Probiotics and Child Gastrointestinal Health: Advances in Microbiology, Infectious Diseases and Public Health Volume 10 [1st ed.] 978-3-030-14635-1;978-3-030-14636-8

Table of contents :
Front Matter ....Pages i-viii
Front Matter ....Pages 1-1
Shaping Microbiota During the First 1000 Days of Life (Marta Selma-Royo, Maria Tarrazó, Izaskun García-Mantrana, Carlos Gómez-Gallego, Seppo Salminen, Maria Carmen Collado)....Pages 3-24
Necrotizing Enterocolitis and the Preterm Infant Microbiome (Jillian R. Baranowski, Erika C. Claud)....Pages 25-36
Can Postbiotics Represent a New Strategy for NEC? (Fabio Mosca, Maria Lorella Gianni, Maria Rescigno)....Pages 37-45
Front Matter ....Pages 47-47
Preventing and Treating Colic (Flavia Indrio, Vanessa Nadia Dargenio, Paola Giordano, Ruggiero Francavilla)....Pages 49-56
Targeting Food Allergy with Probiotics (Lorella Paparo, Rita Nocerino, Carmen Di Scala, Giusy Della Gatta, Margherita Di Costanzo, Aniello Buono et al.)....Pages 57-68
Use of Probiotics to Prevent Celiac Disease and IBD in Pediatrics (Gloria Serena, Alessio Fasano)....Pages 69-81
Front Matter ....Pages 83-83
Fighting Fatty Liver Diseases with Nutritional Interventions, Probiotics, Symbiotics, and Fecal Microbiota Transplantation (FMT) (Valerio Nobili, Antonella Mosca, Tommaso Alterio, Sabrina Cardile, Lorenza Putignani)....Pages 85-100
Probiotics in the Treatment of Inflammatory Bowel Disease (Stefano Guandalini, Naire Sansotta)....Pages 101-107
Acute Infectious Diarrhea (Andrea Lo Vecchio, Vittoria Buccigrossi, Maria Cristina Fedele, Alfredo Guarino)....Pages 109-120
Probiotics in Functional Gastrointestinal Disorders (Iva Hojsak)....Pages 121-137
Clostridium difficile Colitis Prevention and Treatment (Meltem Dinleyici, Yvan Vandenplas)....Pages 139-146
Back Matter ....Pages 147-150

Citation preview

Advances in Experimental Medicine and Biology 1125 Advances in Microbiology, Infectious Diseases and Public Health

Stefano Guandalini Flavia Indrio Editors

Probiotics and Child Gastrointestinal Health Advances in Microbiology, Infectious Diseases and Public Health Volume 10

Advances in Experimental Medicine and Biology Volume 1125 Advances in Microbiology, Infectious Diseases and Public Health Subseries Editor Gianfranco Donelli, Microbial Biofilm Laboratory, Fondazione Santa Lucia IRCCS, Rome, Italy Subseries Editorial Board Murat Akova (Turkey), Massimo Andreoni (Italy), Beate Averhoff (Germany), Joana Azeredo (Portugal), Fernando Baquero (Spain), George Belibasakis (Switzerland), Emilio Bouza (Spain), Maria Rosaria Capobianchi (Italy), Tom Coenye (Belgium), Anne Collignon (France), Rita Colwell (USA), Mahmoud Ghannoum (USA), Donato Greco (Italy), Jeffrey B. Kaplan (USA), Vera Katalinic-Jankovic (Croatia), Karen Krogfelt (Denmark), Maria Paola Landini (Italy), Paola Mastrantonio (Italy), Teresita Mazzei (Italy), Eleftherios Mylonakis (USA), Jiro Nakayama (Japan), Luisa Peixe (Portugal), Steven Percival (UK), Mario Poljak (Slovenia), Edoardo Pozio (Italy), Issam Raad (USA), Evangelista Sagnelli (Italy), Stefania Stefani (Italy), Paul Stoodley (USA), Jordi Vila (Spain)

