). Equol production is associated with beneficial effects of soy in CVD. Individuals who produced ODMA and equol have been reported to have lower levels of the gut microbial metabolite trimethylamine yet were associated with increased proinflammatory cytokines further underscoring the complexity of the metabolic interaction between man and his microbiome. Dietary impact on cancer risk also demands interrogation of the tripartite relationship between diet, inflammation, and the microbiome. Unequivocal evidence has shown that migrant populations assume the colon cancer incidence of the host population after only one generation. A crossover study in African Americans and rural Africans showing a switch of diet induces a rapid change in metrics of colon cancer risk (O’Keefe et al., 2015). Other research programs have shown clear links between bacterial and host modulation of dietary choline and cancer in terms of both risk and prognosis (Glunde, Penet, Jiang, Jacobs, & Bhujwalla, 2015; Trousil et al., 2014). It is widely accepted that SCFAs play an important role in maintaining the epithelial integrity of the mucosa in inflammatory bowel disease. Acute studies in both animals and humans demonstrate that SCFA can have a favorable effect on inflammatory bowel disease activity markers. The challenge of using SCFAs as a mainstream therapy has been in developing a methodology that will increase colonic SCFAs over a prolonged period of time to assess disease remission. Recent research has produced a method of delivering SCFA to the colon over a prolonged (>6 month) period of time based on SCFA inulin esters (Polyviou et al., 2016). There are many potential metabolic intersections between the human host and their microbiome, and this arena provides a broad landscape in which to develop nutriceuticals and health-promoting foods.

3. FUTURE OF NUTRIMETABONOMICS 3.1 REIMS and DESI Imaging Technologies Several promising new MS-based methods for profiling and imaging of foods and for profiling bacterial communities in foods are on the horizon. Mass spectrometric methods have been used to differentiate and to phenotype bacteria for several decades based on the composition of their lipid coat and fatty acid profiling, beginning with pyrolysis MS (Basile, Voorhees, &

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Hadfield, 1995; DeLuca, Sarver, Harrington, & Voorhees, 1990) and GC-MS (Miller, 1982) methods. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry has also been applied to taxonomic characterization of bacteria (Mazzeo et al., 2006), but is limited by the requirement for extensive sample preparation including embedding within a chemical matrix. Rapid evaporative ionization mass spectrometry (REIMS) is a recently developed matrix-independent method that can accurately speciate microorganisms based upon their species-specific phospholipid fingerprint (Bolt et al., 2016). The technique operates by applying a radiofrequency-derived electrical current directly to the bacterial colony or biological sample and generating a vapor from the bacterial biomass, which contains ions that can be directly imported into a mass spectrometer. The technique is rapid and could be applied directly to foods to identify harmful microorganisms present in foodstuffs. In a similar manner, the REIMS technology can be applied directly to foods to monitor composition directly. This has obvious application in food adulteration, and its major strength lies in the rapidity of the method allowing high-throughput screening of food products. The best known exemplar for this technique is the differentiation of meat burgers according to the species the meat originated from, detecting horse, beef, and venison and establishing the relative proportion of each (Balog et al., 2016). The complexity of gene–environment interactions that drives the association between nutrition, metabolic phenotypes, and disease is underpinned by vast interactive networks of signaling molecules that bridge the various layers of biomolecular organization in humans. Improved methods and systems biology frameworks for conducting analysis at the interface between epigenetics and molecular phenotypes (Herna´ndezAguilera et al., 2016).

3.2 Nutrition in the Intensive Care Setting Metabolic phenotyping studies in the critical care setting are relatively sparse, but have been used to characterize a wide range of patients from pneumonia and acute lung injury to trauma patients (Mao et al., 2009). There is growing recognition of the role of nutritional management in the intensive care setting, and recent studies have shown the value of applying profiling studies to evaluate various nutritional management strategies. For example, recovery of mitochondrial function has been found to be predictive of recovery from multiple organ dysfunction. Metabolic

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phenotyping has been highlighted as a vehicle for patient stratification with respect to therapeutic management with respect to administration of potentially beneficial agents such as thiamine, ascorbic acid, tocopherol, selenium, zinc, and potential metabolic resuscitators (coenzyme Q10 (CoQ10), cytochrome oxidase (CytOx), L-carnitine, melatonin) (Leite & de Lima, 2016). Other metabolic profiling studies have identified altered plasma levels of sucrose, mannose, 3D-hydroxybutyrate, lactate, methionine, arginine, and various acylcarnitines to be associated with sepsis (Englert & Rogers, 2016). These molecules may provide a useful biomarker panel against which to measure nutritional and other therapeutic management strategies in intensive care patients. Further profiling studies have shown the association between nutritional status and prognosis in the clinical care setting. Mogensen et al. reported a correlation between metabolic profiles in critical care patients with malnutrition and 28-day survival, with dysregulation of glutathione and purine metabolism being particularly important (Mogensen et al., 2016). The term metabolic resuscitation has become popular and is indicative of the growing recognition of the need for specific nutritional care in the critical care patient. A recent study reported that amino acids fluctuate and that their levels correlated with prognosis as assessed by the widely used clinical scoring systems based on clinical scoring systems (SOFA, APACHE II) with a particularly strong correlation between worsening prognosis and a decline in sulfur-containing amino acids, such as taurine (Su et al., 2015). APACHE (Acute Physiology And Chronic Health Evaluation II) and SOFA (sequential organ failure assessment) scores are based on multiple physiological parameters such as temperature and heart rate combined with blood chemistry measurements such as white cell count and sodium levels. Thus, metabolic profiling technology has the clear potential as a tool for nutritional support in sepsis patients.

3.3 Neonatal Nutrition Pregnancy offers a window of opportunity to shape the health of both the mother and fetus, and good nutrition is considered a vital part of managing the pregnancy journey. Metabolic phenotyping applied to pregnant women has shown differential profiles between individuals undergoing a healthy pregnancy and those with intrauterine growth restriction (IUGR), which was characterized by lower levels of urinary acetate, trimethylamine, tyrosine, and formate and higher levels of N-acetyl glycoproteins (Maitre et al., 2014). These biomarkers of growth restriction also provide a panel of

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markers to target via nutritional management. Breast milk is generally considered to be healthier than formula milk and breast-feeding has been associated with lower risk of infants and children developing asthma, eczema, and downstream obesity (Lodge et al., 2015; Victora et al., 2016). Several studies have examined early feeding regimens using metabolic phenotyping, some of these studies in preterm or IUGR infants. After just 3 days of formula nutrition urinary excretion of glucose, galactose, glycine, and myoinositol increased, while breast bed babies had higher urinary levels of adipic acid, citric acid, homoserine, and aminomalonic acid (Dessi et al., 2016). The gut bacterial community, introduced at, or even before, birth undergoes dynamic colonization of the intestinal tract resulting in microbial communities that support our immune function and our ability to harvest calories from our food and perform chemical signaling functions between the gut and other organs and tissues. The gut microbiome is inextricably linked with dietary processing and is largely symbiotic with its human host. Dysfunction of the microbiome has been associated with multiple diseases ranging from inflammatory bowel disease to obesity-related conditions and even neurodevelopmental disorders such as autism (De Angelis et al., 2013; Goto, Kurashima, & Kiyono, 2015; Ley, Turnbaugh, Klein, & Gordon, 2006). The transmissibility of microbiomes, be they beneficial or adverse, is a controversial subject, particularly in the case of their association with obesity and insulin resistance (Mueller, Bakacs, Combellick, Grigoryan, & Dominguez-Bello, 2015). Collado et al. reported higher levels of fecal Bacteroides spp., Staphylococcus spp., and Clostridium difficile counts in 6-month-old babies from OW mothers and also showed that weight gain during pregnancy impacted on the microbial composition (Collado, Isolauri, Laitinen, & Salminen, 2010). Preterm babies have been shown to have increased risk of MS and CVD later on in life and are also at higher risk of neurodevelopmental complications (Lapillonne & Griffin, 2013; Moster, Lie, & Markestad, 2008). One school of thought proposes that it is the nutritional management of preterm or low-birth-weight infants that is responsible for the downstream health implications rather than the phenomenon of being born with immature organs and systems. In a mouse model of feeding to achieve catch-up growth in neonatal undernourished mice, the gut microbial metabolites phenyllactate (plasma) and 4-cresyl sulfate (urine) remained different from either undernourished counterparts fed normally or control mice (Preidis et al., 2016), implicating a nutritionally modified microbiome.

