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The Brain-Gut-Microbiome Axis

  • Clair R. Martin
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, Microbiome Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Vadim Osadchiy
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, Microbiome Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Amir Kalani
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, Microbiome Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Emeran A. Mayer
    Correspondence
    Correspondence Address correspondence to: Emeran A. Mayer, MD, G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California at Los Angeles, MC737818-10833 Le Conte Avenue, Los Angeles, California 90095-7378. fax: (310) 825-1919.
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, Microbiome Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
Open AccessPublished:April 11, 2018DOI:https://doi.org/10.1016/j.jcmgh.2018.04.003
      Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases.

      Keywords

      Abbreviations used in this paper:

      ANS (autonomic nervous system), ASD (autism spectrum disorder), BBB (blood-brain barrier), BGM (brain-gut-microbiome), CNS (central nervous system), ECC (enterochromaffin cell), EEC (enteroendocrine cell), FFAR (free fatty acid receptor), FGF (fibroblast growth factor), 5-HT (serotonin), FXR (farnesoid X receptor), GF (germ-free), GI (gastrointestinal), GLP-1 (glucagon-like peptide-1), GPR (G-protein–coupled receptor), IBS (irritable bowel syndrome), LPS (lipopolysaccharide), SCFA (short-chain fatty acid), SPF (specific-pathogen-free), TGR5 (G protein-coupled bile acid receptor), Trp (tryptophan), 2BA (secondary bile acid)
      The past decade has seen a paradigm shift in our understanding of the brain-gut axis. The exponential growth of evidence detailing the bidirectional interactions between the gut microbiome and the brain supports a comprehensive model that integrates the central nervous, gastrointestinal, and immune systems with this newly discovered organ. Data from preclinical and clinical studies have shown remarkable potential for novel treatment targets not only in functional gastrointestinal disorders but in a wide range of psychiatric and neurologic disorders, including Parkinson's disease, autism spectrum disorders, anxiety, and depression, among many others.
      Results from preclinical studies published during the past decade strongly support the concept of bidirectional brain-gut-microbiome (BGM) interactions. Alterations in these interactions have been implicated not only in the pathogenesis and pathophysiology of classic brain-gut disorders such as irritable bowel syndrome (IBS) and other functional gastrointestinal disorders,
      • Mayer E.A.
      Gut feelings: the emerging biology of gut-brain communication.
      • Rhee S.H.
      • Pothoulakis C.
      • Mayer E.A.
      Principles and clinical implications of the brain-gut-enteric microbiota axis.
      but a growing list of psychiatric and neurologic pathologies including affective disorders,
      • Cryan J.F.
      • Dinan T.G.
      Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.
      • Park A.J.
      • Collins J.
      • Blennerhassett P.A.
      • Ghia J.E.
      • Verdu E.F.
      • Bercik P.
      • Collins S.M.
      Altered colonic function and microbiota profile in a mouse model of chronic depression.
      autism spectrum disorders (ASD),
      • Cryan J.F.
      • Dinan T.G.
      Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.
      • Vuong H.E.
      • Hsiao E.Y.
      Emerging roles for the gut microbiome in autism spectrum disorder.
      Parkinson's disease,
      • Sampson T.R.
      • Debelius J.W.
      • Thron T.
      • Janssen S.
      • Shastri G.G.
      • Ilhan Z.E.
      • Challis C.
      • Schretter C.E.
      • Rocha S.
      • Gradinaru V.
      • Chesselet M.F.
      • Keshavarzian A.
      • Shannon K.M.
      • Krajmalnik-Brown R.
      • Wittung-Stafshede P.
      • Knight R.
      • Mazmanian S.K.
      Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease.
      multiple sclerosis,
      • Berer K.
      • Mues M.
      • Koutrolos M.
      • Rasbi Z.A.
      • Boziki M.
      • Johner C.
      • Wekerle H.
      • Krishnamoorthy G.
      Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination.
      and chronic pain.
      • Amaral F.A.
      • Sachs D.
      • Costa V.V.
      • Fagundes C.T.
      • Cisalpino D.
      • Cunha T.M.
      • Ferreira S.H.
      • Cunha F.Q.
      • Silva T.A.
      • Nicoli J.R.
      • Vieira L.Q.
      • Souza D.G.
      • Teixeira M.M.
      Commensal microbiota is fundamental for the development of inflammatory pain.
      Although most of the literature associates gut microbiota composition with human health, development, and disease, evidence for causality remains sparse. The BGM axis’ interface with fundamental and disease-susceptible processes make it a novel therapeutic target, but this network remains insufficiently understood for intervention. In this review, we address current evidence supporting bottom-up and top-down signaling within the BGM axis and the emerging evidence supporting its contribution to human disease.