This book series focuses on current progress in the broad field of medical microbiology, and covers both basic and applied topics related to the study of microbes, their interactions with human and animals, and emerging issues relevant for public health. Original research and review articles present and discuss multidisciplinary findings and developments on various aspects of microbiology, infectious diseases, and their diagnosis, treatment and prevention. The book series publishes review and original research contributions, short reports as well as guest edited thematic book volumes. All contributions will be published online first and collected in book volumes. There are no publication costs. Advances in Microbiology, Infectious Diseases and Public Health is a subseries of Advances in Experimental Medicine and Biology, which has been publishing significant contributions in the field for over 30 years and is indexed in Medline, Scopus, EMBASE, BIOSIS, Biological Abstracts, CSA, Biological Sciences and Living Resources (ASFA-1), and Biological Sciences. 2017 Impact Factor: 1.760.

More information about this series at http://www.springer.com/series/13513

Stefano Guandalini • Flavia Indrio Editors

Probiotics and Child Gastrointestinal Health Advances in Microbiology, Infectious Diseases and Public Health Volume 10

Editors Stefano Guandalini Department of Pediatrics University of Chicago Chicago, IL, USA

Flavia Indrio Department of Pediatrics, Ospedale Giovanni XXI University of Bari Aldo Moro Amendola, Bari, Italy

ISSN 0065-2598 ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISSN 2365-2675 ISSN 2365-2683 (electronic) Advances in Microbiology, Infectious Diseases and Public Health ISBN 978-3-030-14635-1 ISBN 978-3-030-14636-8 (eBook) https://doi.org/10.1007/978-3-030-14636-8 # Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

We have seen this happening so many times in science and medicine: something new appears on the scene, gains momentum, reaches a top of consensus, and then starts losing its appeal. The pendulum is swinging. Is this occurring now also for probiotics? After enjoying a tremendous rise of popularity both in the general public and in the scientific community for close to two decades, very recently much less enthusiastic opinions and even vocal skepticism have been expressed by some parts of the scientific community, based on data showing lack of efficacy of probiotics in fields considered “strong.” Will also the general public begin swinging in the opposite direction? At what point of the curve will the pendulum finally stop to point at an honest, objective, unbiased assessment? This book aims at providing a fair, rigorously evidence-based answer to some of the most relevant questions currently open for the potential use of probiotics in pediatric gastrointestinal health, ranging from NEC to colic, food allergy to celiac disease, IBD to liver disease, acute diarrhea to the ever-socommon functional disorders, to Clostridium difficile infections. We are grateful to all the authors – all well-respected investigators and recognized authorities in their area – for the effort they have put in generating rigorous analyses and syntheses of the currently available evidence and are confident the reader will find valuable information throughout this book. Chicago, USA Amendola, Italy

Stefano Guandalini Flavia Indrio

v

Contents

Part I

The Newborn

Shaping Microbiota During the First 1000 Days of Life . . . . . . . . Marta Selma-Royo, Maria Tarrazó, Izaskun García-Mantrana, Carlos Gómez-Gallego, Seppo Salminen, and Maria Carmen Collado

3

Necrotizing Enterocolitis and the Preterm Infant Microbiome . . . . Jillian R. Baranowski and Erika C. Claud

25

Can Postbiotics Represent a New Strategy for NEC? . . . . . . . . . . Fabio Mosca, Maria Lorella Gianni, and Maria Rescigno

37

Part II

The Infant

Preventing and Treating Colic . . . . . . . . . . . . . . . . . . . . . . . . . . . . Flavia Indrio, Vanessa Nadia Dargenio, Paola Giordano, and Ruggiero Francavilla

49

Targeting Food Allergy with Probiotics . . . . . . . . . . . . . . . . . . . . . Lorella Paparo, Rita Nocerino, Carmen Di Scala, Giusy Della Gatta, Margherita Di Costanzo, Aniello Buono, Cristina Bruno, and Roberto Berni Canani

57

Use of Probiotics to Prevent Celiac Disease and IBD in Pediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gloria Serena and Alessio Fasano Part III

