Microbes and the Mind: The Impact of the Microbiome on Mental Health

By S. Karger

Interest in the mind-body connection has grown in recent years, with accumulating evidence showing that the gut microbiome can alter behavioral, neural, and psychological outcomes. This publication brings together a group of international experts who are investigating the microbiome and its potential to contribute to the causes and treatment of mental illness. The contributions are not aimed solely at specialists in clinical and experimental neuroscience. They cover a range of key topics, including the role of the microbiome in mental health and specific psychiatric disorders that occur across the lifespan, interactions with the immune system, diet, and pharmacological interventions. Furthermore, the microbial metabolite production and the potential for psychobiotic interventions that target the microbiome to improve mental health outcomes are discussed. This book is unique in its focus on the mechanisms and consequences of the activities of gut microorganisms in mental health and illness, providing expert insight into the current state of the art and important future directions for this emerging area of research. Additionally, it provides an excellent knowledge base for newcomers and a refresher for researchers and clinicians working in the fields of neuroscience, psychology, or psychiatry.

• Language: English
• Publisher: S. Karger
• Release date: May 6, 2021
• ISBN: 9783318068566

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Microbes and the Mind

Modern Trends in Psychiatry

Vol. 32

Series Editor

B.E. Leonard Galway

Microbes and the Mind

The Impact of the Microbiome on Mental Health

Volume Editors

Caitlin S.M. Cowan Sydney, NSW

Brian E. Leonard Galway

8 figures, 8 in color, and 4 tables, 2021

Modern Trends in Psychiatry

(Formerly published as `Modern Problems of Pharmacopsychiatry‘ (1968-1997) and `Modern Trends in Pharmacopsychiatry‘ (1998-2017))

Library of Congress Cataloging-in-Publication Data

Names: Cowan, Caitlin S. M., editor. | Leonard, B. E., editor.

Title: Microbes and the mind : the impact of the microbiome on mental health / volume editors, Caitlin S.M. Cowan, Brian E. Leonard.

Description: Basel ; Hartford : Karger, 2021. | Series: Modern trends in psychiatry, ISSN 2504-0464 ; vol. 32 | Includes bibliographical references and indexes.

Identifiers: LCCN 2020054442 (print) | LCCN 2020054443 (ebook) | ISBN 9783318068559 (hardcover ; alk. paper) | ISBN 9783318068566 (ebook)

Subjects: | MESH: Gastrointestinal Microbiome--physiology | Mental Health | Mental Disorders--etiology | Inflammation--etiology

Classification: LCC QR46 (print) | LCC QR46 (ebook) | NLM QW 100 | DDC 612.001/579--dc23

LC record available at https://lccn.loc.gov/2020054442

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and PubMed/MEDLINE.

Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.

© Copyright 2021 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)

www.karger.com

Printed on acid-free and non-aging paper (ISO 9706)

ISSN 2504–0464

e-ISSN 2504–124X

ISBN 978–3–318–06855–9

e-ISBN 978–3–318–06856–6

Contents

Preface

Cowan, C.S.M. (Cork/Sydney, NSW); Leonard, B.E. (Galway)

Introduction

Cowan, C.S.M. (Cork/Sydney, NSW); Leonard, B.E. (Galway)

The Microbiome-Gut-Brain Axis in Neurocognitive Development and Decline

Cowan, C.S.M. (Cork/Sydney, NSW); Cryan, J.F. (Cork)

Maternal Exposure to Adversity: Impact on the Microbiota-Gut-Brain Axis Inflammation and Offspring Psychiatric Outcomes

Rajasekera, T.A.; Gur, T.L. (Columbus, OH)

Gut Microbiota as a Mediator of Host Neuro-Immune Interactions: Implications in Neuroinflammatory Disorders

Caputi, V.; Popov, J. (Cork); Giron, M.C. (Padua); O’Mahony, S. (Cork)

The Effect of Microbiota on Behaviour

Champagne-Jorgensen, K.; McVey Neufeld, K.-A. (Hamilton, ON)

Is Anxiety Associated with the Gut Microbiota?