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Human milk oligosaccharides, present in breast milk, have been found to promote growth in models of infant undernutrition (Charbonneau et al., 2016) and protect against pathogenic infections such as Campylobacter and Group B Streptococcus. Metabolic profiling methods for determining the glycomic profile have been developed for both nano-liquid chromatography chip time-of-flight mass spectrometry (Totten et al., 2014) and NMR platforms (Andreas et al., 2016). The association between nutrition and cognitive development is intriguing and underresearched. A few metabolic profiling studies have begun to probe the relationship between the diet and the gut–brain axis. One such study in pigs has shown that early-life supplementation with phospholipids and gangliosides alters the brain biochemistry and improves spatial learning in piglets (Liu et al., 2014). Several methodologies and strategies for profiling human breast milk have been developed and should prove useful in investigating the tripartite relationship between the early colonizing microbiome, infant nutrition, and the metabolic profiles (Andreas et al., 2015; Wu et al., 2016).

3.4 Sports Nutrition Appropriate nutrition enhances physical performance and recovery (American Dietetic Association et al., 2009; Potgieter, 2013; Trakman, Forsyth, Devlin, & Belski, 2016). Athlete’s dietary choices, amounts, and timing of food intake and supplements can help reduce the risk of injury while providing a more effective training (Kreider et al., 2010). To date, the majority of exercise–diet–metabolism studies rely on single targeted markers. On the other hand, metabolic phenotyping captures information of the athlete’s biochemistry that reflects physiological status, genetic, microbiome, and other environmental interactions such as dietary exposure and lifestyle (Holmes, Wilson, et al., 2008; Nicholson, 2006). This has the potential to provide personalized recommendations that will enhance the sportsman’s performance. Metabolic profiling studies have been applied to identify exercise-related metabolites (Daskalaki et al., 2015) and interindividual variation in response to exercise (Kirwan, Coffey, Niere, Hawley, & Adams, 2009), and to compare the effect of different exercise sessions and different levels of training exercises (Wang et al., 2015). Likewise, the use of metabolic profiling is essential to objectively monitor and assess athletes’ food intake at an individual level that allows accurate understanding of the impact of diet on performance and recovery. This will enable the development of optimized personalized food and training plans.

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Currently, there is growing interest in increasing our understanding of the impact of functional foods and supplements on athletes’ metabolic behavior, before, during, and after physical activity. Several metabolic profiling studies have evaluated the impact of formulated sports drinks, enriched with macronutrients and/or micronutrients or plant-based extract to improve sportsman’s performance and recovery. Serum metabolic profiles revealed a different systemic metabolic response in the early recovery phase postexercise when comparing the ingestion of water, low-carbohydrate beverages, high-carbohydrate beverages, and low-carbohydrate-protein beverages, immediately after 90 min of ergometer cycling (Chorell, Moritz, Branth, Antti, & Svensson, 2009). This suggests that the postexercise intake of low-carbohydrate–protein beverages improved the metabolic status of less-fit subjects by increasing the serum levels of pseudouridine and decreasing levels of 3-methylhistidine, a marker of muscle turnover. A similar study evaluated the metabolic effect of a green tea-based sports drink, rich in polyphenols, in comparison to oligomineral water, which resulted in improving energy metabolism and glucose homeostasis (Miccheli et al., 2009). Postexercise serum and urinary metabolic profiles of rowing athletes revealed lower lactate and higher glucose and citrate plasma levels and an increment of urinary acetone and 3-hydroxybutyrate during rehydration. The benefit of phenolic ingestion during and postexercise on athletes’ performance and recovery was investigated by MS metabolic profiling strategies. The acute effect of banana intake compared to 6% carbohydrate drink during and after 75-km cycling performance and postexercise resulted in no detectable differences in performance, blood glucose levels, oxidative stress, inflammation, and innate immune levels (Nieman et al., 2012). However, further studies compared the effect of the ingestion of banana, water, and pear before and during 75-km cycling and indicated that banana and pear intake was associated with a meaningful performance enhancement, diminished inflammation, decreased fatty acid mobilization and oxidation, and contributes unique phenolics that elevate antioxidant capacity (Nieman et al., 2015). On the other hand, metabolic profiling strategies are well suited to investigate changes in gut microbial metabolites after supplements and/or food intake. Long-distance runners were supplemented with blueberry and a green tea polyphenol-rich soy protein-based product after 3 days of intensified training which increased ketogenesis during recovery and a distinct gut-derived phenolic signature (hippurate, 4-hydroxyhippurate, 4-methylcathecol sulfate) which the authors propose is mediated through increased gastrointestinal permeability (Nieman et al., 2013).

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Nieman et al. also investigated the influence of 2 weeks’ intake of pistachio nuts on cyclists’ performance and postexercise recovery. Although traditional biomarkers for exercise-induced inflammation and oxidative stress did not show differences between pistachio and nonpistachio consumption, the metabolic profiling analysis revealed differences in 19 blood metabolites related to leukotoxic effects and oxidative stress. In addition, gut-derived raffinose, sucrose, and myoinositol were present in the circulation of endurance athletes as a result of the prolonged and intense exertion and the 2-week pistachio intake (Nieman et al., 2014). To summarize, the application of metabolic profiling strategies has the potential to revolutionize sports nutrition since it provides athletes with a personalized toolset to enhance their performance, reduce likelihood of muscle injury, and potentially extend the working life of elite sportsmen.

4. CONCLUDING REMARKS As the applications for metabolic phenotyping in nutrition expand, the analytical technologies for metabonomics and lipidomics are becoming more robust and compound libraries are growing, together with innovative methods of modeling and mining spectroscopic data. We are beginning to see the routine use of these technologies in food screening and sales of specialized products such as the FoodScreener, an automated NMR-based system for authenticity testing of fruit juices and wines is increasing. Newer technologies such as the REIMS for direct MS-based testing of food provenance hold great promise for identifying food fraud in a matter of minutes, for example, detecting adulteration of beef burgers with horse meat and have potential to revolutionize the food screening industry. MS libraries of bacteria present in foods also open the door to interesting opportunities in food security. Scale-up of metabolic profiling technology for profiling of biofluids opens the door to metabolome-wide association studies (MWAS), analogous to GWAS, and defined as the broad nonselective analysis and statistical interrogation of metabolic phenotypes in relation to epidemiologic endpoints and risk factors to generate testable physiological or pathway hypotheses (Holmes, Loo, et al., 2008) and MWAS–GWAS studies. This will facilitate disease-diet correlations to be extracted from large cohorts with the ability to simultaneously address dietary reporting accuracy, adherence to diet and interindividual differences in metabolism of foods and nutrients. For the first time personalized nutrition, informed by accurate phenotyping technology, is a tangible prospect both in terms of achieving required sample

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throughput and economic viability. Realization of this goal has the potential to significantly impact disease risk and drive improved health initiatives, particularly if the nutrition community joins forces to drive method standardization and creation of shared databases.