69

The Child

Fighting Fatty Liver Diseases with Nutritional Interventions, Probiotics, Symbiotics, and Fecal Microbiota Transplantation (FMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Valerio Nobili, Antonella Mosca, Tommaso Alterio, Sabrina Cardile, and Lorenza Putignani

85

Probiotics in the Treatment of Inflammatory Bowel Disease . . . . . 101 Stefano Guandalini and Naire Sansotta

vii

viii

Acute Infectious Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Andrea Lo Vecchio, Vittoria Buccigrossi, Maria Cristina Fedele, and Alfredo Guarino Probiotics in Functional Gastrointestinal Disorders . . . . . . . . . . . . 121 Iva Hojsak Clostridium difficile Colitis Prevention and Treatment . . . . . . . . . . 139 Meltem Dinleyici and Yvan Vandenplas Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Contents

Part I The Newborn

Adv Exp Med Biol - Advances in Microbiology, Infectious Diseases and Public Health (2019) 1125: 3–24 https://doi.org/10.1007/5584_2018_312 # Springer Nature Switzerland AG 2019 Published online: 26 January 2019

Shaping Microbiota During the First 1000 Days of Life Marta Selma-Royo, Maria Tarrazó, Izaskun García-Mantrana, Carlos Gómez-Gallego, Seppo Salminen, and Maria Carmen Collado

early microbiota exposure within the male and the female reproductive tracts at the point of conception and during gestation, focusing on the potential impact on infant development during the first 1000 days of life. Furthermore, we conclude that some dietary strategies including specific probiotics could become potentially valuable tools to modulate the gut microbiota during this early critical window of opportunity for targeted health outcomes throughout the entire lifespan.

Abstract

The data obtained in prior studies suggest that early microbial exposition begins prior to conception and gestation. Given that the hostmicrobe interaction is shaped by the immune system response, it is important to understand the key immune system-microbiota relationship during the period from conception to the first years of life. The present work summarizes the available evidence concerning M. Selma-Royo and I. García-Mantrana Department of Biotechnology, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain

Keywords

Diet · Gestation · Health · Meconium · Microbiota · Placenta · Probiotics · Semen · Vagina

M. Tarrazó Service of Obstetrics and Gynecology, Hospital Universtario Doctor Peset, Valencia, Spain C. Gómez-Gallego Functional Foods Forum, University of Turku, Turku, Finland Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland S. Salminen Functional Foods Forum, University of Turku, Turku, Finland M. C. Collado (*) Department of Biotechnology, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain Functional Foods Forum, University of Turku, Turku, Finland e-mail: [email protected]

1

Perinatal Microbial Environment and Its Relevance for Human Health

The human microbiome is defined as the complex communities of microorganisms that live on, as well as in, the human body, and it is principally composed of bacteria but also of viruses, fungi, archaea and bacteriophages (Milani et al. 2017; Perez-Muñoz et al. 2017). The microbiome is present in different sites of the human body, including the skin, oral, nasopharyngeal and genito-urinary tract (Rautava et al. 2012; Milani 3

4

et al. 2017). The differential microbiome compositions depend on the host’s genetics as well as the host’s environmental characteristics, including humidity, pH, nutrients and oxygen levels (Milani et al. 2017). The microbiome is responsible for numerous essential functions within the human body, including assisting with digestion and metabolism, the production of vitamins, maintaining the gut barrier and regulating the development of the immune system (Rautava et al. 2012; Gensollen et al. 2016). Microbiome dysbiosis has previously been associated with an increased risk of non-communicable diseases (NCDs), such as asthma, obesity, diabetes and autoimmune conditions (e.g. Crohn’s disease), all of which are characterized by the over-responsiveness of the immune system, which in turn leads to an increasing pro-inflammatory status (Clemente et al. 2012; Koleva et al. 2015; Gensollen et al. 2016; Tamburini et al. 2016). The first 1000 days of life (i.e. from gestation until the first 2 years of life) are crucial for both the colonization and the establishment of pioneer microorganisms within the human body and, additionally, for the development and maturation of the immune system. Hence, this period is considered to represent a ‘window of opportunity’ during which any event will have a pivotal impact on the metabolic, immunological and microbiological programming that affects later human health (Agosti et al. 2017). Any alterations and disruption to the step-wise neonatal microbiota colonization have the potential to increase the risk and predisposition of individuals to developing diseases in the short and long term (Verdu et al. 2016). However, recent contradictory scientific evidence suggests that the first microbial contact may actually take place prior to birth and, further, that such contact might play an important role in the development of the foetus. This evidence has contributed to our changing perspective on the sterile environment and the origins of microbiota acquisition (Collado et al. 2016; Perez-Muñoz et al. 2017). Nevertheless, the maternal microbiota represents the most relevant prenatal and postnatal microbial source for