Foster, J.A. (Hamilton, ON)

Production of Psychoactive Metabolites by Gut Bacteria

Wiley, N.C. (Cork/Fermoy); Cryan, J.F.; Dinan, T.G.; Ross, R.P. (Cork); Stanton, C. (Cork/Fermoy)

Diet and Mental Health

Loughman, A.; Staudacher, H.M.; Rocks, T. (Geelong, VIC); Ruusunen, A. (Geelong, VIC/Kuopio); Marx, W.; O’Neil, A.; Jacka, F.N. (Geelong, VIC)

Psychotropic Drugs and the Microbiome

Cussotto, S.; Clarke, G.; Dinan, T.G.; Cryan, J.F. (Cork)

Psychobiotics: Evolution of Novel Antidepressants

Dinan, T.G.; Butler, M.I.; Cryan, J.F. (Cork)

Author Index

Subject Index

Published online: May 6, 2021

Cowan CSM, Leonard BE (eds): Microbes and the Mind. The Impact of the Microbiome on Mental Health. Mod Trends Psychiatry. Basel, Karger, 2021, vol 32, pp VII–VIII (DOI: 10.1159/000511097)

______________________

Preface

The A.G. Karger monograph series on pharmacopsychiatry commenced 10 years ago to highlight the advances in psychopharmacology and biological psychiatry of interest to psychiatrists, neurologists, and neuroscientists. The current volume is the sixth in the series and is devoted to the impact of the gut microbiome on mental health and psychiatric disorders.

As editors of this monograph, we are acutely aware that the increasing interest of mental health professionals would benefit from an international publication which encapsulates some of the key advances in microbiome research. To achieve this, we have enlisted the help of a group of international experts to cover some of the most important advances in microbiome research in mental health.

In the past decade, a revolution has occurred in neuroscience research with the (re)discovery of the impact of the gut microbiome on physical and mental health and disease. The terms microbiome and microbiota are used, largely interchangeably, to describe the microorganisms associated with biotic and abiotic habitats (i.e., a particular host or environment). Ten years ago, little was known about the microorganisms that inhabit the gut and other regions of the body. Even now, knowledge is largely limited to the microorganisms inhabiting the gastrointestinal tract. Despite these remaining gaps in our knowledge of complex microbiome-body-brain interactions, there is now a strong and growing evidence base for the importance of taking such a holistic view of human health. There is no doubt that this approach has already provided novel insights into the factors contributing to mental health, as we hope you will see in the chapters of this volume. Moreover, we are convinced that the study of the microbiome-gut-brain axis has great potential to improve patient outcomes in the treatment of mental health problems. Clearly, we are not alone in this belief; the microbiome has entered into the lexicon and consciousness of neuroscientists and mental health researchers globally.

What has stimulated the recent interest in the gut microbiome by neuroscientists? In the academic literature, the influence of gut bacteria on human disease other than infections of the gut can be traced back to early last century when strains of Lactobacillus were used to treat poor mood states. Since then, rapidly evolving technologies for studying and analysing the microbiome, alongside an increasing emphasis on interdisciplinary collaboration amongst scientists, have spurred interest in microorganisms outside the traditional microbiology lab. Several authors in this monograph will discuss the impact of the microbiome on different aspects of brain function, ranging from changes in the immune and endocrine systems to changes in cognition and behaviour. Together, the chapters illustrate the importance of the microbiome in mental health and psychiatric disorders. The contributors to this monograph have focussed on the gut microbiome, which is necessitated by the limited data from other body sites, diverse human populations, and other animal species. They have all done an excellent job of critically describing recent advances in our understanding of the microbiome-gut-brain axis and integrating their expert knowledge for readers new to the field (or those just wanting a refresher). Hopefully, the increasing emphasis on microbiome sequencing and other technologies will continue to advance our knowledge of the impact of the microbiome to other important areas of mental health and illness.