      BGM State of the Science

       Preclinical Evidence

      Several experimental approaches in animal models have been used to study the influence of gut microbiota on the BGM axis, including manipulation with antibiotics,
      • Bercik P.
      • Denou E.
      • Collins J.
      • Jackson W.
      • Lu J.
      • Jury J.
      • Deng Y.
      • Blennerhassett P.
      • Macri J.
      • McCoy K.D.
      • Verdu E.F.
      • Collins S.M.
      The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
      fecal microbial transplantation,
      • Bercik P.
      • Denou E.
      • Collins J.
      • Jackson W.
      • Lu J.
      • Jury J.
      • Deng Y.
      • Blennerhassett P.
      • Macri J.
      • McCoy K.D.
      • Verdu E.F.
      • Collins S.M.
      The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
      • Collins S.M.
      • Kassam Z.
      • Bercik P.
      The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications.
      colonization with synthetic
      • Desai M.S.
      • Seekatz A.M.
      • Koropatkin N.M.
      • Kamada N.
      • Hickey C.A.
      • Wolter M.
      • Pudlo N.A.
      • Kitamoto S.
      • Terrapon N.
      • Muller A.
      • Young V.B.
      • Henrissat B.
      • Wilmes P.
      • Stappenbeck T.S.
      • Nunez G.
      • Martens E.C.
      A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility.
      or human
      • Bowey E.
      • Adlercreutz H.
      • Rowland I.
      Metabolism of isoflavones and lignans by the gut microflora: a study in germ-free and human flora associated rats.
      • Mallett A.K.
      • Bearne C.A.
      • Rowland I.R.
      • Farthing M.J.
      • Cole C.B.
      • Fuller R.
      The use of rats associated with a human faecal flora as a model for studying the effects of diet on the human gut microflora.
      microbiota, cultured gut organ systems,
      • Bellono N.W.
      • Bayrer J.R.
      • Leitch D.B.
      • Castro J.
      • Zhang C.
      • O'Donnell T.A.
      • Brierley S.M.
      • Ingraham H.A.
      • Julius D.
      Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways.
      • Yissachar N.
      • Zhou Y.
      • Ung L.
      • Lai N.Y.
      • Mohan J.F.
      • Ehrlicher A.
      • Weitz D.A.
      • Kasper D.L.
      • Chiu I.M.
      • Mathis D.
      • Benoist C.
      An intestinal organ culture system uncovers a role for the nervous system in microbe-immune crosstalk.
      probiotic administration,
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      and germ-free (GF) animal models.
      • Sudo N.
      • Chida Y.
      • Aiba Y.
      • Sonoda J.
      • Oyama N.
      • Yu X.N.
      • Kubo C.
      • Koga Y.
      Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
      Despite limitations to these approaches, significant progress has been made since Sudo et al
      • Sudo N.
      • Chida Y.
      • Aiba Y.
      • Sonoda J.
      • Oyama N.
      • Yu X.N.
      • Kubo C.
      • Koga Y.
      Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
      first showed that the absence of normal gut microbiota early in life has significant effects on stress responsiveness in the adult and that these changes can be partially reversed by early colonization of the gut with conventional microbiota, even a single species. Subsequent investigations have further characterized the associated neurochemical changes, including altered cortical and hippocampal brain-derived neurotrophic factor levels,
      • Sudo N.
      • Chida Y.
      • Aiba Y.
      • Sonoda J.
      • Oyama N.
      • Yu X.N.
      • Kubo C.
      • Koga Y.
      Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
      • Neufeld K.M.
      • Kang N.
      • Bienenstock J.
      • Foster J.A.
      Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
      reduced hippocampal serotonin (5-HT) receptor 1A expression,
      • Neufeld K.M.
      • Kang N.
      • Bienenstock J.
      • Foster J.A.
      Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
      increased striatal monoamine turnover,
      • Diaz Heijtz R.
      • Wang S.
      • Anuar F.
      • Qian Y.
      • Bjorkholm B.
      • Samuelsson A.
      • Hibberd M.L.
      • Forssberg H.
      • Pettersson S.
      Normal gut microbiota modulates brain development and behavior.
      and reduced synaptic plasticity gene expression,
      • Diaz Heijtz R.
      • Wang S.
      • Anuar F.
      • Qian Y.
      • Bjorkholm B.
      • Samuelsson A.
      • Hibberd M.L.
      • Forssberg H.
      • Pettersson S.
      Normal gut microbiota modulates brain development and behavior.
      showing the microbiome’s diverse and potent influence over central nervous system (CNS) phenotypes. Accordingly, in addition to stress responsiveness,
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      • Desbonnet L.
      • Garrett L.
      • Clarke G.
      • Kiely B.
      • Cryan J.F.
      • Dinan T.G.
      Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression.
      the gut microbiota are implicated in relation to anxiety-like
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      • Neufeld K.M.
      • Kang N.
      • Bienenstock J.
      • Foster J.A.
      Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
      • Diaz Heijtz R.
      • Wang S.
      • Anuar F.
      • Qian Y.
      • Bjorkholm B.
      • Samuelsson A.
      • Hibberd M.L.
      • Forssberg H.
      • Pettersson S.
      Normal gut microbiota modulates brain development and behavior.
      • Desbonnet L.
      • Garrett L.
      • Clarke G.
      • Kiely B.
      • Cryan J.F.
      • Dinan T.G.
      Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression.
      • Clarke G.
      • Grenham S.
      • Scully P.
      • Fitzgerald P.
      • Moloney R.D.
      • Shanahan F.
      • Dinan T.G.
      • Cryan J.F.
      The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
      • Bercik P.
      • Park A.J.
      • Sinclair D.
      • Khoshdel A.
      • Lu J.
      • Huang X.
      • Deng Y.
      • Blennerhassett P.A.
      • Fahnestock M.
      • Moine D.
      • Berger B.
      • Huizinga J.D.
      • Kunze W.
      • McLean P.G.
      • Bergonzelli G.E.
      • Collins S.M.
      • Verdu E.F.
      The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.
      • Crumeyrolle-Arias M.
      • Jaglin M.
      • Bruneau A.
      • Vancassel S.
      • Cardona A.
      • Dauge V.
      • Naudon L.
      • Rabot S.
      Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.
      • Savignac H.M.
      • Kiely B.
      • Dinan T.G.
      • Cryan J.F.
      Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice.
      • De Palma G.
      • Blennerhassett P.
      • Lu J.
      • Deng Y.
      • Park A.J.
      • Green W.
      • Denou E.
      • Silva M.A.
      • Santacruz A.
      • Sanz Y.
      • Surette M.G.
      • Verdu E.F.
      • Collins S.M.
      • Bercik P.
      Microbiota and host determinants of behavioural phenotype in maternally separated mice.
      • Hsiao E.Y.
      • McBride S.W.
      • Hsien S.
      • Sharon G.
      • Hyde E.R.
      • McCue T.
      • Codelli J.A.
      • Chow J.
      • Reisman S.E.
      • Petrosino J.F.
      • Patterson P.H.
      • Mazmanian S.K.
      Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.
      • Kelly J.R.
      • Borre Y.
      • C OB
      • Patterson E.
      • El Aidy S.
      • Deane J.
      • Kennedy P.J.
      • Beers S.
      • Scott K.
      • Moloney G.
      • Hoban A.E.
      • Scott L.
      • Fitzgerald P.
      • Ross P.
      • Stanton C.
      • Clarke G.
      • Cryan J.F.
      • Dinan T.G.
      Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat.
      • Desbonnet L.
      • Clarke G.
      • Traplin A.
      • O'Sullivan O.
      • Crispie F.
      • Moloney R.D.
      • Cotter P.D.
      • Dinan T.G.
      • Cryan J.F.
      Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour.
      and depression-like behavior,
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      • Savignac H.M.
      • Kiely B.
      • Dinan T.G.
      • Cryan J.F.
      Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice.
      • De Palma G.
      • Blennerhassett P.
      • Lu J.
      • Deng Y.
      • Park A.J.
      • Green W.
      • Denou E.
      • Silva M.A.
      • Santacruz A.
      • Sanz Y.
      • Surette M.G.
      • Verdu E.F.
      • Collins S.M.
      • Bercik P.
      Microbiota and host determinants of behavioural phenotype in maternally separated mice.
      • Kelly J.R.
      • Borre Y.
      • C OB
      • Patterson E.
      • El Aidy S.
      • Deane J.
      • Kennedy P.J.
      • Beers S.
      • Scott K.
      • Moloney G.
      • Hoban A.E.
      • Scott L.
      • Fitzgerald P.
      • Ross P.
      • Stanton C.
      • Clarke G.
      • Cryan J.F.
      • Dinan T.G.
      Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat.
      • Schroeder F.A.
      • Lin C.L.
      • Crusio W.E.
      • Akbarian S.
      Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse.
      • Desbonnet L.
      • Garrett L.
      • Clarke G.
      • Bienenstock J.
      • Dinan T.G.
      The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat.
      • Arseneault-Breard J.
      • Rondeau I.
      • Gilbert K.
      • Girard S.A.
      • Tompkins T.A.
      • Godbout R.
      • Rousseau G.
      Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model.
      • Zheng P.
      • Zeng B.
      • Zhou C.
      • Liu M.
      • Fang Z.
      • Xu X.
      • Zeng L.
      • Chen J.
      • Fan S.
      • Du X.
      • Zhang X.
      • Yang D.
      • Yang Y.
      • Meng H.
      • Li W.
      • Melgiri N.D.
      • Licinio J.
      • Wei H.
      • Xie P.
      Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism.
      nociceptive response,
      • Amaral F.A.
      • Sachs D.
      • Costa V.V.
      • Fagundes C.T.
      • Cisalpino D.
      • Cunha T.M.
      • Ferreira S.H.
      • Cunha F.Q.
      • Silva T.A.
      • Nicoli J.R.
      • Vieira L.Q.
      • Souza D.G.
      • Teixeira M.M.
      Commensal microbiota is fundamental for the development of inflammatory pain.
      • Ait-Belgnaoui A.
      • Han W.
      • Lamine F.
      • Eutamene H.
      • Fioramonti J.
      • Bueno L.
      • Theodorou V.
      Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: a possible action through interaction with epithelial cell cytoskeleton contraction.
      • Eutamene H.
      • Lamine F.
      • Chabo C.
      • Theodorou V.
      • Rochat F.
      • Bergonzelli G.E.
      • Corthesy-Theulaz I.
      • Fioramonti J.
      • Bueno L.
      Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats.
      • Rousseaux C.
      • Thuru X.
      • Gelot A.
      • Barnich N.
      • Neut C.
      • Dubuquoy L.
      • Dubuquoy C.
      • Merour E.
      • Geboes K.
      • Chamaillard M.
      • Ouwehand A.
      • Leyer G.
      • Carcano D.
      • Colombel J.F.
      • Ardid D.
      • Desreumaux P.
      Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.
      • Ma X.
      • Mao Y.K.
      • Wang B.
      • Huizinga J.D.
      • Bienenstock J.
      • Kunze W.
      Lactobacillus reuteri ingestion prevents hyperexcitability of colonic DRG neurons induced by noxious stimuli.
      • Kunze W.A.
      • Mao Y.K.
      • Wang B.
      • Huizinga J.D.
      • Ma X.
      • Forsythe P.
      • Bienenstock J.
      Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening.
      feeding behavior, taste preference, metabolic consequences,
      • Duca F.A.
      • Swartz T.D.
      • Sakar Y.
      • Covasa M.
      Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota.
      • Vijay-Kumar M.
      • Aitken J.D.
      • Carvalho F.A.
      • Cullender T.C.
      • Mwangi S.
      • Srinivasan S.
      • Sitaraman S.V.
      • Knight R.
      • Ley R.E.
      • Gewirtz A.T.
      Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.
      • Tanida M.
      • Yamano T.
      • Maeda K.
      • Okumura N.
      • Fukushima Y.
      • Nagai K.
      Effects of intraduodenal injection of Lactobacillus johnsonii La1 on renal sympathetic nerve activity and blood pressure in urethane-anesthetized rats.
      and their respective underlying physiologies. These preclinical studies have been reviewed extensively in the literature.
      • Cryan J.F.
      • Dinan T.G.
      Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.
      • Vuong H.E.
      • Hsiao E.Y.
      Emerging roles for the gut microbiome in autism spectrum disorder.
      • Mayer E.A.
      • Tillisch K.
      • Gupta A.
      Gut/brain axis and the microbiota.
      • Mayer E.A.
      • Knight R.
      • Mazmanian S.K.
      • Cryan J.F.
      • Tillisch K.
      Gut microbes and the brain: paradigm shift in neuroscience.
      • Bercik P.
      • Collins S.M.
      • Verdu E.F.
      Microbes and the gut-brain axis.
      Despite acknowledged limitations to the GF model,
      • Desbonnet L.
      • Clarke G.
      • Traplin A.
      • O'Sullivan O.
      • Crispie F.
      • Moloney R.D.
      • Cotter P.D.
      • Dinan T.G.
      • Cryan J.F.
      Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour.
      • Mayer E.A.
      • Tillisch K.
      • Gupta A.
      Gut/brain axis and the microbiota.
      • Martin C.R.
      • Mayer E.A.
      Gut-brain axis and behavior.
      phenotype reversal by recolonization with specific-pathogen-free (SPF), human-derived, and synthetic microbiota validates some of the conclusions. Still, the well-characterized role of microbiota in neurogenesis and neurodevelopment
      • Sharon G.
      • Sampson T.R.
      • Geschwind D.H.
      • Mazmanian S.K.
      The central nervous system and the gut microbiome.
      moderates the translational relevance of these findings for adult conditions.
      An alternative to the GF model approach is the use of broad-spectrum antibiotics to induce transient changes on the composition and diversity of fecal microbiota,
      • Bercik P.
      • Denou E.
      • Collins J.
      • Jackson W.
      • Lu J.
      • Jury J.
      • Deng Y.
      • Blennerhassett P.
      • Macri J.
      • McCoy K.D.
      • Verdu E.F.
      • Collins S.M.
      The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
      although the effects on mucosa-associated microbial communities are incompletely understood. Antimicrobials also may interact directly with host physiology in mechanisms independent of the microbiome, such as their well-documented neurotoxic effects (reviewed by Grill and Maganti
      • Grill M.F.
      • Maganti R.K.
      Neurotoxic effects associated with antibiotic use: management considerations.
      ). Nonetheless, broad-spectrum antibiotic treatment remains a powerful tool to identify gut microbial influence on the CNS. In mice with SPF microbiota, oral antibiotic administration increased exploratory behavior and hippocampal expression of brain-derived neurotrophic factor, which was associated with changes in the microbial profile.
      • Bercik P.
      • Denou E.
      • Collins J.
      • Jackson W.
      • Lu J.
      • Jury J.
      • Deng Y.
      • Blennerhassett P.
      • Macri J.
      • McCoy K.D.
      • Verdu E.F.
      • Collins S.M.
      The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
      The failure to replicate these antibiotic-induced effects in GF mice suggests the CNS changes are not the result of off-target antibiotic interactions, however, developmental alterations in the GF model make this finding inconclusive. Long-term antibiotic treatment in adult mice reduced hippocampal neurogenesis and lead to deficits in novel object recognition tasks through a mechanism dependent on circulating monocytes.
      • Mohle L.
      • Mattei D.
      • Heimesaat M.M.
      • Bereswill S.
      • Fischer A.
      • Alutis M.
      • French T.
      • Hambardzumyan D.
      • Matzinger P.
      • Dunay I.R.
      • Wolf S.A.
      Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis.
      Adoptive transfer of Ly-6chi monocytes or voluntary exercise and probiotic treatment rescued these phenotypes.
      • Mohle L.
      • Mattei D.
      • Heimesaat M.M.
      • Bereswill S.
      • Fischer A.
      • Alutis M.
      • French T.
      • Hambardzumyan D.
      • Matzinger P.
      • Dunay I.R.
      • Wolf S.A.
      Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis.
      In contrast to the complete or partial depletion of gut microbiota as an experimental approach to identify and characterize microbial influence on the host CNS, the introduction of known microorganisms (usually as probiotics) to conventional models allows for normal development and risks fewer off-target effects. However, it is critical to acknowledge the possibility that transient exposure induces host responses inaccessible to resident communities. Orally administered probiotics have been shown to reduce basal or induced anxiety-like behavior,
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      • Desbonnet L.
      • Garrett L.
      • Clarke G.
      • Kiely B.
      • Cryan J.F.
      • Dinan T.G.
      Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression.
      • Bercik P.
      • Park A.J.
      • Sinclair D.
      • Khoshdel A.
      • Lu J.
      • Huang X.
      • Deng Y.
      • Blennerhassett P.A.
      • Fahnestock M.
      • Moine D.
      • Berger B.
      • Huizinga J.D.
      • Kunze W.
      • McLean P.G.
      • Bergonzelli G.E.
      • Collins S.M.
      • Verdu E.F.
      The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.
      • Savignac H.M.
      • Kiely B.
      • Dinan T.G.
      • Cryan J.F.
      Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice.
      • Desbonnet L.
      • Garrett L.
      • Clarke G.
      • Bienenstock J.
      • Dinan T.G.
      The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat.
      • Messaoudi M.
      • Lalonde R.
      • Violle N.
      • Javelot H.
      • Desor D.
      • Nejdi A.
      • Bisson J.F.
      • Rougeot C.
      • Pichelin M.
      • Cazaubiel M.
      • Cazaubiel J.M.
      Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.
      attenuate induced obsessive-compulsive–like behavior,
      • Kantak P.A.
      • Bobrow D.N.
      • Nyby J.G.
      Obsessive-compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus rhamnosus GG).
      improve inflammation-associated sickness behavior,
      • D'Mello C.
      • Ronaghan N.
      • Zaheer R.
      • Dicay M.
      • Le T.
      • MacNaughton W.K.
      • Surrette M.G.
      • Swain M.G.
      Probiotics improve inflammation-associated sickness behavior by altering communication between the peripheral immune system and the brain.
      and even normalize developmental trajectories of emotion-related behavior after early life stress.
      • Cowan C.S.
      • Callaghan B.L.
      • Richardson R.
      The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats.
      Although infrequently used as an intervention directed specifically at the gut microbiota, diet can have profound, rapid, and reproducible effects on the structure of the gut microbiota in human beings and mice.
      • David L.A.
      • Maurice C.F.
      • Carmody R.N.
      • Gootenberg D.B.
      • Button J.E.
      • Wolfe B.E.
      • Ling A.V.
      • Devlin A.S.
      • Varma Y.
      • Fischbach M.A.
      • Biddinger S.B.
      • Dutton R.J.
      • Turnbaugh P.J.
      Diet rapidly and reproducibly alters the human gut microbiome.
      • Carmody R.N.
      • Gerber G.K.
      • Luevano Jr., J.M.
      • Gatti D.M.
      • Somes L.
      • Svenson K.L.
      • Turnbaugh P.J.
      Diet dominates host genotype in shaping the murine gut microbiota.
      • Turnbaugh P.J.
      • Ridaura V.K.
      • Faith J.J.
      • Rey F.E.
      • Knight R.
      • Gordon J.I.
      The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice.
      Alterations in the gut microbial community through dietary change also have been shown to influence memory and learning,
      • Li W.
      • Dowd S.E.
      • Scurlock B.
      • Acosta-Martinez V.
      • Lyte M.
      Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria.
      • Jorgensen B.P.
      • Hansen J.T.
      • Krych L.
      • Larsen C.
      • Klein A.B.
      • Nielsen D.S.
      • Josefsen K.
      • Hansen A.K.
      • Sorensen D.B.
      A possible link between food and mood: dietary impact on gut microbiota and behavior in BALB/c mice.
      while probiotic administration rescued diet-induced memory deficits in rats.
      • Beilharz J.E.
      • Kaakoush N.O.
      • Maniam J.
      • Morris M.J.
      Cafeteria diet and probiotic therapy: cross talk among memory, neuroplasticity, serotonin receptors and gut microbiota in the rat.
      In summary, preclinical studies have identified unequivocally the potent influence of gut microbiota on the CNS, but issues of reproducibility and off-target intervention effects demand continued improvement of experimental approaches.

       Clinical Evidence

      Experimental approaches to study the role of gut microbes to brain signaling have been restricted mostly to small clinical studies showing the association of gut microbial community structure with brain parameters and subjective outcomes of interventions with probiotics and prebiotics. Although no high-quality, controlled studies in human beings have reported the effects of interventions such as antibiotics or fecal microbial transplants on the brain or behavior, studies of probiotic interventions are increasing rapidly in number and gradually in scale and quality. A double-blind, placebo-controlled, pilot study of the probiotic Bifidobacterium longum NCC3001 in 44 adults with IBS and diarrhea was shown to reduce responses in the amygdala and frontolimbic regions to negative emotional stimuli as measured by functional magnetic resonance imaging.
      • Pinto-Sanchez M.I.
      • Hall G.B.
      • Ghajar K.
      • Nardelli A.
      • Bolino C.
      • Lau J.T.
      • Martin F.P.
      • Cominetti O.
      • Welsh C.
      • Rieder A.
      • Traynor J.
      • Gregory C.
      • De Palma G.
      • Pigrau M.
      • Ford A.C.
      • Macri J.
      • Berger B.
      • Bergonzelli G.
      • Surette M.G.
      • Collins S.M.
      • Moayyedi P.
      • Bercik P.
      Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome.
      Although depression scores were lower with the intervention, anxiety and IBS symptoms were not affected. In healthy female control subjects, consumption of a fermented milk product with probiotics over 4 weeks was associated with significant changes in the functional connectivity between brain regions during an emotion recognition task, notably without concomitant detectable changes in gut microbial composition.
      • Tillisch K.
      • Labus J.
      • Kilpatrick L.
      • Jiang Z.
      • Stains J.
      • Ebrat B.
      • Guyonnet D.
      • Legrain-Raspaud S.
      • Trotin B.
      • Naliboff B.
      • Mayer E.A.
      Consumption of fermented milk product with probiotic modulates brain activity.
      Probiotic consumption also has been reported to reduce self-reported feelings of sadness and aggressive thoughts.
      • Steenbergen L.
      • Sellaro R.
      • van Hemert S.
      • Bosch J.A.
      • Colzato L.S.
      A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood.
      A probiotic cocktail used to achieve reduction of anxiety- and depression-related behaviors in mice
      • Messaoudi M.
      • Lalonde R.
      • Violle N.
      • Javelot H.
      • Desor D.
      • Nejdi A.
      • Bisson J.F.
      • Rougeot C.
      • Pichelin M.
      • Cazaubiel M.
      • Cazaubiel J.M.
      Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.
      also was administered to healthy human beings to a similar effect.
      • Messaoudi M.
      • Violle N.
      • Bisson J.F.
      • Desor D.
      • Javelot H.
      • Rougeot C.
      Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers.
      The translation of promising findings obtained in rodent studies has been limited. In a clinical trial with Lactobacillus rhamnosus (JB-1), the effects of which were seminally shown on mice by Bravo et al,
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      performed no better than placebo on stress-related measures, hypothalamic pituitary adrenal axis response, inflammation, or cognitive performance in an 8-week trial with healthy males.
      • Kelly J.R.
      • Allen A.P.
      • Temko A.
      • Hutch W.
      • Kennedy P.J.
      • Farid N.
      • Murphy E.
      • Boylan G.
      • Bienenstock J.
      • Cryan J.F.
      • Clarke G.
      • Dinan T.G.
      Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects.
      Moreover, the pilot trial of Bifidobacterium longum NCC3001 described earlier did not recapitulate the effects observed in mice by the same research group
      • Bercik P.
      • Park A.J.
      • Sinclair D.
      • Khoshdel A.
      • Lu J.
      • Huang X.
      • Deng Y.
      • Blennerhassett P.A.
      • Fahnestock M.
      • Moine D.
      • Berger B.
      • Huizinga J.D.
      • Kunze W.
      • McLean P.G.
      • Bergonzelli G.E.
      • Collins S.M.
      • Verdu E.F.
      The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.
      and has been criticized for its fragility.
      • Meyer C.
      • Vassar M.
      The fragility of probiotic Bifidobacterium longum NCC3001 use for depression in patients with irritable bowel syndrome.
      This translational disconnect, or inconsistency, highlights the likelihood of host-specific microbiota interactions and underscores the importance of cautious extrapolation of preclinical findings. Furthermore, as shown by several studies, probiotic supplementation in human beings does not appear to change the gut’s microbiota composition but induces its effect on behavior via transient modification of the collective microbiome transcriptional state, as shown in GF mice and confirmed in monozygotic twins.
      • McNulty N.P.
      • Yatsunenko T.
      • Hsiao A.
      • Faith J.J.
      • Muegge B.D.
      • Goodman A.L.
      • Henrissat B.
      • Oozeer R.
      • Cools-Portier S.
      • Gobert G.
      • Chervaux C.
      • Knights D.
      • Lozupone C.A.
      • Knight R.
      • Duncan A.E.
      • Bain J.R.
      • Muehlbauer M.J.
      • Newgard C.B.
      • Heath A.C.
      • Gordon J.I.
      The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins.
      This finding demands measurement of probiotic intervention on gut microbial profiles with technologies integrating metatranscriptomics and metabolomics and fundamental reconsideration of the functional equivalence of transient vs resident microorganisms. Better characterization of microbial community dynamics and metabolism coupled with improved models of their community ecology will help refine the mechanisms responsible for these effects and identify putative targets for therapeutic intervention.