M. Selma-Royo et al.

the foetus and, later, the infant. Yet, despite the growing knowledge base, the different prenatal factors that can affect the maternal microbiota and, consequently, the foetal microbiota remain unclear. The present review, therefore, aims to describe the available evidence concerning early microbial contact during the first 1000 days of life (Fig. 1). The review will also provide an overview of the theory regarding the maternal-foetal-neonatal microbiota and, additionally, the potential offered by the application of dietary interventions with probiotics during this critical window of opportunity.

2

Preconception Microbial Environment: Reproductive Microbiotas

In healthy non-pregnant women, the vaginal microbiota is a complex ecosystem populated by more than 200 bacterial species, with Lactobacillus spp. representing the dominant species, followed by other less abundant bacteria such as Prevotella, Streptococcus, Bacteroides and Veillonella (Aagaard et al. 2012; Mendling 2016). Based on the composition of the Lactobacillus, five types of microbial communities that differ in terms of both their composition and their abundance have been described (Ravel et al. 2011). These communities can be clustered into five groups, which are known as the ‘community state types’ (CSTs), with each group hosting a specific bacteria: Lactobacillus (L.) crispatus (CSTI), L. gasseri (CSTII), L. iners (CSTIII), diverse group (CSTIV; exhibiting a lower presence of Lactobacillus spp.) and L. jensenii (CSTV) (Ravel et al. 2011). The prevalence of the different CSTs differs according to the individual’s geographical location and ethnic origin. For example, a higher abundance of CSTIV among African-American and Hispanic women has been reported in the USA (Stout et al. 2017). The Lactobacillus genus plays an important role in both the maintenance of a low pH and the secretion of metabolites in order to prevent pathogenic colonization in the vagina (Ravel et al. 2011; Aagaard et al. 2012). A growing body of

Shaping Microbiota During the First 1000 Days of Life

5

Fig. 1 Early microbial contact from conception to birth Overview of microbes present in male and female reproductive tracts, in the maternal-foetal-neonatal microbiota as placenta, amniotic fluid and meconium. Microbes are present before egg fertilization and would play a key role during conception. Furthermore, microbiota changes during pregnancy would support the foetal development, and accumulating data suggest the presence of microbes in placenta and amniotic fluid although the biological impact is still uncovered

scientific evidence has demonstrated the potential use of the Lactobacillus species as biomarkers of vaginal health (Petrova et al. 2015). However, the vaginal microbiota does not remain static. Indeed, temporal dynamics have been found in the vaginal microbiota over a 2-week period (Gajer et al. 2012), whereby some communities changed and others remained relatively stable, depending on the CST. Recent studies have highlighted the need to analyse the host factors that affect the vaginal microbiota, since little is currently known about the impact it has on the different bacterial communities or the short- and long-term impacts on the individual’s overall health status (Witkin 2018). The female reproductive system contains bacteria that have an impact on women’s health also outside of the vagina (Chen et al. 2017; Younes et al. 2018). Several studies have demonstrated that the uterus harbours a specific endometrial microbiota that has been linked to both reproductive and uterine health (Moreno et al. 2016; Tao