In conclusion, we hope that the reader will find this monograph as interesting and rewarding as we have experienced as the editors.

Caitlin S.M. Cowan, Sydney, NSW

Brian E. Leonard, Galway

Published online: May 6, 2021

Cowan CSM, Leonard BE (eds): Microbes and the Mind. The Impact of the Microbiome on Mental Health. Mod Trends Psychiatry. Basel, Karger, 2021, vol 32, pp 1–11 (DOI: 10.1159/000510413)

______________________

Introduction

Caitlin S.M. Cowana, b Brian E. Leonardc

aAPC Microbiome Ireland, University College Cork, Cork, Ireland; bSchool of Psychology, University of Sydney, Sydney, NSW, Australia; cPharmacology Department, National University of Ireland, Galway, Ireland

______________________

Abstract

The theme of this monograph reflects the growing research interest in the contribution of the microbiome-gut-brain axis to mental health. This chapter introduces readers to the study of the microbiome in psychiatric research and emphasises how research into the gut microbiome has had a significant impact on our understanding of mental health. A brief summary of the historical background for microbiome research in mental health is followed by examples of evidence linking gut microorganisms to changes in brain function. As novel technological developments have played a major role in providing the evidence for microbiome modulation of brain function, an overview of modern techniques and technologies is then provided. These have broadened our understanding of the range of microorganisms, in addition to bacteria, which contribute to the changes initiated by the microbiome. In addition, common experimental models are reviewed in light of the important role that animal studies, particularly in germ-free rodents, have played in establishing microbiome-gut-brain interactions. This introduction concludes with a summary of the challenges for future microbiome research, providing a forward-thinking perspective echoed in many of the following chapters.

© 2021 S. Karger AG, Basel

The term microbiota has been defined as the group of microorganisms assimilated with a particular environment or host. The term is frequently used synonymously with microbiome, although the latter is generally more broadly defined to include the microbial genes and/or their metabolites and surrounding environment [1, 2]. While it has been frequently claimed that the term microbiome was coined by the Nobel laureate Joshua Lederberg in 2001 [3], the term did not appear in the article which is frequently cited. In fact, the first description of what became known as the human microbiome was made by Antonie van Leeuwenhoek in 1683 when he wrote to the Royal Society in London: I then most always saw, with great wonder, that in the said matter there were many very little living animalcules (bacteria), very prettily a-moving. He described five different kinds of bacteria present in his mouth and compared his own oral and faecal microbiome with that of others.

By the 19th century other investigators had published evidence of the existence and importance of gut microorganisms. These included Pasteur, Winogradsky, Valk, Koch, Escherich, and others who laid the foundation of the role of the microbiome in human health and disease. Their work formed the basis of the germ theory of disease, leading to many crucial advances in the treatment of infection and in medical science more generally. Holmes and Cotton attempted to apply these ideas in psychiatry, both becoming hell-bent on establishing focal infection as the cause of dementia praecox (now known as schizophrenia), with tragic consequences [4].

In this period, the heavy emphasis on pathogenic host-microbe antagonism largely obscured the positive role that some microorganisms play in supporting a healthy environment. However, there were some early proponents of beneficial microbes, who are now considered the forefathers of modern probiotics. Metchnikoff (another Nobel laureate) is perhaps the most famed for linking the bacterial components of fermented foods to longevity in Bulgarians in 1905 [5], although others attribute this discovery to the Bulgarian physician Grigorov [6]. In 1906, Tissier proposed the use of Bacillus bifidus communis (now recognised as a Bifidobacterium species, which he had isolated from infant faeces) to treat gastrointestinal disease [6]. Around the same time, Kendall [7] was one of the first investigators to systematically study the relationship between diet and the faecal microbiome, describing experimentally induced changes in the faecal bacteria of monkeys.