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CHAPTER EIGHT

Nutritional Aspects of Dysphagia Management
†, A. Costa{, C. Gallegos*,1, E. Brito-de la Fuente*, P. Clave G. Assegehegn* *I&D Centre Complex Formulations and Processing Technologies, Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany † Centro de Investigacio´n Biom
edica en Red de Enfermedades Hepa´ticas y Digestivas (CIBERehd), Hospital de Mataro´, Universitat Auto`noma de Barcelona, Mataro´, Barcelona, Spain { Dysphagia Unit, Universitat de Barcelona, Hospital de Mataro´, Mataro´, Barcelona, Spain 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Screening and Diagnosis of OD 3. Consequences of Dysphagia 3.1 Aspiration Pneumonia 3.2 Malnutrition and Dehydration 4. Nutritional Management of Dysphagic Patients 4.1 Rheological Aspects of Swallowing and Dysphagia 4.2 Enteral Nutrition for Dysphagia Patients: Minimal-Massive Intervention 4.3 Thickening Powders 4.4 RTU ONS for Dysphagia Management 5. Conclusions References

272 277 283 283 286 289 289 295 300 308 310 311

Abstract This chapter describes the nutritional aspects of dysphagia management by starting with the definition of these two conditions (dysphagia and malnutrition) that share three main clinical characteristics: (a) their prevalence is very high, (b) they can lead to severe complications, and (c) they are frequently underrecognized and neglected conditions. From an anatomical standpoint, dysphagia can result from oropharyngeal and/or esophageal causes; from a pathophysiological perspective, dysphagia can be caused by organic or structural diseases (either benign or malignant) or diseases causing impaired physiology (mainly motility and/or perception disorders). This chapter gathers up-to-date information on the screening and diagnosis of oropharyngeal dysphagia, the consequences of dysphagia (aspiration pneumonia, malnutrition, and dehydration), and on the nutritional management of dysphagic patients. Concerning this last topic, this chapter reviews the rheological aspects of swallowing and dysphagia (including shear and elongational flows) and its influence on the characteristics of the enteral

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nutrition for dysphagia management (solid/semisolid foods and thickened liquids; ready-to-use oral nutritional supplements and thickening powders), with special focus on the real characteristics of the bolus after mixing with human saliva.

1. INTRODUCTION This chapter describes the nutritional aspects of dysphagia management by starting with the definition of these two conditions (dysphagia and malnutrition) that share three main clinical characteristics: (a) their prevalence is very high, (b) they can lead to severe complications, (c) they are frequently underrecognized and most patients do not receive an appropriate treatment, and frequently they are neglected conditions. The word “dysphagia” derives from the Greek terms dys meaning “disordered” or “ill,” and phago meaning “eat” or “swallow.” Swallowing is defined as “the function of clearing food and drink through the oral cavity, pharynx, and esophagus into the stomach at an appropriate rate and speed defined by the International Classification of Functioning, Disability and Health (ICF, code b5105) promoted by the World Health Organization (WHO). Dysphagia is classified under “digestive symptoms and signs” in the International Classification of Diseases (ICD-10, code R13), also promoted by WHO. However, the term is often used, not fully appropriately, to mean a disorder or disease. In addition, patients affected can be unaware of their swallow dysfunction. From an anatomical standpoint, dysphagia can result from oropharyngeal and/or esophageal causes; from a pathophysiological perspective, dysphagia can be caused by organic or structural diseases (either benign or malignant) or diseases causing impaired physiology (mainly motility and/or perception disorders). Oropharyngeal, head, neck, and esophageal structural causes (such as tumors, webs, pouches, and rings) of dysphagia are reviewed elsewhere (Feldman, Friedman, & Brandt, 2010; Shaker, Belafsky, Postma, & Easterling, 2013). This chapter focuses on advances in understanding dysphagia caused by diseases that impair oropharyngeal physiology. Oropharyngeal dysphagia (OD) is a symptom of a swallow dysfunction that provokes difficulty or inability to form or move the alimentary bolus safely from the mouth to the esophagus. It can include oropharyngeal aspiration (the entry of secretions, food, or drink from the oropharynx into the trachea or the lungs) and choking (the subsequent mechanical obstruction of

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pulmonary air flow) (Clav
e, Terre, de Kraa, & Serra, 2004). OD should be differentiated from globus pharyngis, a specific somatoform disorder consisting of the continuous feeling of having a “lump in the throat,” phlegm, or some sort of obstruction when there is none. Despite the severity of OD complications, the standard of care for the majority of these patients is very poor as most are not diagnosed or treated (Barczi, Sullivan, & Robbins, 2000; Clav
e & Shaker, 2015). Prevalence of OD is extremely high. The phenotype of patients in which OD develops varies significantly and includes three main groups: elderly people, patients with neurological and neurodegenerative diseases (NDGD), and patients with head and neck diseases. In a recent consensus document developed between the European Society for Swallowing Disorders (ESSD) and the European Union Geriatric Medicine Society (EUGMS), OD matches the definition of a geriatric syndrome as it is a highly prevalent clinical condition in old age, as well as being multifactorial, associated with multiple comorbidities and bad prognosis and is only treatable when a multidimensional approach is used (Baijens et al., 2016). These societies concluded that OD should be given more importance and attention and thus be included in all standard screening protocols. In addition, it should be treated and regularly monitored to prevent its main complications. More research is needed to develop and standardize new treatments and management protocols for older patients with OD, this being a challenging mission for those societies. OD is highly prevalent among older people (Robbins, Bridges, & Taylor, 2006), which affects approximately between 15% and 40% of them (Barczi et al., 2000). Data related to prevalence of OD in NDGD varies greatly. For instance, in Parkinson’s disease, prevalence of OD ranges between 52% and 82% (Kalf, de Swart, Bloem, & Munneke, 2012); in Alzheimer’s, between 57% and 84% (Horner, Alberts, Dawson, & Cook, 1994; Langmore, Olney, Lomen-Hoerth, & Miller, 2007), and in motor neuron disease, depending on the stage of the disease, between 30% and 100% (Haverkamp, Appel, & Appel, 1995). Prevalence of OD following stroke varies between 37% and 78%, depending on the diagnostic method used (Daniels et al., 1998; Martino et al., 2005), whereas the incidence of OD in traumatic brain injury is approximately 25% (Mackay, Morgan, & Bernstein, 1999). Between 44% and 50% of head and neck cancer patients are reported to present OD, either as a symptom of their disorder or following chemotherapy (Clav
e & Shaker, 2015; Garcı´a-Peris et al., 2007; Lazarus, 2009). Table 1 summarizes the prevalence

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Table 1 Prevalence of Oropharyngeal Dysphagia in Several Target Populations and Phenotypes of Patients Target Prevalence Phenotype Population Evaluation Method (%) Elderly

Independently living older people

Screening (questionnaires)

11.4–33.7

Clinical exploration (V-VST)

23

Hospitalized in an acute Not specified/clinical exploration (water geriatric unit swallow test or V-VST)

29.4–47.0

Hospitalized with community-acquired pneumonia

Clinical exploration (water swallow test or 55.0–91.7 V-VST)

Hospitalized with community-acquired pneumonia

Instrumental exploration

75

Institutionalized

Screening (questionnaires)

40

Clinical exploration (water swallow test)

38

Screening and clinical exploration

51

Screening (questionnaires)