et al. 2017; Miles et al. 2017; Chen et al. 2017; Benner et al. 2018). The endometrial microbiota is characterized by a high amount of Lactobacillus, followed by Gardnerella, Prevotella, Atopobium and Sneathia, which have also been identified in the vagina (Moreno et al. 2016; Moreno and Franasiak 2017). However, it appears that the endometrial bacteria population differs somewhat from that in the vagina, which suggests that the two microbiotas are related, but not identical (Franasiak and Scott 2017). Furthermore, the fallopian tubes are known to be colonized by bacteria such as Lactobacillus, Staphylococcus, Enterococcus, Prevotella and Propionibacterium, with Pseudomonas being the identified genus (Pelzer et al. 2018). Importantly, recent reviews have highlighted the link between commensal bacteria in the uterus, fertility and pregnancy complications (Prince et al. 2014; Franasiak and Scott 2017; Moreno and Franasiak 2017; Power et al. 2017).

6

M. Selma-Royo et al.

Yet, very little research has previously been conducted concerning the male microbiota identified in the reproductive tract. Recent studies have demonstrated the presence of microbiota in semen, with the Firmicutes representing the most predominant phyla, followed by the Bacteroidetes, Proteobacteria and Actinobacteria, of which Lactobacillus, Prevotella, Gillisia, Corynebacterium and Gardnerella are the most common genera (Mändar et al. 2015). It has been hypothesized that the predominance of Gardnerella vaginalis in the vaginal microbiota is related to inflammation challenges in males, which could be related with colonization/infection from the vagina (Mändar et al. 2017). It has further been suggested that a link exists between the male and female reproductive microbiomes that has an effect on fertility, reproduction, health and gestation. In fact, the majority of prior semen microbiome studies have focused on the issue of infertility, highlighting differences in the microbial profiles and diversity (Hou et al. 2013; Weng et al. 2014; Monteiro et al. 2018). For example, a recent study reported different seminal microbiomes in patients with obstructive or non-obstructive azoospermia, thereby showing an increase in the Bacteroidetes and Firmicutes as well as a decrease in the Proteobacteria and Actinobacteria when compared to healthy men (Chen et al. 2018). Taken together, the uterine and seminal microbiomes appear to be highly relevant for reproductive medicine, with the evidence suggesting the potential of specific microbiota profiles as biomarkers in assisting in the development of new tools for diagnosing and treating infertility. In this scenario, the human reproduction takes place under ‘microbial environment’, and those microbes must have greater attention due to their relevance from preconception onwards.

3

Maternal Microbiota During Pregnancy

During pregnancy, the maternal physiology and metabolism are adjusted in order to afford the foetus an optimal intrauterine environment and

so promote correct growth (Wahlqvist et al. 2015). Gestational physiological changes, such as endocrine, immunological and metabolic alterations, favour a pro-inflammatory status, which is reflected in specific shifts seen in the maternal microbiota at different body sites, including the vagina, gut and oral cavity (Nuriel-Ohayon et al. 2016).

3.1

Vaginal and Uterine Microbiota

During pregnancy, microbial diversity within the vaginal microbiota decreases, while members of Lactobacillus species increase, potentially reinforcing their protective function (Romero et al. 2014; MacIntyre et al. 2015). The uterine microbes may prove beneficial to the foetus and newborn favouring tolerance towards organisms which enhance postnatal well-being such as the Lactobacillus genus (Sisti et al. 2016). However, there is accumulating evidence of dysbiosis occurring in the vaginal microbiome during pregnancy leading to an increased risk of preterm birth (Bretelle et al. 2015), with such disturbances having been found to occur as early as during the first trimester (Haque et al. 2017). It has further been demonstrated that women whose medical history includes repeated urinary tract infections exhibit an increased risk of preterm delivery. Differences in the vaginal microbiota in terms of the composition, stability and diversity have been observed between full-term deliveries and preterm deliveries (Nuriel-Ohayon et al. 2016). Bacterial communities characterized by high levels of Atopobium, Gardnerella and Ureaplasma as well as lower levels of Lactobacillus spp. or a higher presence of Candida albicans have been found to be correlated with preterm birth (DiGiulio et al. 2010; Hyman et al. 2014; Bretelle et al. 2015; Farr et al. 2015). In addition, the seminal microbiota may interfere with both conception and preterm delivery. It has been reported that a higher presence of typical seminal bacteria, such as L. iners, during pregnancy is associated with preterm deliveries, whereas the dominance of L. crispatus, another common bacterial species in semen, has been