      Signaling Mechanisms From the Gut Microbiota to the Brain

      Current evidence indicates that bottom-up modulation of the CNS by the microbiome occurs primarily through neuroimmune and neuroendocrine mechanisms, often involving the vagus nerve.
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      • Tolhurst G.
      • Heffron H.
      • Lam Y.S.
      • Parker H.E.
      • Habib A.M.
      • Diakogiannaki E.
      • Cameron J.
      • Grosse J.
      • Reimann F.
      • Gribble F.M.
      Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2.
      • Wang Y.
      • Telesford K.M.
      • Ochoa-Reparaz J.
      • Haque-Begum S.
      • Christy M.
      • Kasper E.J.
      • Wang L.
      • Wu Y.
      • Robson S.C.
      • Kasper D.L.
      • Kasper L.H.
      An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling.
      • Singh V.
      • Roth S.
      • Llovera G.
      • Sadler R.
      • Garzetti D.
      • Stecher B.
      • Dichgans M.
      • Liesz A.
      Microbiota dysbiosis controls the neuroinflammatory response after stroke.
      This communication is mediated by several microbially derived molecules that include short-chain fatty acids (SCFAs), secondary bile acids (2BAs), and tryptophan metabolites.
      • Tolhurst G.
      • Heffron H.
      • Lam Y.S.
      • Parker H.E.
      • Habib A.M.
      • Diakogiannaki E.
      • Cameron J.
      • Grosse J.
      • Reimann F.
      • Gribble F.M.
      Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2.
      • Yano J.M.
      • Yu K.
      • Donaldson G.P.
      • Shastri G.G.
      • Ann P.
      • Ma L.
      • Nagler C.R.
      • Ismagilov R.F.
      • Mazmanian S.K.
      • Hsiao E.Y.
      Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.
      • Wikoff W.R.
      • Anfora A.T.
      • Liu J.
      • Schultz P.G.
      • Lesley S.A.
      • Peters E.C.
      • Siuzdak G.
      Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.
      These molecules propagate signals primarily through interaction with enteroendocrine cells (EECs), enterochromaffin cells (ECCs), and the mucosal immune system, but some cross the intestinal barrier, enter systemic circulation, and may cross the blood-brain barrier.
      • Yano J.M.
      • Yu K.
      • Donaldson G.P.
      • Shastri G.G.
      • Ann P.
      • Ma L.
      • Nagler C.R.
      • Ismagilov R.F.
      • Mazmanian S.K.
      • Hsiao E.Y.
      Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.
      • Samuel B.S.
      • Shaito A.
      • Motoike T.
      • Rey F.E.
      • Backhed F.
      • Manchester J.K.
      • Hammer R.E.
      • Williams S.C.
      • Crowley J.
      • Yanagisawa M.
      • Gordon J.I.
      Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.
      • Haghikia A.
      • Jorg S.
      • Duscha A.
      • Berg J.
      • Manzel A.
      • Waschbisch A.
      • Hammer A.
      • Lee D.H.
      • May C.
      • Wilck N.
      • Balogh A.
      • Ostermann A.I.
      • Schebb N.H.
      • Akkad D.A.
      • Grohme D.A.
      • Kleinewietfeld M.
      • Kempa S.
      • Thone J.
      • Demir S.
      • Muller D.N.
      • Gold R.
      • Linker R.A.
      Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine.
      It remains poorly understood if these molecules reach brain sites directly or only induce central responses via long-distance neural signaling by vagal and/or spinal afferents.
      • Bravo J.A.
      • Forsythe P.
      • Chew M.V.
      • Escaravage E.
      • Savignac H.M.
      • Dinan T.G.
      • Bienenstock J.
      • Cryan J.F.
      Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
      • Goehler L.E.
      • Gaykema R.P.
      • Opitz N.
      • Reddaway R.
      • Badr N.
      • Lyte M.
      Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni.
      In addition to generating these metabolites that activate endogenous CNS signaling mechanisms, the microbiota can independently produce or contribute to the production of a number of neuroactive molecules including but not limited to γ-aminobutyric acid,
      • Barrett E.
      • Ross R.P.
      • O'Toole P.W.
      • Fitzgerald G.F.
      • Stanton C.
      gamma-Aminobutyric acid production by culturable bacteria from the human intestine.
      • Minuk G.Y.
      Gamma-aminobutyric-acid (Gaba) production by 8 common bacterial pathogens.
      5-HT,
      • Ozogul F.
      Effects of specific lactic acid bacteria species on biogenic amine production by foodborne pathogen.
      • Shishov V.A.
      • Kirovskaya T.A.
      • Kudrin V.S.
      • Oleskin A.V.
      Amine neuromediators, their precursors, and oxidation products in the culture of Escherichia coli K-12.
      norepinephrine,
      • Shishov V.A.
      • Kirovskaya T.A.
      • Kudrin V.S.
      • Oleskin A.V.
      Amine neuromediators, their precursors, and oxidation products in the culture of Escherichia coli K-12.
      • Asano Y.
      • Hiramoto T.
      • Nishino R.
      • Aiba Y.
      • Kimura T.
      • Yoshihara K.
      • Koga Y.
      • Sudo N.
      Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice.
      and dopamine,
      • Ozogul F.
      Effects of specific lactic acid bacteria species on biogenic amine production by foodborne pathogen.
      • Shishov V.A.
      • Kirovskaya T.A.
      • Kudrin V.S.
      • Oleskin A.V.
      Amine neuromediators, their precursors, and oxidation products in the culture of Escherichia coli K-12.
      • Asano Y.
      • Hiramoto T.
      • Nishino R.
      • Aiba Y.
      • Kimura T.
      • Yoshihara K.
      • Koga Y.
      • Sudo N.
      Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice.
      although it is unknown if they reach relevant receptors or achieve sufficient levels to elicit a host response.

       Neuroendocrine and Enteroendocrine Signaling Pathways

      An important pathway by which gut microbes and their metabolites communicate with the CNS involves the cells making up the endocrine system of the gut.
      • Furness J.B.
      • Rivera L.R.
      • Cho H.J.
      • Bravo D.M.
      • Callaghan B.
      The gut as a sensory organ.
      There are at least 12 different types of these cells with several subtypes (in particular A, K, and L cells) present as subgroups along the intestine that contain different combinations of molecules. EECs are interspersed between gut epithelial cells throughout the length of the gut and contain more than 20 different types of signaling molecules, which often are colocalized and co-released. Released in response to chemical and or mechanical stimuli, these molecules can enter the systemic circulation and reach centers in the CNS involved in ingestive behavior (including the nucleus tractus solitarius and the hypothalamus) or act locally and activate closely adjacent afferent vagal terminals in the gut or liver to generate brain signals. A series of receptors involved in the regulation of satiety and hunger have been identified on these cells, which are activated by microbial metabolites including bile acids and SCFAs.
      Although bile acids are endogenous molecules synthesized from cholesterol in the liver, the size and composition of the host’s pool of these molecules is heavily influenced by dietary intake, especially of fat,
      • Morton G.J.
      • Kaiyala K.J.
      • Foster-Schubert K.E.
      • Cummings D.E.
      • Schwartz M.W.
      Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans.
      and the downstream metabolism by the gut microbiota (reviewed by de Aguiar et al
      • de Aguiar Vallim T.Q.
      • Tarling E.J.
      • Edwards P.A.
      Pleiotropic roles of bile acids in metabolism.
      and Wahlstrom et al
      • Wahlstrom A.
      • Sayin S.I.
      • Marschall H.U.
      • Backhed F.
      Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism.
      ). Ileal expression of farnesoid X receptor (FXR), a nuclear receptor, is activated by bile acids leading to production of fibroblast growth factor 19 (FGF19), or its similarly functioning ortholog FGF15 in mice, which can enter the systemic circulation and cross the blood-brain barrier.
      • Hsuchou H.
      • Pan W.
      • Kastin A.J.
      Fibroblast growth factor 19 entry into brain.
      Activation of the arcuate nucleus of the hypothalamus by the FXR/FGF19 action on agouti-related peptide/neuropeptide Y
      • Marcelin G.
      • Jo Y.H.
      • Li X.
      • Schwartz G.J.
      • Zhang Y.
      • Dun N.J.
      • Lyu R.M.
      • Blouet C.
      • Chang J.K.
      • Chua Jr., S.
      Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism.
      has been implicated in improved central regulation of energy and glucose metabolism
      • Tomlinson E.
      • Fu L.
      • John L.
      • Hultgren B.
      • Huang X.
      • Renz M.
      • Stephan J.P.
      • Tsai S.P.
      • Powell-Braxton L.
      • French D.
      • Stewart T.A.
      Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity.
      • Fu L.
      • John L.M.
      • Adams S.H.
      • Yu X.X.
      • Tomlinson E.
      • Renz M.
      • Williams P.M.
      • Soriano R.
      • Corpuz R.
      • Moffat B.
      • Vandlen R.
      • Simmons L.
      • Foster J.
      • Stephan J.P.
      • Tsai S.P.
      • Stewart T.A.
      Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.
      • Ryan K.K.
      • Kohli R.
      • Gutierrez-Aguilar R.
      • Gaitonde S.G.
      • Woods S.C.
      • Seeley R.J.
      Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats.
      and suppression of hypothalamic pituitary adrenal axis activity.
      • Perry R.J.
      • Lee S.
      • Ma L.
      • Zhang D.
      • Schlessinger J.
      • Shulman G.I.
      FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis.
      Some intestinal L cells express surface receptor G protein-coupled bile acid receptor (TGR5), which is activated mostly by secondary bile acids, which are strongly influenced by microbial activity.
      • Maruyama T.
      • Miyamoto Y.
      • Nakamura T.
      • Tamai Y.
      • Okada H.
      • Sugiyama E.
      • Nakamura T.
      • Itadani H.
      • Tanaka K.
      Identification of membrane-type receptor for bile acids (M-BAR).
      • Ridlon J.M.
      • Kang D.J.
      • Hylemon P.B.
      Bile salt biotransformations by human intestinal bacteria.
      TGR5 signaling controls glucose homeostasis by mechanisms including increased glucagon-like peptide-1 (GLP-1) release by these L cells.
      • Thomas C.
      • Gioiello A.
      • Noriega L.
      • Strehle A.
      • Oury J.
      • Rizzo G.
      • Macchiarulo A.
      • Yamamoto H.
      • Mataki C.
      • Pruzanski M.
      • Pellicciari R.
      • Auwerx J.
      • Schoonjans K.
      TGR5-mediated bile acid sensing controls glucose homeostasis.
      Interestingly, these L cells also express FXR, which can regulate GLP-1 synthesis.
      • Trabelsi M.S.
      • Daoudi M.
      • Prawitt J.
      • Ducastel S.
      • Touche V.
      • Sayin S.I.
      • Perino A.
      • Brighton C.A.
      • Sebti Y.
      • Kluza J.
      • Briand O.
      • Dehondt H.
      • Vallez E.
      • Dorchies E.
      • Baud G.
      • Spinelli V.
      • Hennuyer N.
      • Caron S.
      • Bantubungi K.
      • Caiazzo R.
      • Reimann F.
      • Marchetti P.
      • Lefebvre P.
      • Backhed F.
      • Gribble F.M.
      • Schoonjans K.
      • Pattou F.
      • Tailleux A.
      • Staels B.
      • Lestavel S.
      Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells.
      SCFAs have been implicated as major signaling molecules mediating host-microbe communication via EECs and ECCs. These molecules are generated by microbial fermentation of host dietary-resistant starch and nonstarch polysaccharides and serve an important part in the host’s energy harvest while also stimulating colonic blood flow, fluid and electrolyte uptake, and mucosal proliferation.
      • Topping D.L.
      • Clifton P.M.
      Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides.
      Dietary fiber intake is a major regulator of SCFA concentrations. In instances in which the host diet is low in fermentable fibers, microbes feed on mucus glycans and use alternative, less energetically favorable sources, resulting in reduced fermentative activity and SCFA production.
      • Russell W.R.
      • Gratz S.W.
      • Duncan S.H.
      • Holtrop G.
      • Ince J.
      • Scobbie L.
      • Duncan G.
      • Johnstone A.M.
      • Lobley G.E.
      • Wallace R.J.
      • Duthie G.G.
      • Flint H.J.
      High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health.
      Both preclinical and clinical data have shown that microbial activity, in particular the production of SCFAs, stimulate L cells located at the distal ileum to secrete peptide YY and GLP-1, which induce satiety and behavioral changes.
      • Tolhurst G.
      • Heffron H.
      • Lam Y.S.
      • Parker H.E.
      • Habib A.M.
      • Diakogiannaki E.
      • Cameron J.
      • Grosse J.
      • Reimann F.
      • Gribble F.M.
      Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2.
      • Samuel B.S.
      • Shaito A.
      • Motoike T.
      • Rey F.E.
      • Backhed F.
      • Manchester J.K.
      • Hammer R.E.
      • Williams S.C.
      • Crowley J.
      • Yanagisawa M.
      • Gordon J.I.
      Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41.
      • Cani P.D.
      • Lecourt E.
      • Dewulf E.M.
      • Sohet F.M.
      • Pachikian B.D.
      • Naslain D.
      • De Backer F.
      • Neyrinck A.M.
      • Delzenne N.M.
      Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal.
      Acetate, butyrate, and propionate modulate the expression and secretion of GLP-1 via free fatty acid receptor 2 (FFAR2)/G-protein–coupled receptor 43 (GPR43) and FFAR3/GPR41 on L cells,
      • Tolhurst G.
      • Heffron H.
      • Lam Y.S.
      • Parker H.E.
      • Habib A.M.
      • Diakogiannaki E.
      • Cameron J.
      • Grosse J.
      • Reimann F.
      • Gribble F.M.
      Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2.
      and GPR41s have been identified on different EECs in the gut.
      • Nohr M.K.
      • Egerod K.L.
      • Christiansen S.H.
      • Gille A.
      • Offermanns S.
      • Schwartz T.W.
      • Moller M.
      Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia.
      This widespread distribution of these receptors on and in EECs and ECCs involved in the regulation of food intake and digestion is consistent with the important role of the gut microbes in these processes and the expectations of holobiont co-evolution.