37–45

Clinical exploration

51–55

Instrumental exploration

64–78

Clinical exploration

25–45

Instrumental exploration

40–81

Stroke: acute phase

Stroke: chronic phase

Neurodegenerative disease

Parkinson disease

Reported by patients

35

Instrumental exploration

82

Alzheimer disease

Instrumental exploration

57–84

Dementia

Reported by caregivers

19–30

Instrumental exploration

57–84

Screening (questionnaires)

24

Instrumental exploration

34.3

Multiple sclerosis

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Table 1 Prevalence of Oropharyngeal Dysphagia in Several Target Populations and Phenotypes of Patients—cont’d Target Prevalence Phenotype Population Evaluation Method (%)

Amyotrophic lateral sclerosis

Clinical and instrumental exploration

47–86

Clinical exploration

50.6

Instrumental exploration

38.5

Zenker diverticulum

Instrumental exploration

86

Osteophytes

Screening

17–28

Structural

Head and neck cancer

Abbreviation: V-VST, volume–viscosity swallowing test. Adapted from Newman, R., Vilardell, N., Clav
e, P., & Speyer, R. (2016). Effect of bolus viscosity on the safety and efficacy of swallowing and the kinematics of the swallow response in patients with oropharyngeal dysphagia: White paper by the European Society for Swallowing Disorders (ESDD). Dysphagia, 31, 232–249; Clav
e, P., & Shaker, R. (2015). Dysphagia: Current reality and scope of the problem. Nature Reviews Gastroenterology & Hepatology, 12, 259–270.

of OD in different phenotypes of patients or diseases according to the evaluation method used for OD. The pathophysiology of swallowing dysfunction in neurological patients and elderly people is characterized by a slow swallow response with delayed closure of the laryngeal vestibule and opening of the upper esophageal sphincter (UES) and aspiration may also result from insufficient hyoid and laryngeal elevation, which would fail to protect the airway (Carrio´n et al., 2015; Serra-Prat et al., 2012). In frail elderly patients, OD is associated to delayed and prolonged swallow response, weak tongue thrust, and weak and delayed impaired hyoid motion (Clav
e et al., 2006). Aspirations and penetrations into the airways during the pharyngeal phase are specifically related to delayed laryngeal vestibule closure. Impaired efficacy is mainly characterized by oropharyngeal residue caused by weak tongue bolus propulsion forces and slow vertical hyoid motion (Kahrilas, Lin, Rademaker, & Logemann, 1997). Moreover, a decreased sensitivity of the pharyngeal and supraglottic areas, associated to a decrease of myelinated nerve fibers of the superior laryngeal nerve, has been described in older patients and strongly contributes to the pathophysiology of their swallow dysfunction (Aviv, 1997; Aviv et al., 1994; Rofes, Arreola, Romea, et al., 2010). In patients with poststroke OD, it was found that several impairments in pharyngeal

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sensitivity and cortical activation are associated to stroke severity. Specifically, these sensory deficits have been related to an impaired safety of swallow and aspirations in both elderly people and poststroke patients (Rofes, Ortega, Vilardell, Mundet, & Clav
e, 2016). OD associated with head and neck malignancy is caused by the combination of disrupted normal anatomy secondary to mass effect, nerve involvement, soft tissue tethering, or tumorinduced pain and the sequelae of treatments. Other head and neck conditions associated with dysphagia are trauma to the throat or larynx or posttracheal intubation, use of tracheostomy tubes, and cervical spine surgery. Congenital malformations (cleft lip, cleft palate), Zenker’s diverticulum, and cricopharyngeal muscle dysfunction can also cause OD. Cervical osteophytes, primarily with large lesions below the level of C3 and cervical hyperostosis (Forestier–Rotes syndrome) can produce dysphagia due to both obstruction of the cervical esophagus from the mass of the osteophyte or to inflammation around osteophyte formation (Sifrim, Vilardell, & Clav
e, 2014). On the other hand, there is no universally accepted definition of malnutrition, as evidenced by the many attempts to do so. One of the most widely accepted is the one proposed by Elia, Stratton, Russell, Green, and Pang (2006): malnutrition is the state of nutrition in which a deficiency of energy, protein, and other nutrients causes measurable adverse effects on the composition and function of tissues/organs and clinical outcome. It is also possible to consider malnutrition as a pathological condition resulting from a relative or absolute absence of one or more essential nutrients. One of the major challenges for clinicians is to assess malnutrition in a sick patient and evaluate its specific effects on patient outcomes. Indeed, the clinical manifestations of the disease may confuse the detection of malnutrition and vice versa, being recognized the interaction between them. Therefore, it is a challenge to show that malnutrition independently worsens the prognosis of a disease, which is merely improved by nutritional therapy. Malnutrition (MN) is also a geriatric syndrome related to increased healthcare costs and impaired health outcomes as it increases hospital stay and risk of infections, impairs recovery, and increases mortality (Bonnefoy et al., 2015). MN is also underestimated and underdiagnosed among elderly hospitalized patients despite being classified in the International Classification of Diseases. A resolution of the Council of Europe claimed that undernutrition among hospital patients was highly prevalent and identified OD as a major contributor to MN. The overall prevalence of MN among older persons admitted to general hospitals for acute diseases is estimated to be 38.7% (Carrio´n et al., 2015).

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A recent study from the Hospital of Mataro´ (Barcelona, Spain) found OD is a prevalent risk factor for malnutrition in a cohort of older patients admitted with an acute disease to a general hospital. In this study, it was shown that prevalence of dysphagia was higher than malnutrition in the older patients, OD was an independent risk factor for malnutrition, and both conditions were related to poor outcome. Despite its enormous impact on functional capacity, health, and quality of life (Jensen et al., 2010), OD is underestimated and underdiagnosed as a cause of major nutritional and respiratory complications in many patients admitted to hospitals, and the level of healthcare resources dedicated to dysphagic patients is very low. The relationship between OD and pneumonia is well recognized and gives rise to the term “aspiration pneumonia” for those patients with abnormal swallowing function and pneumonia. In contrast, the association between OD and MN is less recognized, probably because the nutritional complication develops slowly and insidiously. The aim of this chapter is to describe the methods and strategies for diagnosis of OD, the nutritional (malnutrition, dehydration) and respiratory (aspiration pneumonia) complications of this condition, and the nutritional management basis of dysphagic patients.

2. SCREENING AND DIAGNOSIS OF OD The goal of the diagnostic strategy for dysphagia is to evaluate two deglutition-defining characteristics: (a) efficacy, the patient’s ability to ingest all the calories and water he/she needs to remain adequately nourished and hydrated and (b) safety, the patient’s ability to ingest all needed calories and water with no respiratory complications (Clav
e et al., 2006). To assess both characteristics of deglutition, two groups of diagnostic methods are available: (a) clinical methods such as deglutition-specific medical history and clinical examination, usually used as screening methods and (b) the exploration of deglutition using specific complementary studies such as fiberoptic endoscopic evaluation of swallowing (FEES) or videofluoroscopy (VFS). Clinical screening for OD should be low risk, quick, and low cost and aim at selecting the highest risk patients who require further clinical or instrumental assessment, and can include: (a) Deglutition-specific questionnaires: The Eating Assessment Tool (EAT-10) is a self-administered, symptom-specific outcome instrument for dysphagia. The EAT-10 has displayed excellent internal consistency, test–retest reproducibility, and criterion-based validity. The normative