Shaping Microbiota During the First 1000 Days of Life

identified as protective (Bennett 2017). In any case, the detection of abnormalities within the vaginal microbiome during gestation could provide new insights on potential microbial biomarkers for predicting the likelihood of preterm delivery.

3.2

Gut Microbiota

While during the first trimester of gestation the composition of the gut microbiota remains stable and resembles pre-pregnancy microbiota, from the end of the first trimester onwards, its composition changes radically (Magon and Kumar 2012). Indeed, it has been reported that the gut microbiota changes during pregnancy to reflect a more pro-inflammatory profile in a manner similar to the changes observed in the case of diabetes or metabolic syndrome (Koren et al. 2012). However, this inflammatory status is implicated in metabolic adaptations to gestation, and it contributes to a healthy pregnancy, meaning that it is beneficial for the development of the offspring (Koren et al. 2012). The changes are mainly observed in terms of an increase in the abundance of Actinobacteria and Proteobacteria phyla, along with a decrease in the butyrateproducing bacteria and a decline in the diversity of the gut bacteria (Koren et al. 2012). Yet, other studies have reported no significant microbial changes in the gut during pregnancy (DiGiulio et al. 2015), which indicates that further research is needed to clarify the impact of pregnancy on the gut microbiota. In addition, it has been widely demonstrated that antibiotic exposure during pregnancy alters the mother’s bacterial ecosystem and, consequently, that of the offspring (Stokholm et al. 2014). Antibiotic use during gestation increases the vaginal colonization by the Staphylococcus species, and potential microbial shifts in other areas than the gut could be linked to an increased risk of allergies and obesity (Kuperman and Koren 2016). Furthermore, the maternal microbiota is influenced during pregnancy by both the mother’s diet and nutritional status. It has recently been reported that the maternal diet during pregnancy

7

has a vital impact on both the maternal and infant microbiotas (Mandal et al. 2016; Barrett et al. 2018; Lundgren et al. 2018). Human studies suggests that changes in the female gut microbiota during pregnancy are vulnerable to modulation by the maternal pre-gestational body max index (BMI), as well as to weight gain over gestation (Collado et al. 2008, 2010; Santacruz et al. 2010). A lower presence of Bifidobacterium spp. has been observed in overweight and obese mothers, as well as in mothers who gained excessive weight during pregnancy, when compared to lean mothers or to those mothers who maintained a weight gain in keeping with recommendations (Collado et al. 2008). Another study reported similar shifts according to weight status during pregnancy, and lower levels of Bacteroides spp., along with higher abundances of Staphylococcus spp. and Escherichia coli, were identified in overweight pregnant women (Santacruz et al. 2010). Such changes in the maternal gut microbiota could be associated with differences in the intestinal colonization process in neonates born via vaginal delivery (Mueller et al. 2016).

3.3

Oral Microbiota

Pregnancy also induces changes in the oral microbiota (Adriaens et al. 2009; Borgo et al. 2014). In fact, significant differences have been reported when comparing the abundances of several species in the oral cavities of pregnant and non-pregnant women. The oral microbiota during gestation is characterized by an increase in the viable bacterial counts, along with higher levels of pathogenic bacteria, such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans and Candida, which validates the growing body of evidence proving the link between oral infections and periodontal disease associated with pregnancy complications, which includes preterm delivery (Offenbacher et al. 2006; Zi et al. 2015; Fujiwara et al. 2017). These data suggest that the oral microbiota also plays a key role in the maternal and neonatal outcomes, including pregnancy complications, risk of preterm birth and early foetal/neonatal microbial colonization.