       Enterochromaffin Cell Signaling

      One of the best characterized examples of these microbial host interactions is the bidirectional interaction between microbes, ECCs, and the central nervous system (Figure 1). 5-HT is produced by the ECCs of the gastrointestinal (GI) tract, with 95% of the body’s 5-HT stored in ECCs and enteric neurons, and only 5% stored in the CNS.
      • Kim D.Y.
      • Camilleri M.
      Serotonin: a mediator of the brain-gut connection.
      Considering 5-HT’s central role in regulating GI motility and secretion, there is likely immense selective pressure on the gut microorganisms to act on the serotonergic system to modulate their environment effectively (eg, by influencing regional transit times and fluid secretions). An analysis of the plasma metabolite profile of germ-free mice shows a more than 2-fold decrease in 5-HT levels relative to conventionally colonized mice.
      • Wikoff W.R.
      • Anfora A.T.
      • Liu J.
      • Schultz P.G.
      • Lesley S.A.
      • Peters E.C.
      • Siuzdak G.
      Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.
      SCFAs and 2BAs derived from spore-forming bacteria of the gut regulate a significant percentage of ECC 5-HT synthesis and release.
      • Yano J.M.
      • Yu K.
      • Donaldson G.P.
      • Shastri G.G.
      • Ann P.
      • Ma L.
      • Nagler C.R.
      • Ismagilov R.F.
      • Mazmanian S.K.
      • Hsiao E.Y.
      Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.
      The essential amino acid tryptophan (Trp) is a key molecule in the BGM axis because it is the precursor to the neurotransmitter 5-HT and a number of other metabolites that contribute to the neuroendocrine signaling within the BGM.
      • Ruddick J.P.
      • Evans A.K.
      • Nutt D.J.
      • Lightman S.L.
      • Rook G.A.
      • Lowry C.A.
      Tryptophan metabolism in the central nervous system: medical implications.
      Because the host is unable to produce tryptophan, dietary intake of proteins that contain it serve as the primary regulator of its availability. Gut microbiota contribute to the peripheral availability of Trp, which is imperative to the CNS synthesis of 5-HT. GF mice show increased levels of plasma Trp and hippocampal 5-HT, and, interestingly, colonization with bacteria normalizes plasma Trp but not hippocampal 5-HT.
      • Clarke G.
      • Grenham S.
      • Scully P.
      • Fitzgerald P.
      • Moloney R.D.
      • Shanahan F.
      • Dinan T.G.
      • Cryan J.F.
      The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
      Although the exact mechanisms of peripheral Trp regulation are unknown, the same study suggests that the microbiota modulate the degradation of Trp down the kynurenine pathway. In a separate study, this pathway interaction was observed and linked to behavioral phenotypes. Administration of Lactobacillus reuteri normalized stress-induced behavioral changes and was associated with decreased circulating kynurenine levels resulting from microbially derived H2O2 inhibition of ido1 messenger RNA expression.
      • Marin I.A.
      • Goertz J.E.
      • Ren T.
      • Rich S.S.
      • Onengut-Gumuscu S.
      • Farber E.
      • Wu M.
      • Overall C.C.
      • Kipnis J.
      • Gaultier A.
      Microbiota alteration is associated with the development of stress-induced despair behavior.
      Figure thumbnail gr1
      Figure 1Bidirectional brain-gut-microbiome interactions related to serotonin signaling. Enterochromaffin cells (shown in green) contain more than 90% of the body’s serotonin (5-HT). 5-HT synthesis in ECCs is modulated by SCFAs and 2BAs produced by spore-forming Clostridiales, which increase their stimulatory actions on ECCs with increased dietary tryptophan availability.
      • Yano J.M.
      • Yu K.
      • Donaldson G.P.
      • Shastri G.G.
      • Ann P.
      • Ma L.
      • Nagler C.R.
      • Ismagilov R.F.
      • Mazmanian S.K.
      • Hsiao E.Y.
      Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.
      ECCs communicate with afferent nerve fibers through synapse-like connections between neuropod-like extensions and afferent nerve terminals.
      • Bohorquez D.V.
      • Liddle R.A.
      The gut connectome: making sense of what you eat.
      The autonomic nervous system can activate ECCs to release 5-HT into the gut lumen, where it can interact with gut microbes.
      • Yang H.
      • Stephens R.L.
      • Tache Y.
      TRH analogue microinjected into specific medullary nuclei stimulates gastric serotonin secretion in rats.
      TPH1, tryptophan hydroxylase type 1.

       Neuroimmune Signaling

      The wide-ranging interaction of commensal bacteria with the gut-associated immune system and consequently the CNS is beyond the scope of this review and has been reviewed extensively elsewhere.
      • Fung T.C.
      • Olson C.A.
      • Hsiao E.Y.
      Interactions between the microbiota, immune and nervous systems in health and disease.
      Mouse models of multiple sclerosis and stroke have identified substantial roles for gut microbial regulation of autoimmunity, inflammation, and immune cell trafficking.
      • Wang Y.
      • Telesford K.M.
      • Ochoa-Reparaz J.
      • Haque-Begum S.
      • Christy M.
      • Kasper E.J.
      • Wang L.
      • Wu Y.
      • Robson S.C.
      • Kasper D.L.
      • Kasper L.H.
      An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling.
      • Ochoa-Reparaz J.
      • Mielcarz D.W.
      • Ditrio L.E.
      • Burroughs A.R.
      • Begum-Haque S.
      • Dasgupta S.
      • Kasper D.L.
      • Kasper L.H.
      Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression.
      • Ochoa-Reparaz J.
      • Mielcarz D.W.
      • Ditrio L.E.
      • Burroughs A.R.
      • Foureau D.M.
      • Haque-Begum S.
      • Kasper L.H.
      Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis.
      • Benakis C.
      • Brea D.
      • Caballero S.
      • Faraco G.
      • Moore J.
      • Murphy M.
      • Sita G.
      • Racchumi G.
      • Ling L.
      • Pamer E.G.
      • Iadecola C.
      • Anrather J.
      Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells.
      • Winek K.
      • Engel O.
      • Koduah P.
      • Heimesaat M.M.
      • Fischer A.
      • Bereswill S.
      • Dames C.
      • Kershaw O.
      • Gruber A.D.
      • Curato C.
      • Oyama N.
      • Meisel C.
      • Meisel A.
      • Dirnagl U.
      Depletion of cultivatable gut microbiota by broad-spectrum antibiotic pretreatment worsens outcome after murine stroke.
      It is important to highlight that the gut microbiota influence the development and function of the CNS resident immune cells, especially microglia.
      • Erny D.
      • Hrabe de Angelis A.L.
      • Jaitin D.
      • Wieghofer P.
      • Staszewski O.
      • David E.
      • Keren-Shaul H.
      • Mahlakoiv T.
      • Jakobshagen K.
      • Buch T.
      • Schwierzeck V.
      • Utermohlen O.
      • Chun E.
      • Garrett W.S.
      • McCoy K.D.
      • Diefenbach A.
      • Staeheli P.
      • Stecher B.
      • Amit I.
      • Prinz M.
      Host microbiota constantly control maturation and function of microglia in the CNS.
      Relative to SPF mice, GF mice have compromised microglia maturation and morphology, leading to weakened early responses to pathogen exposure.
      • Erny D.
      • Hrabe de Angelis A.L.
      • Jaitin D.
      • Wieghofer P.
      • Staszewski O.
      • David E.
      • Keren-Shaul H.
      • Mahlakoiv T.
      • Jakobshagen K.
      • Buch T.
      • Schwierzeck V.
      • Utermohlen O.
      • Chun E.
      • Garrett W.S.
      • McCoy K.D.
      • Diefenbach A.
      • Staeheli P.
      • Stecher B.
      • Amit I.
      • Prinz M.
      Host microbiota constantly control maturation and function of microglia in the CNS.
      This phenotype can be normalized by postnatal SCFA supplementation or colonization with a complex microbial community. Remarkably, antibiotic treatment to eradicate bacteria in SPF adult mice leads microglia to regain immature status, which then can be normalized by recolonization with complex microbiota, suggesting that active microbial signaling is required throughout adulthood to preserve microglial maturation.
      • Erny D.
      • Hrabe de Angelis A.L.
      • Jaitin D.
      • Wieghofer P.
      • Staszewski O.
      • David E.
      • Keren-Shaul H.
      • Mahlakoiv T.
      • Jakobshagen K.
      • Buch T.
      • Schwierzeck V.
      • Utermohlen O.
      • Chun E.
      • Garrett W.S.
      • McCoy K.D.
      • Diefenbach A.
      • Staeheli P.
      • Stecher B.
      • Amit I.
      • Prinz M.
      Host microbiota constantly control maturation and function of microglia in the CNS.

       Direct Neural Signaling

      Most evidence to date relies on vagal receptors that sense regulatory gut peptides, inflammatory molecules, dietary components, and bacterial metabolites to relay signals to the CNS,
      • de Lartigue G.
      • de La Serre C.B.
      • Raybould H.E.
      Vagal afferent neurons in high fat diet-induced obesity; intestinal microflora, gut inflammation and cholecystokinin.
      but there is also some evidence for direct activation of neurons by gut microbiota. Toll-like receptors 3 and 7, which recognize viral RNA, and Toll-like receptors 2 and 4, which recognize peptidoglycan and lipopolysaccharide, are expressed in the murine and human enteric nervous systems.
      • Barajon I.
      • Serrao G.
      • Arnaboldi F.
      • Opizzi E.
      • Ripamonti G.
      • Balsari A.
      • Rumio C.
      Toll-like receptors 3, 4, and 7 are expressed in the enteric nervous system and dorsal root ganglia.
      • Brun P.
      • Giron M.C.
      • Qesari M.
      • Porzionato A.
      • Caputi V.
      • Zoppellaro C.
      • Banzato S.
      • Grillo A.R.
      • Spagnol L.
      • De Caro R.
      • Pizzuti D.
      • Barbieri V.
      • Rosato A.
      • Sturniolo G.C.
      • Martines D.
      • Zaninotto G.
      • Palu G.
      • Castagliuolo I.
      Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system.
      L rhamnosus (JB-1), B fragilis, and isolated polysaccharide A of B fragilis all have been shown to activate intestinal afferent neurons ex vivo.
      • Mao Y.K.
      • Kasper D.L.
      • Wang B.
      • Forsythe P.
      • Bienenstock J.
      • Kunze W.A.
      Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons.
      However, it remains unclear to what degree luminal microbial antigens make direct physical contact with neurons in vivo.
      • Keita A.V.
      • Soderholm J.D.
      The intestinal barrier and its regulation by neuroimmune factors.
      Microbial metabolites also are likely candidates mediating direct activation of neurons. The receptors FXR and TGR5 are expressed in brain neurons, but bile acid concentrations are low or undetectable in these tissues of healthy subjects.
      • Huang C.
      • Wang J.
      • Hu W.
      • Wang C.
      • Lu X.
      • Tong L.
      • Wu F.
      • Zhang W.
      Identification of functional farnesoid X receptors in brain neurons.
      • Keitel V.
      • Gorg B.
      • Bidmon H.J.
      • Zemtsova I.
      • Spomer L.
      • Zilles K.
      • Haussinger D.
      The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain.
      Several studies have localized GPR41/FFAR3 receptors to the superior cervical ganglion,
      • Kimura I.
      • Inoue D.
      • Maeda T.
      • Hara T.
      • Ichimura A.
      • Miyauchi S.
      • Kobayashi M.
      • Hirasawa A.
      • Tsujimoto G.
      Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).
      prevertebral ganglia,
      • Won Y.J.
      • Lu V.B.
      • Puhl 3rd, H.L.
      • Ikeda S.R.
      beta-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3.
      submucosal and myenteric ganglia neurons,
      • Nohr M.K.
      • Pedersen M.H.
      • Gille A.
      • Egerod K.L.
      • Engelstoft M.S.
      • Husted A.S.
      • Sichlau R.M.
      • Grunddal K.V.
      • Poulsen S.S.
      • Han S.
      • Jones R.M.
      • Offermanns S.
      • Schwartz T.W.
      GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes.
      sympathetic ganglia of the thoracic and lumbar sympathetic trunks, and vagal ganglion,
      • Nohr M.K.
      • Egerod K.L.
      • Christiansen S.H.
      • Gille A.
      • Offermanns S.
      • Schwartz T.W.
      • Moller M.
      Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia.
      suggesting neuronal activation by microbially derived SCFAs. Upon GPR41 activation, primary-cultured superior cervical neurons release norepinephrine, establishing this as a direct functional interface for microbial derivatives and the sympathetic nervous system.
      • Kimura I.
      • Inoue D.
      • Maeda T.
      • Hara T.
      • Ichimura A.
      • Miyauchi S.
      • Kobayashi M.
      • Hirasawa A.
      • Tsujimoto G.
      Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

      Barriers to Bottom-Up Signaling

      There are 2 natural barriers to signaling within the BGM axis: the intestinal barrier and the blood brain barrier. Because gut microbes, stress, and inflammation are able to modulate the permeability of both structures, the amount of information reaching the brain from the gut is highly variable, depending on the state of the host.