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data from the original study suggest that an EAT-10 score of 3 or higher is abnormal. The instrument may be utilized to document the initial dysphagia severity in persons with swallowing disorders (Belafsky et al., 2008). There is also a validated specific symptom inventory to assess the severity of OD in patients with neuromyogenic dysphagia. The inventory consisted in 17 questions each answered on a 100mm visual analog scale. Applied to patients with neuromyogenic dysphagia, the 17-question inventory shows strong test–retest reliability over 2 weeks. Also, content, construct validity, and score are highly correlated with an independent global assessment severity score (Wallace, Middleton, & Cook, 2000). (b) Clinical assessment: Current methods for clinical screening of dysphagia are, for example, the water swallow test (Gordon, Hewer, & Wade, 1987), the 3-oz water test developed in the Burke Rehabilitation Center (DePippo, Holas, & Reding, 1992), the timed swallow test (Nathadwarawala, Nicklin, & Wiles, 1992), and the standardized bedside swallow assessment (SBSA) (Smithard et al., 1998; Westergren, 2006). Patients are asked to drink different amounts of water from a glass without interruption. Coughing during or after completion or the presence of a postswallow wet-hoarse voice quality, or swallow speed of less than 10 mL/s are scored as abnormal and the test is reported as “failed.” These clinical bedside methods can detect dysphagia, although with differing diagnostic accuracy. The Burke’s 3-oz water swallow test identified 80% of patients aspirating during subsequent VFS examination (sensitivity 76%, specificity 59%) (DePippo et al., 1992). The SBSA showed a variable sensitivity (47–68%) and specificity (67–86%) in detecting aspiration when used by speech swallow therapists or doctors (Smithard et al., 1998; Westergren, 2006). Note that these screening procedures involve continuous swallowing of quite large amounts of liquid and may place the patient at high risk for aspiration. Furthermore, many of these studies on bedside screening lack methodological quality and, therefore, the psychometric properties of the screening procedure being studied cannot be determined accurately (Bours, Speyer, Lemmens, Limburg, & de Wit, 2009). Clav
e et al. (2008) developed a safer clinical method (the volume– viscosity swallow test, V-VST) using a series of 5–20 mL nectar, liquid, and pudding boluses sequentially administered in a progression of increasing difficulty. Cough, fall in oxygen saturation
3%, and changes in quality of voice were considered clinical signs of impaired

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safety, whereas piecemeal deglutition and oropharyngeal residue were considered signs of impaired efficacy. The V-VST is a safe, quick, and accurate clinical method with 88.2% sensitivity for impaired safety, 100% sensitivity for aspiration, and up to 88.4% sensitivity for impaired efficacy of swallows. Fig. 1 shows the algorithm for management (screening, diagnosis, and treatment) of OD at the Hospital de Mataro´ (Barcelona, Spain).

Vulnerable patient

Doctor/nurse/SLT/HCP Suspected impairment of deglutition Clinical signs or symptoms of dysphagia/malnutrition respiratory complications/aspiration pneumonia

Nurse/speech swallow therapist/dietitian Volume–viscosity swallow test (V-VST)

V-VST = Negative

V-VST = Positive

Dietitian Efficacy impairment

Speech swallow therapist Safety impairment

Oral health assessment Oropharyngeal bacterial colonization

Nutritional risk malnutrition sarcopenia

Penetration and/or aspiration/choking

Pneumonia/ respiratory infection

Doctor/specialised nurse/speech swallow therapist Diagnostic tests: videofluoroscopy (VFC) • Signs of Safety and Efficacy • Aspirations vs penetration • Swallow response • Treatment

Dietitian • Nutritional assessment

Doctor • Clinical follow-up

• Assessment of dehydration

• Complications

• Textures/viscosity

• Pharmacological treatments

Speech swallow therapist • Dysphagia rehabilitation strategies. Compensation • Active treatments. Recovery

Repeat V-VST according natural history of each disease

Fig. 1 Proposed algorithm for diagnosis and treatment of oropharyngeal functional dysphagia using the V-VST for screening and VFS studies for patient assessment. Note the involvement of several professional domains of the dysphagia multidisciplinary team and the flows of information.

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The V-VST is considered to be a highly adequate instrument for screening of dysphagia and agrees with the recommendations stated in the systematic review on bedside screening for dysphagia by Bours et al. (2009), which combine a water test and pulse oxymetry and use coughing, choking, and voice alteration as endpoints. The use of different viscosities in the V-VST can be considered to be an improvement compared to a simple water test using only liquid. In a recent study, some of the authors determined the accuracy of the EAT-10 and the V-VST for clinical evaluation of OD by using a new xanthan gum thickener and using VFS as gold standard. According to VFS, prevalence of OD was 87%, 75.6% with impaired efficacy and 80.9% with impaired safety of swallow including 17.6% aspirations. The EAT-10 showed a diagnostic accuracy of 0.89 for OD with an optimal cut-off at 2 (0.89 sensitivity and 0.82 specificity). The V-VST showed 0.94 sensitivity and 0.88 specificity for OD, 0.79 sensitivity and 0.75 specificity for impaired efficacy, 0.87 sensitivity and 0.81 specificity for impaired safety, and 0.91 sensitivity and 0.28 specificity for aspirations. It was concluded that clinical methods for screening (EAT-10) and assessment (V-VST) of OD offer excellent psychometric properties that allow adequate management of OD. Their universal application among at-risk populations will improve the identification of patients with OD at risk for malnutrition and aspiration pneumonia. A recent systematic review further confirms these data and provides an update of currently available bedside screenings to identify OD in neurological patients (Rofes, Arreola, Mukherjee, & Clav
e, 2014). (c) Instrumental explorations: Following initial screening and clinical assessment, further assessment by means of instrumental techniques are performed to obtain a more accurate and objective diagnosis. The instrumental techniques considered to be the gold standard in the examination of the swallowing mechanism are VFS and FEES. VFS is the gold standard to study the oral and pharyngeal mechanisms of dysphagia (Cook & Kahrilas, 1999). VFS is a dynamic exploration that evaluates the safety and efficacy of deglutition, characterizes the alterations of deglutition in terms of videofluoroscopic symptoms, and helps to select and assess specific therapeutic strategies. Technical requirements for clinical VFS are an X-ray tube with fluoroscopy and a videotape recorder; additionally, there are computer-assisted methods of analysis

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of images allowing quantitative temporal and spatial measurements. Main observations during VFS are done in the lateral plane while swallowing 5–20 mL boluses of at least three consistencies: liquid, nectar, and pudding. The patient is kept at a minimal risk for aspiration by starting the study with low volumes and thick consistencies, and continuing with liquids and high volumes as tolerated (Clav
e et al., 2006). Major signs of impaired efficacy during the oral stage include apraxia and decreased control and bolus propulsion by the tongue. Many older patients present deglutitional apraxia (difficulty, delay, or inability to initiate the oral stage) following a stroke. This symptom is also seen in patients with Alzheimer’s, dementia, and patients with diminished oral sensitivity. Impaired lingual control (inability to form the bolus) or propulsion results in oral or vallecular residue when alterations occur at the base of the tongue. The main sign regarding safety during the oral stage is glossopalatal (tongue-soft palate) seal insufficiency, a serious dysfunction that results in the bolus falling into the hypopharynx before triggering the oropharyngeal swallow response and while the airway is still open, which causes predeglutitive aspiration (Logemann, 1993). Videofluoroscopic signs of safety during the pharyngeal stage include penetrations and/ or aspirations. Penetration refers to the entering of contrast into the laryngeal vestibule within the boundaries of the vocal cords. When aspiration occurs, contrast goes beyond the cords into the tracheobronchial tree (Fig. 2B). The potential of VFS regarding image digitalization and quantitative analysis currently allows accurate swallow response measurements in patients with dysphagia (Fig. 2). A slow closure of the laryngeal vestibule and a slow aperture of the UES (as seen in Fig. 2B) are the most characteristic aspiration-related parameters (Clav
e et al., 2006; Kahrilas et al., 1997). Penetration and aspiration may also result from an insufficient or delayed hyoid and laryngeal elevation, which fail to protect the airway. A high, permanent postswallow residue may lead to postswallow aspiration, since the hypopharynx is full of contrast when the patient inhales after swallowing, and then contrast passes directly into the airway. Thereafter, VFS can determine whether aspiration is associated with impaired glossopalatal seal (predeglutitive aspiration), a delay in triggering the pharyngeal swallow or impaired deglutitive airway protection (laryngeal elevation, epiglottic descent, and closure of