8

M. Selma-Royo et al.

Thus, further research concerning the association between microbial markers and pregnancy outcomes could prove instrumental in preventing undesirable microbial changes during pregnancy, which may be linked to pregnancy complications.

4

Prenatal Microbial Exposition: In Utero Colonization?

Advances in molecular and sequencing technologies have permitted the study of the human microbiota in areas previously considered sterile, including the placenta (Aagaard et al. 2014), amniotic fluid (DiGiulio 2012; Combs et al. 2014) meconium (Moles et al. 2013; Collado et al. 2016; Nagpal et al. 2016; Shi et al. 2018) and foetal membranes (Steel et al. 2005; Parnell et al. 2017; Lannon et al. 2018). Some such studies have been able to isolate and identify bacteria from those areas (Moles et al. 2013; Combs et al. 2014; Collado et al. 2016). However, the ‘in utero colonization hypothesis’ remains subject to debate (Perez-Muñoz et al. 2017). Despite a number of studies conducted in the field in recent years, it is not yet fully clear whether the detection of microbes in such areas would represent a specific microbiota niche (e.g. placenta microbiota) and, additionally, what their biological relevance would be (Tables 1 and 2). Other studies have suggested that there is no evidence of a placenta microbiome and/or early microbial contact (Lauder et al. 2016; Leon et al. 2018; Rehbinder et al. 2018). The critical issue concerns the low amount of DNA and, further, the potential bias stemming from the contaminant DNA, as well as its detection and filtering (Lauder et al. 2016; de Goffau MC et al. 2018), which increase the risk of false positive results. In this sense, it has been a significant which increases the risk of false positive results. For this reason, a significant amount of effort have been expended in identifying new techniques that should reduce the amount of false positive results with regard to the microbiota analysis and also facilitate the contaminant detection in samples with a low microbial biomass (Avershina et al. 2018; Goffau et al. 2018; Davis et al. 2017).

Moreover, the above-mentioned issues give rise to several questions concerning the origin and presence of these bacteria, as well as their role in infant health in terms of both immunological development and colonization process. The most commonly discussed hypothesis suggests a potential vertical ascendant route from the vagina to the foetus or a haematogenous route (from the oral, gut and other areas through the blood to the placenta, including the gut-foetal route and oralfoetoplacental route) (Kuperman and Koren 2016). It is important to note that recent studies have suggested the presence of a ‘blood microbiome’ in healthy individuals (Païssé et al. 2016). Furthermore, it has been reported that the presence of foetal DNA (Liao et al. 2014) and placenta-derived exosomes (Lai et al. 2018) in the maternal circulation actually evidences their potential association with placenta health, preeclampsia and the risk of preterm birth (Taglauer et al. 2014; Seval et al. 2015; Van Boeckel et al. 2018). Prior studies concerning the placental microbiome have hypothesized that the oral microbiota could represent the main source of the bacteria observed in the placenta tissue. Indeed, it has been observed that the composition of the placental microbiome could be more related to that of the oral microbiota than the composition of the vagina or gut microbiota (Nuriel-Ohayon et al. 2016). Such observations are supported by the relation that has been identified between inflammatory oral disease, principally periodontitis, and complicated pregnancy outcomes, such as preterm delivery. Prince et al. observed an incremental increase in the oral commensal bacteria in the placental microbiome of preterm subjects with chorioamnionitis (Prince et al. 2016). This suggests the particular relevance of Fusobacterium nucleatum, which is a common oral bacterium found in the placenta, in relation to negative pregnancy outcomes (Vander Haar et al. 2018), including preterm birth (Doyle et al. 2014), neonatal sepsis (Wang et al. 2013) and hypertension (Barak et al. 2007). The proposed oral-foetoplacental route has been demonstrated in animal models (Fardini et al. 2010). On the other hand, it has been demonstrated in animal

Shaping Microbiota During the First 1000 Days of Life

9

Table 1 Recent studies on the placental microbiome Birth Preterm (