The purpose of this short introductory section is to highlight some of the more important milestone research. It is by no means a comprehensive account and those interested in more details should consult Finegold [8], Logan et al. [9], Dubos [10], and many others!

The Importance of Microbiome Research to Psychiatry

The influence of gut bacteria in the development or exacerbation of changes in brain function has a relatively long history in the medical literature. Dating back to the 5th century BC, Hippocrates and then Galen are purported to have pinpointed the gut as the source of most, if not all, human disease [11]. Arbuthnot Lane and Metchnikoff’s ideas on auto-intoxication, which gained popularity in the late 19th and early 20th centuries, followed from this tradition [12]. In 1898, Brower [13] noted the relation ever recognised between mental depression and perverted action of the great viscus of the abdominal cavity, and further implicated germs in the gastro-intestinal tract as the most important contributors to this relationship. Early in the 20th century, Phillips [14] reported positively on the use of a probiotic treatment (lactic acid bacillus) to improve melancholia. While the results of these early clinical studies fell out of fashion, interest in the role of the microbiome in mental health and the possible beneficial effects of the microbiome in mental well-being is now a leading area of clinical and experimental research.

In recent years contributions made by the gut microbiome in the regulation of the metabolism, immunity, and brain function have been well established [11, 15]. A fundamental and long-overlooked discovery published by Hegstrand and Hine [16] in 1986 broadened the research on the microbiome by demonstrating that there were major differences in the histamine concentrations in the hypothalamus of germ-free rodents compared to their microbially colonised counterparts. This helped to establish the relationship between the gut microbiome and brain function. Since then, germ-free and other experimental models have been used to establish that there are neuronal, molecular, endocrine, and immune pathways that connect the microbiome to the brain and together form the microbiome-gut-brain axis (Fig. 1). Both immune modulation and metabolite production are discussed in detail in the chapters by Caputi et al. [this vol., pp. 74–99] and Wiley et al. [this vol., pp. 40–57], respectively. It is now apparent that the balance between the microbiome and the psychopathological consequences is of particular importance to psychiatry because of the relative ease in which the microbiome can be changed by diet [17], exposure to antibiotics [18], or even the disruption of the sleep pattern [19].

Fig. 1. Summary of the main interconnections between the brain and the gut microbiome (the microbiome-gut-brain axis). These include a number of bidirectional pathways. Note that brackets indicate key components/examples of the specified system. ENS, enteric nervous system; HPA, hypothalamic-pituitary-adrenal; PSNS, parasympathetic nervous system; SCFAs, short-chain fatty acids; SNS, sympathetic nervous system. Adapted from [74].

The role of diet in regulating the microbiome has been the subject of increasing attention in neurological and psychiatric medicine. For over 100 years, the ketogenic diet has been used effectively to treat some forms of epilepsy, particularly in children [20]. Only recently has the microbiome been considered as an underlying mechanism for this treatment [21]. It was demonstrated by Olson et al. [21] that several species of bacteria were more abundant in mice fed a ketogenic diet. Subsequently, it was shown that the anti-seizure effects of the diet were associated with an increase in GABA and glutamate in the hippocampus [21]. This illustrates the complexity of the interaction between diet, the microbiome, and mental health, whereby diet provides the appropriate substrate for strains of microorganisms which impact on dysfunctional neurotransmitter processes.

Because of the theoretical and practical importance of factors such as diet, drug therapy, and environmental stressors on the mental state which are associated with changes in the gut microbiome, chapters in this monograph have been devoted to examining the experimental and clinical evidence in greater detail (see the chapters by Loughman et al. [this vol., pp. 100–112], Rajasekera and Gur [this vol., pp. 26–39], and Cussotto et al. [this vol., pp. 113–133], respectively).

The Human Microbiome in Psychiatric Disorders

In recent years, several excellent reviews have been published which detail the links between the microbiome and specific psychiatric conditions [15, 22–25]. Some of the key studies on the changes associated with depression and schizophrenia will be used to illustrate the importance of these connections.