       Intestinal Barrier

      The intestinal barrier is characterized by 2 layers: a basal monolayer of epithelial cells interconnected by tight junctions, and a mucus layer whose thickness and composition changes over time and that contains secretory IgA and antimicrobial peptides.
      • Kelly J.R.
      • Kennedy P.J.
      • Cryan J.F.
      • Dinan T.G.
      • Clarke G.
      • Hyland N.P.
      Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders.
      Upon detection of specific microbial products, pattern recognition receptors located throughout GI mucosa can mediate the induction of enhanced antimicrobial defense, intestinal inflammation, and even immunologic tolerance.
      • Ivanov I.I.
      • Atarashi K.
      • Manel N.
      • Brodie E.L.
      • Shima T.
      • Karaoz U.
      • Wei D.
      • Goldfarb K.C.
      • Santee C.A.
      • Lynch S.V.
      • Tanoue T.
      • Imaoka A.
      • Itoh K.
      • Takeda K.
      • Umesaki Y.
      • Honda K.
      • Littman D.R.
      Induction of intestinal Th17 cells by segmented filamentous bacteria.
      • Round J.L.
      • Lee S.M.
      • Li J.
      • Tran G.
      • Jabri B.
      • Chatila T.A.
      • Mazmanian S.K.
      The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.
      Under healthy homeostatic conditions, many microorganisms and macromolecules gain entry through microfold cells (M cells), found in gut- and mucosa-associated lymphoid tissue, which enables constant sampling by immune cells.
      • Kucharzik T.
      • Lugering N.
      • Rautenberg K.
      • Lugering A.
      • Schmidt M.A.
      • Stoll R.
      • Domschke W.
      Role of M cells in intestinal barrier function.
      Paneth cells autonomously sense bacteria though MyD88-dependent Toll-like receptor activation, which triggers antimicrobial factors and ultimately limits bacterial penetration of host tissue.
      • Vaishnava S.
      • Behrendt C.L.
      • Ismail A.S.
      • Eckmann L.
      • Hooper L.V.
      Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.
      Microbes and microbe-derived ligands help maintain the cell-cell junctions critical to integrity.
      • Hooper L.V.
      • Wong M.H.
      • Thelin A.
      • Hansson L.
      • Falk P.G.
      • Gordon J.I.
      Molecular analysis of commensal host-microbial relationships in the intestine.
      • Rakoff-Nahoum S.
      • Paglino J.
      • Eslami-Varzaneh F.
      • Edberg S.
      • Medzhitov R.
      Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.
      Probiotic treatment can help normalize stress-induced barrier defects (discussed later) via unknown mechanisms.
      • Da Silva S.
      • Robbe-Masselot C.
      • Ait-Belgnaoui A.
      • Mancuso A.
      • Mercade-Loubiere M.
      • Salvador-Cartier C.
      • Gillet M.
      • Ferrier L.
      • Loubiere P.
      • Dague E.
      • Theodorou V.
      • Mercier-Bonin M.
      Stress disrupts intestinal mucus barrier in rats via mucin O-glycosylation shift: prevention by a probiotic treatment.
      The intestinal mucus layer is the second component of intestinal barrier function. Colonic mucus is organized into 2 layers: a thicker loose outer layer, and an inner layer attached firmly to the epithelium.
      • Atuma C.
      • Strugala V.
      • Allen A.
      • Holm L.
      The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo.
      Commensal microbes inhabit the outer layer, a critical habitat for biofilm formation,
      • Macfarlane S.
      • Dillon J.F.
      Microbial biofilms in the human gastrointestinal tract.
      and a reliable energy source rich in glycoproteins that the microbiota degrade when deprived of dietary fiber, subsequently increasing pathogen susceptibility.
      • Desai M.S.
      • Seekatz A.M.
      • Koropatkin N.M.
      • Kamada N.
      • Hickey C.A.
      • Wolter M.
      • Pudlo N.A.
      • Kitamoto S.
      • Terrapon N.
      • Muller A.
      • Young V.B.
      • Henrissat B.
      • Wilmes P.
      • Stappenbeck T.S.
      • Nunez G.
      • Martens E.C.
      A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility.
      The inner layer usually is bacteria-free and serves to protect epithelial cells from microbial contact through physical separation, innate immune mechanisms including antimicrobial peptides, and adaptive immune mechanisms including secretory IgA.
      • Johansson M.E.
      • Larsson J.M.
      • Hansson G.C.
      The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions.

       Blood-Brain Barrier

      The blood-brain barrier (BBB) regulates molecular traffic between the circulatory system and the cerebrospinal fluid of the CNS. Gut microbiota can up-regulate the expression of tight junction proteins, including occludin and claudin-5, therefore decreasing BBB permeability.
      • Braniste V.
      • Al-Asmakh M.
      • Kowal C.
      • Anuar F.
      • Abbaspour A.
      • Toth M.
      • Korecka A.
      • Bakocevic N.
      • Ng L.G.
      • Kundu P.
      • Gulyas B.
      • Halldin C.
      • Hultenby K.
      • Nilsson H.
      • Hebert H.
      • Volpe B.T.
      • Diamond B.
      • Pettersson S.
      The gut microbiota influences blood-brain barrier permeability in mice.
      From intrauterine life through adulthood, GF mice have a more permeable barrier compared with controls, but introduction of normal gut microbiota to GF adults partially restores function. Permeability is decreased by monocolonization with SCFA-producing bacteria and oral gavage with sodium butyrate. SCFAs may serve as the primary signaling metabolite in BBB development and maintenance likely via entering cells and working as histone deacetylase inhibitors to epigenetically modulate the phenotype or via binding to GPR41 and/or GPR43.
      • Brown A.J.
      • Goldsworthy S.M.
      • Barnes A.A.
      • Eilert M.M.
      • Tcheang L.
      • Daniels D.
      • Muir A.I.
      • Wigglesworth M.J.
      • Kinghorn I.
      • Fraser N.J.
      • Pike N.B.
      • Strum J.C.
      • Steplewski K.M.
      • Murdock P.R.
      • Holder J.C.
      • Marshall F.H.
      • Szekeres P.G.
      • Wilson S.
      • Ignar D.M.
      • Foord S.M.
      • Wise A.
      • Dowell S.J.
      The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids.
      • Michel L.
      • Prat A.
      One more role for the gut: microbiota and blood brain barrier.
      Systemic immune activation may cause disruptive BBB changes and often is modeled using LPS. But in a systematic review, studies evaluating in vivo LPS effects on BBB function only showed disruption 60% of the time, a figure potentially subject to publication bias.
      • Varatharaj A.
      • Galea I.
      The blood-brain barrier in systemic inflammation.
      Interestingly, the host species is the only significant predictor explaining variance: mice are 4 times more likely than rats to show BBB change. Dose-dependent effects were not observed across all studies, although the levels used were mostly equivalent to septic doses. The variability of the BBB response in this model of systemic immune activation limits the generalizability of most preclinical findings to human microbiome interactions, especially in nonpathologic conditions.

      Signaling From the Brain to the Gut Microbiota

      There is more than 40 years worth of literature showing the effect of stress on the community structure of the gut microbiome.
      • Aguilera M.
      • Vergara P.
      • Martinez V.
      Stress and antibiotics alter luminal and wall-adhered microbiota and enhance the local expression of visceral sensory-related systems in mice.
      • Tannock G.W.
      • Savage D.C.
      Influences of dietary and environmental stress on microbial populations in the murine gastrointestinal tract.
      Exposure to social stressors for as little as 2 hours can change community profiles and reduce the relative proportions of the primary phyla,
      • Galley J.D.
      • Nelson M.C.
      • Yu Z.T.
      • Dowd S.E.
      • Walter J.
      • Kumar P.S.
      • Lyte M.
      • Bailey M.T.
      Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota.
      and maternal prenatal stress is associated with an altered infant microbiome potentiating increased inflammation.
      • Zijlmans M.A.
      • Korpela K.
      • Riksen-Walraven J.M.
      • de Vos W.M.
      • de Weerth C.
      Maternal prenatal stress is associated with the infant intestinal microbiota.

       Indirect Modulation via Autonomic Nervous System–Mediated Change in Microbial Environment

      Both branches of the autonomic nervous system (ANS) regulate gut functions including regional motility, secretion of gastric acid, mucus, bicarbonate, gut peptides, antimicrobial peptides, epithelial fluid maintenance, intestinal permeability, and mucosal immune response (reviewed by Mayer
      • Mayer E.A.
      Gut feelings: the emerging biology of gut-brain communication.
      ). These ANS-induced changes in gut physiology affect the microbial habitat, thereby modulating microbiota composition and activity.

       GI Motility

      Regional intestinal transit times affect water content, nutrient availability, and bacterial clearance rates. Relatively rapid flow in the small intestine inhibits permanent colonization of the upper gut, in particular in the proximal small intestine.
      • Macfarlane S.
      • Dillon J.F.
      Microbial biofilms in the human gastrointestinal tract.
      The frequency of migrating motor complexes, which play a crucial role in intestinal transit during the fasting state, is influenced by food intake patterns, sleep quality, and stress. Impaired migrating motor complex regularity can reduce the flow rate, leading to small intestine bacterial overgrowth.
      • Van Felius I.D.
      • Akkermans L.M.
      • Bosscha K.
      • Verheem A.
      • Harmsen W.
      • Visser M.R.
      • Gooszen H.G.
      Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis.
      Intestinal transit time assessed by the Bristol Stool Scale
      • Lewis S.J.
      • Heaton K.W.
      Stool form scale as a useful guide to intestinal transit time.
      • Saad R.J.
      • Rao S.S.
      • Koch K.L.
      • Kuo B.
      • Parkman H.P.
      • McCallum R.W.
      • Sitrin M.D.
      • Wilding G.E.
      • Semler J.R.
      • Chey W.D.
      Do stool form and frequency correlate with whole-gut and colonic transit? Results from a multicenter study in constipated individuals and healthy controls.
      strongly correlates with microbial richness and composition.
      • Vandeputte D.
      • Falony G.
      • Vieira-Silva S.
      • Tito R.Y.
      • Joossens M.
      • Raes J.
      Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates.
      In fact, a microbiome population level analysis identified such transit ratings as the top nonredundant covariate.
      • Falony G.
      • Joossens M.
      • Vieira-Silva S.
      • Wang J.
      • Darzi Y.
      • Faust K.
      • Kurilshikov A.
      • Bonder M.J.
      • Valles-Colomer M.
      • Vandeputte D.
      • Tito R.Y.
      • Chaffron S.
      • Rymenans L.
      • Verspecht C.
      • De Sutter L.
      • Lima-Mendez G.
      • D'Hoe K.
      • Jonckheere K.
      • Homola D.
      • Garcia R.
      • Tigchelaar E.F.
      • Eeckhaudt L.
      • Fu J.
      • Henckaerts L.
      • Zhernakova A.
      • Wijmenga C.
      • Raes J.
      Population-level analysis of gut microbiome variation.
      A study using radiopaque markers for transit corroborated its association to microbial composition and additionally showed association with diversity and metabolism.
      • Roager H.M.
      • Hansen L.B.
      • Bahl M.I.
      • Frandsen H.L.
      • Carvalho V.
      • Gobel R.J.
      • Dalgaard M.D.
      • Plichta D.R.
      • Sparholt M.H.
      • Vestergaard H.
      • Hansen T.
      • Sicheritz-Ponten T.
      • Nielsen H.B.
      • Pedersen O.
      • Lauritzen L.
      • Kristensen M.
      • Gupta R.
      • Licht T.R.
      Colonic transit time is related to bacterial metabolism and mucosal turnover in the gut.
      In vitro simulation with Environmental Controls Systems for Intestinal Microbiota showed that increased transit time causally reduced bacterial biomass and diversity in distal gut regions.
      • Tottey W.
      • Feria-Gervasio D.
      • Gaci N.
      • Laillet B.
      • Pujos E.
      • Martin J.F.
      • Sebedio J.L.
      • Sion B.
      • Jarrige J.F.
      • Alric M.
      • Brugere J.F.
      Colonic transit time is a driven force of the gut microbiota composition and metabolism: in vitro evidence.