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Fig. 2 Instrumental explorations used for OD. The main signs of impaired safety (aspiration) of swallow can be observed by FEES (A, right) or VFS (B, left).

vocal folds during swallow response), or an ineffective pharyngeal clearance (postswallowing aspiration). FEES involves a nasoendoscopic evaluation by means of a fiberoptic rhinolaryngoscope passed through the nares to the pharynx to obtain images of the base of the tongue, pharynx, and larynx. Colored boluses are administered to visualize the events before and after swallowing. Variables studied during FEES are related to efficacy (pharyngeal residue) and safety (penetration and aspiration) of swallow (Diniz, Vanin, Xavier, & Parente, 2009; Leder, Judson, Sliwinski, & Madson, 2013). Both VFS (Choi, Ryu, Kim, Kang, & Yoo, 2011) and FEES (Langmore, 2006) enable comparisons between subjects with and without OD and allow the effects of therapeutic strategies to be assessed, including the use of thickening agents (Clav
e et al., 2006). The recommendation of the ESSD is to develop an agreement on the metrics (VFS/FEES signs and measurements of swallow response) that describe the normal/impaired swallow response.

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3. CONSEQUENCES OF DYSPHAGIA OD causes two groups of severe complications depending on the etiology of the problem. If the patient presents impaired efficacy of swallow, he/she will suffer from malnutrition and dehydration; however, if the patient presents impaired safety of swallow and aspirations, he/she will develop respiratory infections and aspiration pneumonia (AP) with increased morbidity and mortality. It has been also found that OD is a very prevalent and relevant risk factor associated with hospital readmission for both aspiration and nonaspiration pneumonia in elderly persons (Cabr
e et al., 2014).

3.1 Aspiration Pneumonia The pathophysiology of aspiration pneumonia (AP) can be explained as the combination of risk factors that alter swallowing function, cause aspiration, and predispose the oropharynx to bacterial colonization (Fig. 3) (Almirall, Cabr
e, & Clav
e, 2007; Marik & Kaplan, 2003). They include medication, altered conscience, NDGD, stroke, esophageal diseases, aging, malnutrition, antibiotics, dry mouth, impaired immune system, dehydration, and smoking (Almirall, Cabre, & Clav
e, 2012). They can be classified into three types of risk: (1) OD with impaired safety of swallow (aspirations); (2) frailty and impaired health status (malnutrition, sarcopenia, impaired immunity, comorbidities, low functionality); and (3) poor oral health and hygiene with bacterial colonization by respiratory pathogens (Ortega et al., 2013; Tada & Miura, 2012). Prevention of complications of OD and AP should be directed at all the three risk groups. The incidence and the prevalence of aspiration pneumonia (AP) in the community are poorly defined. They increase in direct relation with age and underlying diseases. The risk of AP is higher in older patients because of the high incidence of dysphagia (Cabr
e, 2009). In elderly nursing home residents with OD, AP occurs in 43–50% during the first year, with a mortality of up to 45% (Almirall et al., 2007). Cabr
e et al. (2009) studied 134 older patients (>70 years) consecutively admitted with pneumonia in an acute geriatric unit in a general hospital. Of the 134 patients, 53% were over 84 years old and 55% presented clinical signs of OD; the mean Barthel score was 61 points, indicating a frail population. Patients with dysphagia were older,

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Old patients Oropharyngeal bacterial colonization

Oropharyngeal mucosa drying Oropharyngeal dysphagia (OD)

Impaired safety (oropharyngeal reflex alterations)

Respiratory infections

Impaired efficacy (bolus propulsion alteration)

Aspiration

Readmission

Malnutrition

Different dysfunctions (e.g., adipose, immune, etc.) Aspiration pneumonia

Dehydration

Hypovolemia alteration

Frailty syndrome

Mortality

Functional impairment, disability, and immunosuppression, etc.

Institutionalization

Fig. 3 Pathophysiology of nutritional and respiratory complications of OD in elderly people. Adapted from Ortega, O., Cabr
e, M., & Clav
e, P. (2014). Oropharyngeal dysphagia: Aetiology & effects of ageing. Journal of Gastroenterology and Hepatology Research, 3, 1049–1054.

showed lower functional status, higher prevalence of malnutrition and comorbidities, and higher Fine’s pneumonia severity scores. Patients with dysphagia had higher mortality at 30 days (22.9% vs 8.3%, p ¼ 0.033) and at 1 year of follow-up (55.4% vs 26.7%, p ¼ 0.001). Therefore, OD is a highly prevalent clinical finding and an indicator of disease severity in older patients with pneumonia. The pathogenesis of aspiration pneumonia has been revised (Almirall et al., 2007; Marik & Kaplan, 2003). Aspiration observed at VFS is associated with a 5.6- to 7-fold increase in risk of pneumonia (Schmidt, Holas, Halvorson, & Reding, 1994). Up to 45% of older patients with dysphagia presented penetration into the laryngeal vestibule and 30% aspiration, half of them without cough (silent aspiration); and 45%, oropharyngeal residue (Clav
e et al., 2005). It is accepted that detection of aspiration by VFS is a predictor of pneumonia risk and/or probability of rehospitalization

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(Cook & Kahrilas, 1999). It is also well known that not all patients who aspirated during VFS develop pneumonia. Impairment in host defenses such as abnormal cough reflex (Marik & Kaplan, 2003), impaired pharyngeal clearance (Palmer et al., 2001), amount and bacterial concentration of aspirate, and weakened immune system also strongly contributed to the development of AP (Almirall et al., 2007). Impairment of cough reflex increases the risk of AP in stroke patients (Addington, Stephens, & Gilliland, 1999). Several risk factors contribute to oropharyngeal colonization such as: (1) older age, (2) malnutrition, (3) smoking status, (4) poor oral hygiene, (5) antibiotics, (6) dry mouth, (7) immunity, and (8) feeding tubes. Increased incidence of oropharyngeal colonization with respiratory pathogens is also caused by impairment in salivary clearance (Palmer et al., 2001). The microbial etiology of AP involves Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae for community-acquired AP and Gram-negative aerobic bacilli in nosocomial pneumonia. It is worth bearing in mind the relative unimportance of anaerobic bacteria in AP (Almirall et al., 2007). Surprisingly, in the clinical setting, OD and aspiration are usually not considered etiologic factors in older patients with pneumonia (Almirall et al., 2007; Marik & Kaplan, 2003). Ortega et al. (2014) have recently found two groups of results further linking poor oral health, oral colonization of respiratory pathogens, frailty, and aspiration with the pathophysiology of aspiration pneumonia (Fig. 4). In one study, they assessed oral health in patients with OD and found older patients with OD presented polymorbidity and impaired health status, high prevalence of VFS signs of impaired safety of swallow, and poor oral health A) Poor oral health colonization by respiratory pathogens

C) Frail/vulnerable patient malnutrition poor inmunity

B) O. Dysphagia impaired safety swallow aspirations impaired cough reflex

ASPIRATION PNEUMONIA = A + B + C

Fig. 4 Pathophysiology of aspiration pneumonia.