In both depression and schizophrenia, the activation of the hypothalamic-pituitary-adrenal (HPA) axis plays an important role as a trigger factor. Changes in the HPA axis stress response, alongside changes in plasticity-related genes, monoamine neurotransmitters, and their receptors in the cortico-limbic brain regions, have been demonstrated in germ-free mice [26–29]. Such changes are correlated with an increase in pro-inflammatory cytokines which originate from the action of the gut microbiome on peripheral macrophages and brain microglia [30]. The serum concentration of antibodies against the lipopolysaccharide wall of Gram-negative bacteria is increased in depressed patients [31]. There are also changes in the composition of the gut microbiome in depression, which have been shown to be functionally relevant to symptom expression by faecal microbiome transfer (FMT) from human clinical populations to animal recipients [32, 33]. The bilateral olfactory lesion model of chronic depression has been well validated for showing immune, endocrine, neurotransmitter, and behavioural changes which are attenuated by chronic antidepressant treatment [34]. In this model, Park et al. [35] have shown that depression-like changes in anxiety behaviour are correlated with changes in the composition of the gut microbiome. It can therefore be concluded that the microbiome plays an important role in both the positive and negative aspects of depression.

A similar interaction between a dysfunctional microbiome and depression has also been proposed in schizophrenia [36, 37], while other investigators have laid particular emphasis on the link between the genetic risk, changes in the immune system, and the inflammatory status [38, 39]. These changes are associated with a rise in serological markers of bacterial translocation which, together with the rise in inflammation, correlate with the clinical symptoms [40, 41]. Intriguingly, FMT from schizophrenia patients was sufficient to induce changes in glutamatergic and GABAergic function in the hippocampus, as well as some behavioural changes [42]. These included locomotor hyperactivity and increased startle response, although it was notable that there was no significant change in pre-pulse inhibition, a measure of sensorimotor gating that is considered to be a key marker of rodent models of schizophrenia. While there is currently limited evidence for the efficacy of microbiome-targeting interventions to modulate primary symptoms in schizophrenia, there is at least preliminary support for the use of probiotics to relieve associated gastrointestinal dysfunction [43].

These examples of dysbiosis and the pathophysiology of depression and schizophrenia illustrate the importance of the microbiome in psychiatry. The therapeutic effects of drug treatment, particularly psychotropic drugs, are subject to the impact of the microbiome on drug metabolism which can result in significant changes in the therapeutic response [44] (also discussed in the chapter by Cussotto et al. [this vol., pp. 113–133]). This may help to explain the variability in the efficacy of psychotropic drugs and their side effects.

Modern Techniques for Investigating the Microbiome-Gut-Brain Axis

Observing the Microbiome

The recent resurgence of interest in the microbiome-gut-brain axis has largely been driven by dramatic leaps forward in the technologies allowing in-depth investigation of the microbiome and its component species. Historical investigations were reliant on laboratory culture techniques, which involved isolating and growing single microbial strains in petri dishes. The time-consuming and laborious nature of this task, which requires trial and error to identify the right media and culture conditions for each strain, limited our capacity to understand the vast numbers of different microbial species within the human gut microbiome. Great progress in culturing human gut microbes was made with the introduction and improvement of strictly anaerobic techniques. However, it was not until the 1990s with the advent of molecular techniques for sequencing ribosomal RNA that the full picture began to emerge [45]. It is now estimated that the average human microbiome comprises approximately 3.8 × 10¹³ bacterial cells (more than the estimated average number of human cells in the body) [46]. These vast numbers also reflect substantial diversity; at least 2,000 distinct microbial species (the majority of which remain uncultured) have been identified in the human gut microbiome [47].