       Intestinal Barrier

      Stress can cause epithelial barrier defects (leaky gut) by at least 2 mechanisms: direct modulation of epithelial permeability and alterations in the properties of the intestinal mucosal layer, ultimately leading to increased translocation of gut microbes or microbe-associated molecules.
      • Santos J.
      • Yang P.C.
      • Soderholm J.D.
      • Benjamin M.
      • Perdue M.H.
      Role of mast cells in chronic stress induced colonic epithelial barrier dysfunction in the rat.
      Rodent models have shown that jejunal and colonic permeability increases in response to both acute and chronic stress.
      • Saunders P.R.
      • Santos J.
      • Hanssen N.P.
      • Yates D.
      • Groot J.A.
      • Perdue M.H.
      Physical and psychological stress in rats enhances colonic epithelial permeability via peripheral CRH.
      • Meddings J.B.
      • Swain M.G.
      Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat.
      This increased leakiness facilitates the translocation of bacteria, such as Escherichia coli, and their products, such as lipopolysaccharide (LPS), leading to a proinflammatory environment in the gut, although there are conflicting reports describing stress-induced changes in expression of messenger RNA encoding tight junction proteins in the colon and jejunum.
      • Demaude J.
      • Salvador-Cartier C.
      • Fioramonti J.
      • Ferrier L.
      • Bueno L.
      Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction.
      • Lauffer A.
      • Vanuytsel T.
      • Vanormelingen C.
      • Vanheel H.
      • Salim Rasoel S.
      • Toth J.
      • Tack J.
      • Fornari F.
      • Farre R.
      Subacute stress and chronic stress interact to decrease intestinal barrier function in rats.
      Increased intestinal permeability and susceptibility to experimental inflammation observed in mouse models of depressive behavior induced by maternal separation is reversed by antidepressant therapy, highlighting brain-driven systemic and epithelial immune activity regulating the gut.
      • Varghese A.K.
      • Verdu E.F.
      • Bercik P.
      • Khan W.I.
      • Blennerhassett P.A.
      • Szechtman H.
      • Collins S.M.
      Antidepressants attenuate increased susceptibility to colitis in a murine model of depression.
      The ANS modulates the secretion of mucus by intestinal goblet cells, affecting the thickness and quality of the intestinal mucus layer. In addition to hypersensitivity, psychological stress leads to a less-protective mucus layer via catecholamine signaling, which alters the composition and size of secreted mucus.
      • Da Silva S.
      • Robbe-Masselot C.
      • Ait-Belgnaoui A.
      • Mancuso A.
      • Mercade-Loubiere M.
      • Salvador-Cartier C.
      • Gillet M.
      • Ferrier L.
      • Loubiere P.
      • Dague E.
      • Theodorou V.
      • Mercier-Bonin M.
      Stress disrupts intestinal mucus barrier in rats via mucin O-glycosylation shift: prevention by a probiotic treatment.
      • Rubio C.A.
      • Huang C.B.
      Quantification of the sulphomucin-producing cell population of the colonic mucosa during protracted stress in rats.
      • Soderholm J.D.
      • Yang P.C.
      • Ceponis P.
      • Vohra A.
      • Riddell R.
      • Sherman P.M.
      • Perdue M.H.
      Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine.
      Changes in microbiota composition observed in a mouse model of brain injury are thought to result from altered mucoprotein production and goblet cell population size mediated by increased sympathetic nervous system signaling.
      • Houlden A.
      • Goldrick M.
      • Brough D.
      • Vizi E.S.
      • Lenart N.
      • Martinecz B.
      • Roberts I.S.
      • Denes A.
      Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production.
      • Kim Y.S.
      • Ho S.B.
      Intestinal goblet cells and mucins in health and disease: recent insights and progress.

       Direct Modulation of Gut Microbiota by Luminal Release of Neurotransmitters

      In addition to CNS-induced changes in the intestinal microbial environment (eg, by influencing regional transit and secretions), the host neuroendocrine system can communicate with the microbiota more directly via intraluminal release of host signaling molecules, including but not limited to catecholamines, 5-HT, dynorphin, and cytokines, from neurons, immune cells, and ECCs.
      • Lyte M.
      The role of microbial endocrinology in infectious disease.
      • Mayer E.A.
      • Savidge T.
      • Shulman R.J.
      Brain-gut microbiome interactions and functional bowel disorders.
      The CNS likely modulates this process.
      • Santos J.
      • Saperas E.
      • Nogueiras C.
      • Mourelle M.
      • Antolin M.
      • Cadahia A.
      • Malagelada J.R.
      Release of mast cell mediators into the jejunum by cold pain stress in humans.
      • Stephens R.L.
      • Tache Y.
      Intracisternal injection of a TRH analogue stimulates gastric luminal serotonin release in rats.
      • Yang H.
      • Stephens R.L.
      • Tache Y.
      TRH analogue microinjected into specific medullary nuclei stimulates gastric serotonin secretion in rats.
      Epinephrine and norepinephrine are shown to increase the virulence properties of several enteric pathogens as well as nonpathogenic microbes via stimulation of native quorum-sensing mechanisms.
      • Clarke M.B.
      • Hughes D.T.
      • Zhu C.
      • Boedeker E.C.
      • Sperandio V.
      The QseC sensor kinase: a bacterial adrenergic receptor.
      • Lyte M.
      The role of catecholamines in gram-negative sepsis.
      • Alverdy J.
      • Holbrook C.
      • Rocha F.
      • Seiden L.
      • Wu R.L.
      • Musch M.
      • Chang E.
      • Ohman D.
      • Suh S.
      Gut-derived sepsis occurs when the right pathogen with the right virulence genes meets the right host: evidence for in vivo virulence expression in Pseudomonas aeruginosa.
      • Hughes D.T.
      • Sperandio V.
      Inter-kingdom signalling: communication between bacteria and their hosts.
      • Cogan T.A.
      • Thomas A.O.
      • Rees L.E.
      • Taylor A.H.
      • Jepson M.A.
      • Williams P.H.
      • Ketley J.
      • Humphrey T.J.
      Norepinephrine increases the pathogenic potential of Campylobacter jejuni.
      Other gut microbes contain sequences that share 24% to 42% identity to human genome sequences for the binding sites of melatonin,
      • Paulose J.K.
      • Wright J.M.
      • Patel A.G.
      • Cassone V.M.
      Human gut bacteria are sensitive to melatonin and express endogenous circadian rhythmicity.
      whose gut luminal concentrations have been reported at more than 10-fold serum concentrations in rats and pigs.
      • Bubenik G.A.
      • Brown G.M.
      Pinealectomy reduces melatonin levels in the serum but not in the gastrointestinal tract of rats.
      • Bubenik G.A.
      • Pang S.F.
      • Hacker R.R.
      • Smith P.S.
      Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food.
      In vitro assays of one such microbe, Enterobacter aerogenes, show that melatonin not only induces swarming and motility behavior, but helps synchronize the circadian period and phase across culture plates.
      • Paulose J.K.
      • Wright J.M.
      • Patel A.G.
      • Cassone V.M.
      Human gut bacteria are sensitive to melatonin and express endogenous circadian rhythmicity.
      The gut microbiota show circadian rhythmicity in both abundance and expression in a manner dependent on the host and its behavior, especially feeding timing, and simulated jet-lag shifts composition, enhancing dysbiosis.
      • Thaiss C.A.
      • Zeevi D.
      • Levy M.
      • Zilberman-Schapira G.
      • Suez J.
      • Tengeler A.C.
      • Abramson L.
      • Katz M.N.
      • Korem T.
      • Zmora N.
      • Kuperman Y.
      • Biton I.
      • Gilad S.
      • Harmelin A.
      • Shapiro H.
      • Halpern Z.
      • Segal E.
      • Elinav E.
      Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis.

      The BGM Axis in GI and Metabolic Disorders

       Functional Intestinal Disorders

      A number of studies (n = 22 in a total of 827 subjects) have reported significant microbial shifts in fecal microbial community composition between healthy controls and IBS patients, based on disease subtypes (diarrhea-predominant IBS, constipation-predominant IBS, and IBS mixed type), age (pediatric vs adult), and compartment (mucosa vs stool).
      • Simren M.
      • Barbara G.
      • Flint H.J.
      • Spiegel B.M.
      • Spiller R.C.
      • Vanner S.
      • Verdu E.F.
      • Whorwell P.J.
      • Zoetendal E.G.
      Rome Foundation Committee. Intestinal microbiota in functional bowel disorders: a Rome foundation report.
      Recent studies have suggested that there are at least 2 subgroups of patients who meet Rome criteria for IBS, based on gut microbial community structure, 1 subgroup not differing from healthy control subjects, despite similar GI symptoms.
      • Labus J.S.
      • Hollister E.B.
      • Jacobs J.
      • Kirbach K.
      • Oezguen N.
      • Gupta A.
      • Acosta J.
      • Luna R.A.
      • Aagaard K.
      • Versalovic J.
      • Savidge T.
      • Hsiao E.
      • Tillisch K.
      • Mayer E.A.
      Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome.
      • Jeffery I.B.
      • O'Toole P.W.
      • Ohman L.
      • Claesson M.J.
      • Deane J.
      • Quigley E.M.
      • Simren M.
      An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota.
      In one of these studies, the dysbiotic IBS subgroup also differed in regional brain volumes from the eubiotic group,
      • Labus J.S.
      • Hollister E.B.
      • Jacobs J.
      • Kirbach K.
      • Oezguen N.
      • Gupta A.
      • Acosta J.
      • Luna R.A.
      • Aagaard K.
      • Versalovic J.
      • Savidge T.
      • Hsiao E.
      • Tillisch K.
      • Mayer E.A.
      Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome.
      suggesting a relationship between microbial community structure and brain structure. Another recent study did not find a group difference in microbial composition between HCs and IBS, even though IBS symptom severity was correlated with dysbiosis.
      • Tap J.
      • Derrien M.
      • Tornblom H.
      • Brazeilles R.
      • Cools-Portier S.
      • Dore J.
      • Storsrud S.
      • Le Neve B.
      • Ohman L.
      • Simren M.
      Identification of an intestinal microbiota signature associated with severity of irritable bowel syndrome.
      Despite a lack of consensus on the wide range of gut microbial differences between IBS subjects and healthy controls and the specific microbial changes that may be correlated to disease outcome, recent molecular-based methods of mucosal brushings or luminal aspirates have suggested decreased diversity in small-bowel microbiota with increased abundance of gram-negative organisms in IBS.
      • Kerckhoffs A.P.
      • Ben-Amor K.
      • Samsom M.
      • van der Rest M.E.
      • de Vogel J.
      • Knol J.
      • Akkermans L.M.
      Molecular analysis of faecal and duodenal samples reveals significantly higher prevalence and numbers of Pseudomonas aeruginosa in irritable bowel syndrome.
      • Pimentel M.F.
      • Giamarellos-Bourboulis E.J.
      • Pyleris E.
      • Pistiki K.
      • Tang J.
      • Lee C.
      • Harkins T.
      • Kim G.
      • Weitsman S.
      • Barlow G.M.
      • Chang C.
      The first large scale deep sequencing of the duodenal microbiome in irritable bowel syndrome reveals striking differences compared to healthy controls.
      Based on analysis of fecal samples, regardless of the analytical methodology used, a number of studies reported a decreased relative abundance of the genera Bifidobacterium and Lactobacillus, and an increased Firmicutes:Bacteroidetes ratios at the phylum level. Because stress has been associated with a reduction in Lactobacilli in preclinical and clinical studies,
      • Galley J.D.
      • Nelson M.C.
      • Yu Z.T.
      • Dowd S.E.
      • Walter J.
      • Kumar P.S.
      • Lyte M.
      • Bailey M.T.
      Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota.
      • Bailey M.T.
      • Dowd S.E.
      • Galley J.D.
      • Hufnagle A.R.
      • Allen R.G.
      • Lyte M.
      Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation.
      • Knowles S.R.
      • Nelson E.A.
      • Palombo E.A.
      Investigating the role of perceived stress on bacterial flora activity and salivary cortisol secretion: a possible mechanism underlying susceptibility to illness.
      one may speculate that the reported IBS-related changes in community structure and resulting metabolism are in part owing to altered ANS modulation of the gut as described earlier.

       Obesity/Food Addiction

      A dysregulation of hedonic feeding behavior (food addiction) plays an important role in the current obesity epidemic.
      • Pedram P.
      • Wadden D.
      • Amini P.
      • Gulliver W.
      • Randell E.
      • Cahill F.
      • Vasdev S.
      • Goodridge A.
      • Carter J.C.
      • Zhai G.
      • Ji Y.
      • Sun G.
      Food addiction: its prevalence and significant association with obesity in the general population.
      The gut microbiota and its metabolites play an crucial role in the modulation of satiety signals (see earlier) and eating behaviors.
      • Tolhurst G.
      • Heffron H.
      • Lam Y.S.
      • Parker H.E.
      • Habib A.M.
      • Diakogiannaki E.
      • Cameron J.
      • Grosse J.
      • Reimann F.
      • Gribble F.M.
      Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2.
      • Lin H.V.
      • Frassetto A.
      • Kowalik Jr., E.J.
      • Nawrocki A.R.
      • Lu M.M.
      • Kosinski J.R.
      • Hubert J.A.
      • Szeto D.
      • Yao X.
      • Forrest G.
      • Marsh D.J.
      Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms.
      • Everard A.
      • Lazarevic V.
      • Derrien M.
      • Girard M.
      • Muccioli G.G.
      • Neyrinck A.M.
      • Possemiers S.
      • Van Holle A.
      • Francois P.
      • de Vos W.M.
      • Delzenne N.M.
      • Schrenzel J.
      • Cani P.D.
      Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice.
      In preclinical studies, fecal transplantation from hyperphagic obese mice to germ-free mice was able to induce hyperphagic behavior and weight gain in the recipients.
      • Vijay-Kumar M.
      • Aitken J.D.
      • Carvalho F.A.
      • Cullender T.C.
      • Mwangi S.
      • Srinivasan S.
      • Sitaraman S.V.
      • Knight R.
      • Ley R.E.
      • Gewirtz A.T.
      Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.
      • Turnbaugh P.J.
      • Ley R.E.
      • Mahowald M.A.
      • Magrini V.
      • Mardis E.R.
      • Gordon J.I.
      An obesity-associated gut microbiome with increased capacity for energy harvest.
      In addition, the gut microbiome has been associated with changes in brain microstructure in obesity, and distinct microbial brain signatures were able to differentiate obese from lean subjects.
      • Fernandez-Real J.M.
      • Serino M.
      • Blasco G.
      • Puig J.
      • Daunis-i-Estadella J.
      • Ricart W.
      • Burcelin R.
      • Fernandez-Aranda F.
      • Portero-Otin M.
      Gut microbiota interacts with brain microstructure and function.
      The gut microbiome produces several neuroactive compounds; these bioactive products include several indole-containing metabolites and 5-HT. The administration of probiotics modifies brain function and even brain metabolites including γ-aminobutyric acid and glutamate.
      • Tillisch K.
      • Labus J.
      • Kilpatrick L.
      • Jiang Z.
      • Stains J.
      • Ebrat B.
      • Guyonnet D.
      • Legrain-Raspaud S.
      • Trotin B.
      • Naliboff B.
      • Mayer E.A.
      Consumption of fermented milk product with probiotic modulates brain activity.
      • Janik R.
      • Thomason L.A.M.
      • Stanisz A.M.
      • Forsythe P.
      • Bienenstock J.
      • Stanisz G.J.
      Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate.
      A handful of studies point to a dramatic change in gut microbial composition after bariatric surgery.
      • Zhang H.
      • DiBaise J.K.
      • Zuccolo A.
      • Kudrna D.
      • Braidotti M.
      • Yu Y.
      • Parameswaran P.
      • Crowell M.D.
      • Wing R.
      • Rittmann B.E.
      • Krajmalnik-Brown R.
      Human gut microbiota in obesity and after gastric bypass.
      • Li J.V.
      • Ashrafian H.
      • Bueter M.
      • Kinross J.
      • Sands C.
      • le Roux C.W.
      • Bloom S.R.
      • Darzi A.
      • Athanasiou T.
      • Marchesi J.R.
      • Nicholson J.K.
      • Holmes E.
      Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk.
      • Damms-Machado A.
      • Mitra S.
      • Schollenberger A.E.
      • Kramer K.M.
      • Meile T.
      • Konigsrainer A.
      • Huson D.H.
      • Bischoff S.C.
      Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption.
      • Furet J.P.
      • Kong L.C.
      • Tap J.
      • Poitou C.
      • Basdevant A.
      • Bouillot J.L.
      • Mariat D.
      • Corthier G.
      • Dore J.
      • Henegar C.
      • Rizkalla S.
      • Clement K.
      Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers.
      • Graessler J.
      • Qin Y.
      • Zhong H.
      • Zhang J.
      • Licinio J.
      • Wong M.L.
      • Xu A.
      • Chavakis T.
      • Bornstein A.B.
      • Ehrhart-Bornstein M.
      • Lamounier-Zepter V.
      • Lohmann T.
      • Wolf T.
      • Bornstein S.R.
      Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.
      Remarkably, fecal transplantation from subjects after bariatric surgery was able to transmit the weight loss effects of bariatric surgery to a germ-free nonoperated recipient, inducing weight loss and reduced food intake.
      • Liou A.P.
      • Paziuk M.
      • Luevano Jr., J.M.
      • Machineni S.
      • Turnbaugh P.J.
      • Kaplan L.M.
      Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity.
      • Tremaroli V.
      • Karlsson F.
      • Werling M.
      • Stahlman M.
      • Kovatcheva-Datchary P.
      • Olbers T.
      • Fandriks L.
      • le Roux C.W.
      • Nielsen J.
      • Backhed F.
      Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation.