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status with high prevalence of periodontal diseases and caries. These patients are at great risk of developing AP. Ortega et al. (2015) also explored the oral and nasal microbiota and the colonization of oral cavity by respiratory pathogens in frail older patients with OD and found: (a) oral health was poor in all groups, 90% presented periodontitis and 72% caries; (b) total bacterial load was similar in all groups, but higher in the oropharynx (>108 CFU/ mL) than in the nose (80 years (Morley, 2008). Even with a conservative estimate of prevalence, sarcopenia affects >50 million people today and will affect >200 million in the next 40 years. The impact of sarcopenia on older people is far reaching; its substantial tolls are measured in terms of morbidity (Sayer et al., 2005), disability (Janssen, Heymsfield, & Ross, 2002), high costs of health care (Janssen, Shepard, Katzmarzyk, & Roubenoff, 2004), and mortality (Gale, Martyn, Cooper, & Sayer, 2007). The EWGSOP recommends using the presence of both low muscle mass and low muscle function (strength or performance) for the diagnosis of sarcopenia. The rationale for use of two criteria is muscle strength does not depend solely on muscle mass, and the relationship between strength and mass is not linear (Goodpaster et al., 2006). The tongue plays a key role in bolus propulsion. Different authors have found elderly patients with dysphagia showed impaired tongue propulsion (Rofes, Arreola, Romea, et al., 2010), and decreased tongue volume due to sarcopenia (Robbins et al., 2005). Older adults present lingual weakness, a finding that has been related to sarcopenia of the head and neck musculature and frailty (Robbins et al., 2005), and one of the major causes for

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dysphagia in the elderly, associated with impairment in efficacy and safety of swallow (Rofes, Arreola, Almirall, et al., 2010). Clav
e et al. (2006) have studied the prevalence, risk factors, and characteristics of malnutrition among different phenotypes of patients with OD. First, they studied the prevalence of malnutrition among patients with chronic dysphagia caused by nonprogressive brain disorders (NPBD, e.g., stroke, brain injury) or by NDGD patients (e.g., ALS, multiple sclerosis). Prevalence and type of malnutrition were studied using the SGA (Subjective Global Assessment), anthropometric measures, and biochemical markers. They found that prevalence and type of malnutrition were similar between NPDB and NDGD patients with neurogenic dysphagia. Malnutrition was found in 16–24% NPBD patients and 22–23.5% NDGD patients. Their study also found a strong correlation between clinical severity of dysphagia and malnutrition and the type of malnutrition in both groups of patients with neurogenic dysphagia was uniformly of the chronic type with a strong reduction in skeletal muscle and fat mass; in contrast, measurements of visceral protein (albumin and lymphocytes) were found to be within the normal range in most patients with neurogenic dysphagia and malnutrition. More recently, Carrio´n et al. (2015) also explored the relationship between OD, nutritional status, and clinical outcome in a cohort of 1662 patients
70 years consecutively hospitalized with acute diseases to an acute geriatric unit. They found that 47.4% patients presented OD and 30.6% malnutrition. Both conditions were significantly associated with polymorbidity, multiple geriatric syndromes, and poor functional capacity. However, patients with dysphagia presented increased prevalence of malnutrition regardless of their functional status and comorbidities and lower albumin and cholesterol levels. Otherwise, patients with malnutrition presented an increased prevalence of dysphagia (68.4%). Patients with dysphagia and patients with malnutrition presented increased intrahospital, 6-month and 1-year mortality rates, and the poorest outcome was for patients with both conditions (1-year mortality was 65.8%). So, prevalence of dysphagia was higher than malnutrition in the elderly patients and dysphagia was found an independent risk factor for malnutrition, and both conditions were related to poor outcome. Therefore, they recommended systematic and integrated management of OD and MN among hospitalized elderly patients. They also explored the nutritional status in older patients with OD in a chronic and an acute clinical situation. Prevalence of impaired nutritional status (malnutrition risk, and sarcopenia) among older patients with OD associated with either chronic or acute conditions was very high. They also

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found, in patients with OD and chronic diseases, poor nutritional status that further impairs OD with an increase in oropharyngeal residue at spoon-thick viscosity. In the acute setting, there is inflammation and an additional protein deficiency. These findings will help develop specific products both for OD and nutritional status in each specific clinical situation. Finally, OD has been shown to cause dehydration in older people, although the real prevalence of dehydration in patients with OD is unknown because of the different methods used and the lack of a gold standard for its assessment (Armstrong, 2007). Studies suggested that bioimpedance was a good technique to study hydration status in older adults in the community (Goldberg et al., 2014). Patients with OD and in a chronic situation showed a general decrease in intracellular water compartment. Intracellular dehydration is a consequence of a loss of body fluids with a lower osmolality in relation to plasma secondary to low intake caused by OD or fluid restriction. Low intake increases the osmotic pressure of the extracellular space and the necessity for osmotic equilibrium between the two spaces causes transmembrane flow of water from the intracellular space to the extracellular space (Cheuvront & Kenefick, 2014). Considering the bioimpedance results, and taking as a reference that intracellular water is 0.4 L kg1 of body mass, it has been found that most patients have reduced intracellular water, suggesting some degree of dehydration. Despite these results and taking into account some of the limitations of the bioimpedance, it is clear that more studies are needed to clarify the real hydration status of elderly patients with OD.

4. NUTRITIONAL MANAGEMENT OF DYSPHAGIC PATIENTS 4.1 Rheological Aspects of Swallowing and Dysphagia Deglutition is the act or process of swallowing. It is a complex operation that involves a highly coordinated activity of many muscles and nerves of the oral cavity, oropharynx, and esophagus. The whole process is partially under voluntary control (e.g., oral or mastication phase) and partially reflexive in nature (e.g., oropharyngeal and esophageal phases). By definition, deglutition involves the passage of a food bolus (solid or liquid) from the oral cavity to the stomach via the pharynx and then to the esophagus. During the oral phase, the food is prepared for swallowing. In this first phase, mastication is involved with the main target to grind or to comminute food with the teeth, thus reducing its size, in preparation for deglutition and then digestion, and

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food is put in contact with saliva that brings a lubrication effect to the mechanical forces applied by the jaws, teeth, and tongue. In addition, an enzymatic reaction due to the presence of α-amylase in the saliva may modify the flow properties (i.e., viscosity) of starch-rich meals (Pedersen, Bardow, Beier-Jensen, & Nauntofte, 2002). Once mastication is voluntarily finished, bolus is propelled by the tongue from the oral cavity to the oropharynx. The oropharyngeal phase is critical to ensure a safe swallowing. It is during this phase that the alimentary and ventilator streams cross each other. In healthy individuals, a dynamic separation of these streams is possible due to the high coordination of muscles and nerves involved in this complex process. It is an extremely fast flow process that takes around a second for the bolus to traverse the pharynx and reach the cricopharyngeal area, also known as UES. At this stage, the breathing stops for a split second before the soft palate is closed, preventing the passage of the bolus to the nasopharynx; glottis closes epiglottis and vocal cords. The esophageal phase begins when the bolus passes through the UES. The lower esophageal sphincter (LES) muscle acts as a valve that opens to allow the passage of the bolus to the stomach. In summary, a safe swallowing has two essential physiological aspects: (1) passage of food from the oral cavity to the stomach and (2) airway protection to prevent contamination of the trachea. Swallowing and respiration (expiration) have tight temporal coordination in healthy individuals but not in people with swallowing or deglutition disorders also known as dysphagia (Matsuo & Palmer, 2009). On the other hand, it is well known that the swallow-respiratory temporal coordination is a function of the method of ingestion, body position, and food bolus consistency. This last clearly suggests that swallowing processes can be analyzed from a fluid kinematics/ dynamics point of view (Engmann & Burbidge, 2013), where food bolus flow properties (e.g., food bolus rheology) are an important tool to better understand swallowing disorders. A kinematic/dynamic analysis of dysphagia aims to gain insight into the mechanisms of bolus and liquids flow during swallowing. As rheology is the study of the deformation and flow of matter, the connection between the dysphagia world and rheology is clear. 4.1.1 Food Bolus Rheology Food bolus rheology is related to the study of flow and deformation of the food bolus. The rheological characterization of the bolus is highly relevant, as it is linked to the performance of the deglutition or swallowing process.