There are various different ways to describe the complex communities of the gut microbiome. The most common of these, which will feature in many of the studies described in later chapters, are alpha and beta diversity (see Fig. 2). Alpha diversity refers to the level of complexity within a given sample, whereas beta diversity is used to compare the similarity of two or more samples. Higher alpha diversity (which can be defined in different ways, see Fig. 2) is often considered to reflect a healthier microbiome. This is based on the assumption that a more diverse community is likely to have a broader functional range and be more resilient in the face of challenges. However, there are certainly situations where high alpha diversity is not beneficial. For example, low diversity in the gut microbiome is considered developmentally appropriate in infancy [49] (see the chapter by Cowan and Cryan [this vol., pp. 12–25] for further discussion of developmental differences in the microbiome). Beta diversity is a bit more complex, using data reduction techniques to gain some idea of the (dis)similarity between samples or groups (e.g., clinical vs. control).

Fig. 2. Alpha and beta diversity are common metrics to describe the diversity within and between samples, respectively. Alpha diversity indicates the complexity of a single sample. This can refer to the number of different species present (richness), whether those species are evenly represented, and/or how closely those species are related to each other. Beta diversity is used to look for overlap, or similarities and differences, between multiple samples. It is often visualised using data reduction techniques such as principle coordinates analysis (PCoA) to detect differences between groups. Figure adapted from Simpson et al. [48].

Currently, the most common techniques for identifying microbiome composition are 16s rRNA sequencing and shotgun metagenomics, both of which are based on genetic sequencing. For those interested, there are several guides written specifically for clinicians and other newcomers to the field, which break down the mechanics of these techniques into an easily digestible format (e.g., see Bastiaanssen et al. [50], Claesson et al. [51], and Jovel et al. [52] for a more technical comparison). The output tells us which microorganisms are present in a given microbiome, to differing degrees of specificity; shotgun metagenomics is more expensive and requires greater computing power to analyse, but offers greater taxonomic resolution. From the genetic sequences, it is also possible to predict functional characteristics of the community using various analysis pipelines (e.g., Piphillin [53]).

One disadvantage though is that these genetic techniques do not assess the viability and actual functionality of any identified species. That is, they cannot tell us whether an identified species is alive or dead at the time of its sequencing, let alone whether the genetic potential for certain functions was being fulfilled. Furthermore, these techniques are generally used to understand the proportions (i.e., relative abundance) of different microbial species, as opposed to the absolute numbers. As such, many studies are now combining these metagenomic approaches with complementary analyses to answer specific questions about the microbiome in more detail. Further attempts to understand the functional output of the microbiome can be made using similar -omics-level analyses of the metabolites (metabolomics) and proteins (metaproteomics) within a particular environment. Coming full circle, others are now using updated, high-throughput culture techniques for isolation and detailed functional analysis of specific microbiome members (e.g., Browne et al. [54]).

Although most studies of the microbiome-gut-brain axis have focused largely on the bacterial members of the microbiome, new research is beginning to elucidate the contribution of other microorganisms to a healthy gut microbiome. In particular, the gut virome and its bacteriophage population plays a large role in shaping bacterial communities and is considered important for maintaining gastrointestinal health [55], while other research is focused on the contribution of fungi (i.e., the mycobiome) to microbiome and host health [56].

Manipulating the Microbiome: Experimental Models

A wide variety of model species have been used to study the impact of the microbiome, which vary in the complexity of both their indigent microbiome and their gastrointestinal systems, as well as how closely these resemble the human condition and how easily they can be manipulated. The most commonly used model species for the study of the microbiome-gut-brain axis has been the mouse, although others include rats and other rodents, primates, pigs, fish, worms, and flies.

Germ-Free Models

Germ-free animals are born and raised in sterile conditions, meaning that they are never exposed to microorganisms and therefore never develop a microbiome (analogous to genetic knock-out models). At least for mammals, the initial generation of germ-free animals must be born by Caesarean section to prevent colonisation by maternal microbes, but subsequent generations may be born by natural means, as long as the sterile environment is maintained. Although germ-free models have been criticised for their lack of practical relevance to the human condition, there is no doubt that they have been instrumental in establishing the existence and importance of the microbiome-gut-brain axis (for