      The BGM Axis in Psychiatric and Neurologic Disorders With GI Comorbidities

      Patients with several psychiatric (depression, anxiety) and neurologic disorders (Parkinson's disease, autism spectrum disorders) have significant gastrointestinal comorbidities, and several recent studies point to an important role of the gut microbiota not only in the pathophysiology of the GI symptoms, but a potential role in the primary disorder as well.

       Depression and Anxiety

      Anxiety and depression often are comorbid conditions in patients with IBS. Preclinical studies have shown the microbiota’s capacity to modulate emotional behaviors, and influence parameters significant to depression pathogenesis and severity.
      • Sudo N.
      • Chida Y.
      • Aiba Y.
      • Sonoda J.
      • Oyama N.
      • Yu X.N.
      • Kubo C.
      • Koga Y.
      Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
      • Neufeld K.M.
      • Kang N.
      • Bienenstock J.
      • Foster J.A.
      Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
      • Diaz Heijtz R.
      • Wang S.
      • Anuar F.
      • Qian Y.
      • Bjorkholm B.
      • Samuelsson A.
      • Hibberd M.L.
      • Forssberg H.
      • Pettersson S.
      Normal gut microbiota modulates brain development and behavior.
      • Clarke G.
      • Grenham S.
      • Scully P.
      • Fitzgerald P.
      • Moloney R.D.
      • Shanahan F.
      • Dinan T.G.
      • Cryan J.F.
      The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
      • Kelly J.R.
      • Clarke G.
      • Cryan J.F.
      • Dinan T.G.
      Brain-gut-microbiota axis: challenges for translation in psychiatry.
      Although studies characterizing the gut microbiome of major depressive disorder vs health have yielded marginally distinct assemblage correlations, 3 different types of studies suggest causality: depressed human-to-rodent fecal microbial transplants have induced depressive behaviors in the animal models
      • Kelly J.R.
      • Borre Y.
      • C OB
      • Patterson E.
      • El Aidy S.
      • Deane J.
      • Kennedy P.J.
      • Beers S.
      • Scott K.
      • Moloney G.
      • Hoban A.E.
      • Scott L.
      • Fitzgerald P.
      • Ross P.
      • Stanton C.
      • Clarke G.
      • Cryan J.F.
      • Dinan T.G.
      Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat.
      • Zheng P.
      • Zeng B.
      • Zhou C.
      • Liu M.
      • Fang Z.
      • Xu X.
      • Zeng L.
      • Chen J.
      • Fan S.
      • Du X.
      • Zhang X.
      • Yang D.
      • Yang Y.
      • Meng H.
      • Li W.
      • Melgiri N.D.
      • Licinio J.
      • Wei H.
      • Xie P.
      Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism.
      ; prebiotic and probiotic administration to healthy controls has improved anxiety and mood; and, finally, incidences of E coli subtype outbreaks in Canada and Germany led to increases in depression and anxiety-related symptoms among the affected population (reviewed by Kelly et al
      • Kelly J.R.
      • Clarke G.
      • Cryan J.F.
      • Dinan T.G.
      Brain-gut-microbiota axis: challenges for translation in psychiatry.
      ).

       Parkinson’s Disease

      Although the clinical hallmarks of Parkinson's disease remain motor deficits, gastrointestinal symptoms (in addition to other nonmotor symptoms) are present that contribute more detrimentally to patient quality of life. These nonmotor symptoms include problems related to dysfunctional autonomic and enteric nervous systems, such as slow-transit constipation, and sensory alterations. The risk of Parkinson's disease development increases with infrequency of bowel movement and constipation severity, and there is a significant comorbidity of Parkinson's disease and IBS-like symptoms.
      • Mertsalmi T.H.
      • Aho V.T.E.
      • Pereira P.A.B.
      • Paulin L.
      • Pekkonen E.
      • Auvinen P.
      • Scheperjans F.
      More than constipation - bowel symptoms in Parkinson's disease and their connection to gut microbiota.
      Moreover, constipation is among the earliest features, appearing as early as 15.3 years before motor dysfunction (reviewed by Fasano et al
      • Fasano A.
      • Visanji N.P.
      • Liu L.W.C.
      • Lang A.E.
      • Pfeiffer R.F.
      Gastrointestinal dysfunction in Parkinson's disease.
      ). To date, clinical studies of Parkinson’s and the gut microbiota remain limited to characterizing the assemblage differences against healthy controls, and some of the reported differences may be a consequence of impaired colonic transit. However, recent evidence showing that a Parkinson’s rodent model’s physical impairments are enhanced by microbiota from Parkinson’s patients but not healthy controls suggests causality.
      • Sampson T.R.
      • Debelius J.W.
      • Thron T.
      • Janssen S.
      • Shastri G.G.
      • Ilhan Z.E.
      • Challis C.
      • Schretter C.E.
      • Rocha S.
      • Gradinaru V.
      • Chesselet M.F.
      • Keshavarzian A.
      • Shannon K.M.
      • Krajmalnik-Brown R.
      • Wittung-Stafshede P.
      • Knight R.
      • Mazmanian S.K.
      Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease.
      Early gastrointestinal symptoms, thus, may be prodromal, making the gut microbiota a promising source of information for diagnosis, prognosis, and, potentially, pathogenesis.

       Autism Spectrum Disorder

      In addition to the core symptoms of ASD (difficulty with social and communicative behavior, repetitive behaviors), gastrointestinal symptoms are common and contribute significantly to the morbidity of affected patients.
      • Vuong H.E.
      • Hsiao E.Y.
      Emerging roles for the gut microbiome in autism spectrum disorder.
      • Mayer E.A.
      • Padua D.
      • Tillisch K.
      Altered brain-gut axis in autism: comorbidity or causative mechanisms?.
      GI symptom severity is correlated strongly to ASD symptom severity, as well as anxiety and sensory over-responsivity conditions modulated by gut microbiota in preclinical models (reviewed by Vuong and Hsiao
      • Vuong H.E.
      • Hsiao E.Y.
      Emerging roles for the gut microbiome in autism spectrum disorder.
      ). Gut dysbiosis is an increasingly documented symptom of ASD but, similar to other clinical conditions, causality remains limited to intriguing, albeit untested, hypotheses and results from uncontrolled clinical studies.
      • Kang D.W.
      • Adams J.B.
      • Gregory A.C.
      • Borody T.
      • Chittick L.
      • Fasano A.
      • Khoruts A.
      • Geis E.
      • Maldonado J.
      • McDonough-Means S.
      • Pollard E.L.
      • Roux S.
      • Sadowsky M.J.
      • Lipson K.S.
      • Sullivan M.B.
      • Caporaso J.G.
      • Krajmalnik-Brown R.
      Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study.
      In summary, there is considerable and growing evidence implicating the gut microbiome not only in the normal development and function of the nervous system but also in a range of acute and chronic diseases affecting the gut, as well as the nervous system throughout life. It remains to be determined if the gut microbiota play a causal role, but its facilitation of pathogenesis and potentiation of severity in disease models suggests that it is not merely a secondary effect of the underlying etiology. In view of the extensive preclinical evidence for both top-down and bottom-up signaling within the BGM axis and the emerging findings from clinical studies, we propose a systems biological model of bidirectional BGM interactions
      • Mayer E.A.
      • Labus J.S.
      • Tillisch K.
      • Cole S.W.
      • Baldi P.
      Towards a systems view of IBS.
      (Figure 2).
      Figure thumbnail gr2
      Figure 2Systems biological model of brain-gut-microbiome interactions. The gut microbiota communicate with the gut connectome, the network of interacting cell types in the gut that include neuronal, glial, endocrine, and immune cells,
      • Bohorquez D.V.
      • Liddle R.A.
      The gut connectome: making sense of what you eat.
      via microbial metabolites, while changes in gut function can modulate gut microbial behavior. The brain connectome, the multiple interconnected structural networks of the central nervous system,
      • Sporns O.
      The human connectome: origins and challenges.
      generates and regulates autonomic nervous system influences that alter gut microbial composition and function indirectly by modulating the microbial environment in the gut. The gut microbiota can communicate to the brain indirectly via gut-derived molecules acting on afferent vagal and/or spinal nerve endings, or directly via microbe-generated signals. Alterations in the gain of these bidirectional interactions in response to perturbations such as psychosocial or gut-directed (eg, diet, medication, infection) stress can alter the stability and behavior of this system, manifesting as brain-gut disorders. Modified from Fung et al.
      • Fung T.C.
      • Olson C.A.
      • Hsiao E.Y.
      Interactions between the microbiota, immune and nervous systems in health and disease.

      Future

      Despite considerable progress characterizing the interaction between the gut microbiome and the CNS over the past 10 years, questions remain regarding their relevance to the pathogenesis, pathophysiology, and treatment of human brain gut disorders and we urge caution in prematurely extrapolating findings in rodent models to human beings. For example, based on clinical experience, long-term treatment with broad-spectrum antibiotics for infectious diseases and total colectomy in ulcerative colitis do not appear to have noticeable effects on mood, affect, or cognition in the vast number of patients. Advances in the field are the consequence of ever-more-powerful biological techniques, such as shotgun metagenomics and metatranscriptomics, coupled to novel bioinformatic and computational approaches that enable multi-omic integration of both microbial and host data using machine learning approaches. Efforts are underway not only to characterize further microbial community structure, function, and the contributions of individual taxa, but also the large communities of viruses (virome) and fungi (mycobiome) that, until recently, have been ignored owing to technological limitations. The decreasing costs of novel multi-omic analysis have facilitated data-driven approaches to identify patient subgroups with distinct patterns of dysbiosis and test the hypothesis that such subgroups will respond to personalized therapy using dietary, prebiotic, or probiotic interventions. However, there is an urgent need for large-scale, highly controlled, longitudinal human studies showing the causes and sequelae of dysbiotic gut states and explaining interindividual variability in susceptibility to BGM-related diseases. The past decade has shown a potent hidden organ. This next decade will see widespread inclusion of this newly discovered organ into diagnostic consideration and in targeted manipulation for therapeutic intervention of many diseases.