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The rheological properties of foods entering into the mouth are fundamentally a function of the food composition. However, once in the mouth, the rheological behavior is modified during the formation of the bolus, which is largely influenced by subjective sensorial perceptions. Thus, rheological properties play an important role in perceptions of food textures or consistencies (Chen & Rosenthal, 2015; Coster & Schwarz, 1987; Smith, Logemann, Burghardt, Zecker, & Rademaker, 2006). For the oral or mastication phase, food bolus rheological/textural properties, such as for instance elasticity and viscosity, cohesiveness, brittleness, chewiness, and gumminess, are important as they are involved in the sensorial perception that describe human swallowing (De Araujo & Rolls, 2004). For example, Jestrovi
c, Coyle, and Sejdi
c (2014), using electroencephalography (EEG) systems, showed specific brain activity patterns related to eating, in particular to bolus viscosity stimuli. The authors explained the nonstationary values of the EEG signals by the modulation of the response from neurons to changes (i.e., increase or decrease) in food bolus viscosity. These results confirm the influence of food texture/rheology properties and sensorial perception of food bolus in the brain that are involved in human body adaptation to bolus stimuli during swallowing (De Araujo & Rolls, 2004). Surface electromyography (sEMG) has been used to measure laryngeal physiology for diagnostic and treatment purposes of swallowing disorders. Watts and Kelly (2015) showed a significant effect of bolus consistency on sEMG measurements, in particular on the peak contraction amplitude, but not on contraction duration. The results from this study revealed that, as bolus consistency moved from less to more solid, sEMG amplitude increased. The authors hypothesized the recruitment of larger motor neuron pools to move more solid bolus toward the UES, as the mechanisms involved in the bolus stimuli reaction. In spite of the relevance of these bolus properties, it is not well established yet which of these food bolus mechanical–sensorial properties are necessary to assess or to diagnose an efficient oral preparatory or food mastication step during bolus formation, and how human body reacts to bolus stimuli, in preparation for the next swallowing step, the oropharyngeal phase. Today, the only clear evidence is that human brain systems are activated by the oral perception of viscosity as well as other rheological properties. The main challenge in this area is to translate lab-based mechanical properties, like food texture/rheology, into the sensorial-physiological domain associated to swallowing. Food textural and rheological properties are used to describe the solidlike behavior of food bolus. Elasticity is a material property representative of

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the solid-like behavior of food boluses that, together with other textural properties, like hardness, gumminess, springiness, creaminess, crispness, brittleness, chewiness, adhesiveness, and cohesiveness, is commonly associated to sensorial perceptions. The classical “in vitro” texture profile analysis (TPA) is the main experimental technique used for the assessment of the solid-like behavior of foods and its relation with sensorial dimensions. This technique is well established and gives important information to better understand the mastication process (Chen & Rosenthal, 2015). However, the “in vivo” investigation of the effect of mechanical properties on food bolus formation and, thus, safe swallowing has been quite limited due to the difficulty to perform “in vivo” experiments (Van der Bilt, Engelen, Pereira, van der Glas, & Abbink, 2006). In this sense, the translation of TPA information to the whole swallowing process still is an area where additional research is needed. On the other hand, the basic rheological property that characterizes the flow behavior of fluid-like materials is the viscosity. Food bolus flow is a dynamic process that depends on the characteristics of the applied force (e.g., magnitude and direction). Thus, the bolus during the swallowing process is submitted to shear and extensional flow (Chen, 2009; Ekberg et al., 2009). However, the focus is usually centered on the measurement of shear viscosity (Brito-de la Fuente, Ekberg, & Gallegos, 2012). For most liquid and semiliquid food boluses, their shear viscosity decreases as shear rate increases and this behavior is known as non-Newtonian shear thinning (Partal & Franco, 2010). The spectrum of food bolus shear-thinning behavior is very wide. Thus, in many occasions, their viscous flow curves exhibit Newtonian regions at low and/or high shear rates. Consequently, the apparent viscosity of these boluses may decrease from a constant value at low shear rates down to another constant value, orders of magnitude lower, at high shear rates. Taking into account, the still limited knowledge concerning the shear rate at which the bolus is submitted during the swallowing process, it is of remarkable relevance the viscous characterization of the boluses in a very wide range of shear rates. Quite often, structured food systems exhibit both a fluid- and solid-like behavior. In this case, more sophisticated rheological studies should be used to describe these materials (Brito-de la Fuente, Ekberg, et al., 2012). There are several guidelines from different dysphagia professional associations around the world (see Section 4.3). All of them are referring to viscosity as the only rheological property involved in diet modification for dietary management of dysphagia. However, only one of these guidelines

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proposes objective viscosity borders and ranges for thickened liquids or food boluses. In this case, the classification and ranges are based on shear viscosities measured at one single shear rate of 50 s1 and at a temperature of 25°C (National Dysphagia Diet Task Force, 2002). There is no scientific evidence or rationale given by the NDDTF on the temperature and shear rate chosen for this scale. In fact, a wide range of shear rates ranging from 5 to 1000 s1 are feasible, being 50 s1 the value most frequently cited, perhaps, because it was adopted by the NDDTF. These conditions have been challenged recently by some authors (Brito-de la Fuente, Staudinger-Prevost, et al., 2012; Chen et al., 2012; O’Leary, Hanson, & Smith, 2010; Quinchia et al., 2011). Consequently, it is quite clear that more research needs to be conducted to determine normative values for the complex swallowing process. Regarding a more close to reality estimation of shear rates and, thus, shear viscosity, there are data from different experimental “in vivo” techniques that allow some estimation of shear rate ranges during the different steps of swallowing. In this sense, the velocity spectrum of food bolus flow in the pharynx and esophagus has been determined by using different “in vivo” techniques. So far, the “golden standard” VFS has been the most frequently used (Bardan, Kern, Arndorfer, Hofmann, & Shaker, 2006). Other nonradiological techniques, like high-resolution manometry (Williams, Pal, Brasseur, & Cook, 2001) and intraluminal impedance (Nguyen et al., 1997), have been also used to generate bolus transit velocity data and then conduct a swallowing kinematic analysis. Ultrasonic pulse Doppler method has been added to this list (Hasegawa, Otoguro, Kumagai, & Nakazawa, 2005). Regardless of the technique used for the kinematic analysis of dysphagia, it is clear that bolus transit time and thus velocity is highly dependent on patient’s medical conditions and food bolus rheological properties. Thus, healthy subjects present high bolus velocity (>35 cm/s). In contrast, neurological patients show slow bolus velocity (