      References

        • Mayer E.A.
        Gut feelings: the emerging biology of gut-brain communication.
        Nat Rev Neurosci. 2011; 12: 453-466
        • Rhee S.H.
        • Pothoulakis C.
        • Mayer E.A.
        Principles and clinical implications of the brain-gut-enteric microbiota axis.
        Nat Rev Gastroenterol Hepatol. 2009; 6: 306-314
        • Cryan J.F.
        • Dinan T.G.
        Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.
        Nat Rev Neurosci. 2012; 13: 701-712
        • Park A.J.
        • Collins J.
        • Blennerhassett P.A.
        • Ghia J.E.
        • Verdu E.F.
        • Bercik P.
        • Collins S.M.
        Altered colonic function and microbiota profile in a mouse model of chronic depression.
        Neurogastroenterol Motil. 2013; 25 (733-e575)
        • Vuong H.E.
        • Hsiao E.Y.
        Emerging roles for the gut microbiome in autism spectrum disorder.
        Biol Psychiatry. 2017; 81: 411-423
        • Sampson T.R.
        • Debelius J.W.
        • Thron T.
        • Janssen S.
        • Shastri G.G.
        • Ilhan Z.E.
        • Challis C.
        • Schretter C.E.
        • Rocha S.
        • Gradinaru V.
        • Chesselet M.F.
        • Keshavarzian A.
        • Shannon K.M.
        • Krajmalnik-Brown R.
        • Wittung-Stafshede P.
        • Knight R.
        • Mazmanian S.K.
        Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease.
        Cell. 2016; 167: 1469-1480 e12
        • Berer K.
        • Mues M.
        • Koutrolos M.
        • Rasbi Z.A.
        • Boziki M.
        • Johner C.
        • Wekerle H.
        • Krishnamoorthy G.
        Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination.
        Nature. 2011; 479: 538-541
        • Amaral F.A.
        • Sachs D.
        • Costa V.V.
        • Fagundes C.T.
        • Cisalpino D.
        • Cunha T.M.
        • Ferreira S.H.
        • Cunha F.Q.
        • Silva T.A.
        • Nicoli J.R.
        • Vieira L.Q.
        • Souza D.G.
        • Teixeira M.M.
        Commensal microbiota is fundamental for the development of inflammatory pain.
        Proc Natl Acad Sci U S A. 2008; 105: 2193-2197
        • Bercik P.
        • Denou E.
        • Collins J.
        • Jackson W.
        • Lu J.
        • Jury J.
        • Deng Y.
        • Blennerhassett P.
        • Macri J.
        • McCoy K.D.
        • Verdu E.F.
        • Collins S.M.
        The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice.
        Gastroenterology. 2011; 141 (e1-3): 599-609
        • Collins S.M.
        • Kassam Z.
        • Bercik P.
        The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications.
        Curr Opin Microbiol. 2013; 16: 240-245
        • Desai M.S.
        • Seekatz A.M.
        • Koropatkin N.M.
        • Kamada N.
        • Hickey C.A.
        • Wolter M.
        • Pudlo N.A.
        • Kitamoto S.
        • Terrapon N.
        • Muller A.
        • Young V.B.
        • Henrissat B.
        • Wilmes P.
        • Stappenbeck T.S.
        • Nunez G.
        • Martens E.C.
        A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility.
        Cell. 2016; 167: 1339-1353 e21
        • Bowey E.
        • Adlercreutz H.
        • Rowland I.
        Metabolism of isoflavones and lignans by the gut microflora: a study in germ-free and human flora associated rats.
        Food Chem Toxicol. 2003; 41: 631-636
        • Mallett A.K.
        • Bearne C.A.
        • Rowland I.R.
        • Farthing M.J.
        • Cole C.B.
        • Fuller R.
        The use of rats associated with a human faecal flora as a model for studying the effects of diet on the human gut microflora.
        J Appl Bacteriol. 1987; 63: 39-45
        • Bellono N.W.
        • Bayrer J.R.
        • Leitch D.B.
        • Castro J.
        • Zhang C.
        • O'Donnell T.A.
        • Brierley S.M.
        • Ingraham H.A.
        • Julius D.
        Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways.
        Cell. 2017; 170: 185-198 e16
        • Yissachar N.
        • Zhou Y.
        • Ung L.
        • Lai N.Y.
        • Mohan J.F.
        • Ehrlicher A.
        • Weitz D.A.
        • Kasper D.L.
        • Chiu I.M.
        • Mathis D.
        • Benoist C.
        An intestinal organ culture system uncovers a role for the nervous system in microbe-immune crosstalk.
        Cell. 2017; 168: 1135-1148 e12
        • Bravo J.A.
        • Forsythe P.
        • Chew M.V.
        • Escaravage E.
        • Savignac H.M.
        • Dinan T.G.
        • Bienenstock J.
        • Cryan J.F.
        Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
        Proc Natl Acad Sci U S A. 2011; 108: 16050-16055
        • Sudo N.
        • Chida Y.
        • Aiba Y.
        • Sonoda J.
        • Oyama N.
        • Yu X.N.
        • Kubo C.
        • Koga Y.
        Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
        J Physiol. 2004; 558: 263-275
        • Neufeld K.M.
        • Kang N.
        • Bienenstock J.
        • Foster J.A.
        Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
        Neurogastroenterol Motil. 2011; 23 (e119): 255-264
        • Diaz Heijtz R.
        • Wang S.
        • Anuar F.
        • Qian Y.
        • Bjorkholm B.
        • Samuelsson A.
        • Hibberd M.L.
        • Forssberg H.
        • Pettersson S.
        Normal gut microbiota modulates brain development and behavior.
        Proc Natl Acad Sci U S A. 2011; 108: 3047-3052
        • Desbonnet L.
        • Garrett L.
        • Clarke G.
        • Kiely B.
        • Cryan J.F.
        • Dinan T.G.
        Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression.
        Neuroscience. 2010; 170: 1179-1188
        • Clarke G.
        • Grenham S.
        • Scully P.
        • Fitzgerald P.
        • Moloney R.D.
        • Shanahan F.
        • Dinan T.G.
        • Cryan J.F.
        The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.
        Mol Psychiatry. 2013; 18: 666-673
        • Bercik P.
        • Park A.J.
        • Sinclair D.
        • Khoshdel A.
        • Lu J.
        • Huang X.
        • Deng Y.
        • Blennerhassett P.A.
        • Fahnestock M.
        • Moine D.
        • Berger B.
        • Huizinga J.D.
        • Kunze W.
        • McLean P.G.
        • Bergonzelli G.E.
        • Collins S.M.
        • Verdu E.F.
        The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.
        Neurogastroenterol Motil. 2011; 23: 1132-1139
        • Crumeyrolle-Arias M.
        • Jaglin M.
        • Bruneau A.
        • Vancassel S.
        • Cardona A.
        • Dauge V.
        • Naudon L.
        • Rabot S.
        Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.
        Psychoneuroendocrinology. 2014; 42: 207-217
        • Savignac H.M.
        • Kiely B.
        • Dinan T.G.
        • Cryan J.F.
        Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice.
        Neurogastroenterol Motil. 2014; 26: 1615-1627
        • De Palma G.
        • Blennerhassett P.
        • Lu J.
        • Deng Y.
        • Park A.J.
        • Green W.
        • Denou E.
        • Silva M.A.
        • Santacruz A.
        • Sanz Y.
        • Surette M.G.
        • Verdu E.F.
        • Collins S.M.
        • Bercik P.
        Microbiota and host determinants of behavioural phenotype in maternally separated mice.
        Nat Commun. 2015; 6: 7735
        • Hsiao E.Y.
        • McBride S.W.
        • Hsien S.
        • Sharon G.
        • Hyde E.R.
        • McCue T.
        • Codelli J.A.
        • Chow J.
        • Reisman S.E.
        • Petrosino J.F.
        • Patterson P.H.
        • Mazmanian S.K.
        Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.
        Cell. 2013; 155: 1451-1463
        • Kelly J.R.
        • Borre Y.
        • C OB
        • Patterson E.
        • El Aidy S.
        • Deane J.
        • Kennedy P.J.
        • Beers S.
        • Scott K.
        • Moloney G.
        • Hoban A.E.
        • Scott L.
        • Fitzgerald P.
        • Ross P.
        • Stanton C.
        • Clarke G.
        • Cryan J.F.
        • Dinan T.G.
        Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat.
        J Psychiatr Res. 2016; 82: 109-118
        • Desbonnet L.
        • Clarke G.
        • Traplin A.
        • O'Sullivan O.
        • Crispie F.
        • Moloney R.D.
        • Cotter P.D.
        • Dinan T.G.
        • Cryan J.F.
        Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour.
        Brain Behav Immun. 2015; 48: 165-173
        • Schroeder F.A.
        • Lin C.L.
        • Crusio W.E.
        • Akbarian S.
        Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse.
        Biol Psychiatry. 2007; 62: 55-64
        • Desbonnet L.
        • Garrett L.
        • Clarke G.
        • Bienenstock J.
        • Dinan T.G.
        The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat.
        J Psychiatr Res. 2008; 43: 164-174
        • Arseneault-Breard J.
        • Rondeau I.
        • Gilbert K.
        • Girard S.A.
        • Tompkins T.A.
        • Godbout R.
        • Rousseau G.
        Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces post-myocardial infarction depression symptoms and restores intestinal permeability in a rat model.
        Br J Nutr. 2012; 107: 1793-1799
        • Zheng P.
        • Zeng B.
        • Zhou C.
        • Liu M.
        • Fang Z.
        • Xu X.
        • Zeng L.
        • Chen J.
        • Fan S.
        • Du X.
        • Zhang X.
        • Yang D.
        • Yang Y.
        • Meng H.
        • Li W.
        • Melgiri N.D.
        • Licinio J.
        • Wei H.
        • Xie P.
        Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism.
        Mol Psychiatry. 2016; 21: 786-796
        • Ait-Belgnaoui A.
        • Han W.
        • Lamine F.
        • Eutamene H.
        • Fioramonti J.
        • Bueno L.
        • Theodorou V.
        Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: a possible action through interaction with epithelial cell cytoskeleton contraction.
        Gut. 2006; 55: 1090-1094
        • Eutamene H.
        • Lamine F.
        • Chabo C.
        • Theodorou V.
        • Rochat F.
        • Bergonzelli G.E.
        • Corthesy-Theulaz I.
        • Fioramonti J.
        • Bueno L.
        Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats.
        J Nutr. 2007; 137: 1901-1907
        • Rousseaux C.
        • Thuru X.
        • Gelot A.
        • Barnich N.
        • Neut C.
        • Dubuquoy L.
        • Dubuquoy C.
        • Merour E.
        • Geboes K.
        • Chamaillard M.
        • Ouwehand A.
        • Leyer G.
        • Carcano D.
        • Colombel J.F.
        • Ardid D.
        • Desreumaux P.
        Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.
        Nat Med. 2007; 13: 35-37
        • Ma X.
        • Mao Y.K.
        • Wang B.
        • Huizinga J.D.
        • Bienenstock J.
        • Kunze W.
        Lactobacillus reuteri ingestion prevents hyperexcitability of colonic DRG neurons induced by noxious stimuli.
        Am J Physiol Gastrointest Liver Physiol. 2009; 296: G868-G875
        • Kunze W.A.
        • Mao Y.K.
        • Wang B.
        • Huizinga J.D.
        • Ma X.
        • Forsythe P.
        • Bienenstock J.
        Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening.
        J Cell Mol Med. 2009; 13: 2261-2270
        • Duca F.A.
        • Swartz T.D.
        • Sakar Y.
        • Covasa M.
        Increased oral detection, but decreased intestinal signaling for fats in mice lacking gut microbiota.
        PLoS One. 2012; 7: e39748
        • Vijay-Kumar M.
        • Aitken J.D.
        • Carvalho F.A.
        • Cullender T.C.
        • Mwangi S.
        • Srinivasan S.
        • Sitaraman S.V.
        • Knight R.
        • Ley R.E.
        • Gewirtz A.T.
        Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.
        Science. 2010; 328: 228-231
        • Tanida M.
        • Yamano T.
        • Maeda K.
        • Okumura N.
        • Fukushima Y.
        • Nagai K.
        Effects of intraduodenal injection of Lactobacillus johnsonii La1 on renal sympathetic nerve activity and blood pressure in urethane-anesthetized rats.
        Neurosci Lett. 2005; 389: 109-114
        • Mayer E.A.
        • Tillisch K.
        • Gupta A.
        Gut/brain axis and the microbiota.
        J Clin Invest. 2015; 125: 926-938
        • Mayer E.A.
        • Knight R.
        • Mazmanian S.K.
        • Cryan J.F.
        • Tillisch K.
        Gut microbes and the brain: paradigm shift in neuroscience.
        J Neurosci. 2014; 34: 15490-15496
        • Bercik P.
        • Collins S.M.
        • Verdu E.F.
        Microbes and the gut-brain axis.
        Neurogastroenterol Motil. 2012; 24: 405-413
        • Martin C.R.
        • Mayer E.A.
        Gut-brain axis and behavior.
        Nestle Nutr Inst Workshop Ser. 2017; 88: 45-53
        • Sharon G.
        • Sampson T.R.
        • Geschwind D.H.
        • Mazmanian S.K.
        The central nervous system and the gut microbiome.
        Cell. 2016; 167: 915-932
        • Grill M.F.
        • Maganti R.K.
        Neurotoxic effects associated with antibiotic use: management considerations.
        Br J Clin Pharmacol. 2011; 72: 381-393
        • Mohle L.
        • Mattei D.
        • Heimesaat M.M.
        • Bereswill S.
        • Fischer A.
        • Alutis M.
        • French T.
        • Hambardzumyan D.
        • Matzinger P.
        • Dunay I.R.
        • Wolf S.A.
        Ly6C(hi) monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis.
        Cell Rep. 2016; 15: 1945-1956
        • Messaoudi M.
        • Lalonde R.
        • Violle N.
        • Javelot H.
        • Desor D.
        • Nejdi A.
        • Bisson J.F.
        • Rougeot C.
        • Pichelin M.
        • Cazaubiel M.
        • Cazaubiel J.M.
        Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.
        Br J Nutr. 2011; 105: 755-764
        • Kantak P.A.
        • Bobrow D.N.
        • Nyby J.G.
        Obsessive-compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus rhamnosus GG).
        Behav Pharmacol. 2014; 25: 71-79
        • D'Mello C.
        • Ronaghan N.
        • Zaheer R.
        • Dicay M.
        • Le T.
        • MacNaughton W.K.
        • Surrette M.G.
        • Swain M.G.
        Probiotics improve inflammation-associated sickness behavior by altering communication between the peripheral immune system and the brain.
        J Neurosci. 2015; 35: 10821-10830
        • Cowan C.S.
        • Callaghan B.L.
        • Richardson R.
        The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats.
        Transl Psychiatry. 2016; 6: e823
        • David L.A.
        • Maurice C.F.
        • Carmody R.N.
        • Gootenberg D.B.
        • Button J.E.
        • Wolfe B.E.
        • Ling A.V.
        • Devlin A.S.
        • Varma Y.
        • Fischbach M.A.
        • Biddinger S.B.
        • Dutton R.J.
        • Turnbaugh P.J.
        Diet rapidly and reproducibly alters the human gut microbiome.
        Nature. 2014; 505: 559-563
        • Carmody R.N.
        • Gerber G.K.
        • Luevano Jr., J.M.
        • Gatti D.M.
        • Somes L.
        • Svenson K.L.
        • Turnbaugh P.J.
        Diet dominates host genotype in shaping the murine gut microbiota.
        Cell Host Microbe. 2015; 17: 72-84