The microbiota–gut–brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both?

The gut–brain axis is the bidirectional communication between the gut and the brain, which occurs through multiple pathways that include hormonal, neural and immune mediators. The signals along this axis can originate in the gut, the brain or both, with the objective of maintaining normal gut function and appropriate behaviour. In recent years, the study of gut microbiota has become one of the most important areas in biomedical research. Attention has focused on the role of gut microbiota in determining normal gut physiology and immunity and, more recently, on its role as modulator of host behaviour (‘microbiota–gut–brain axis’). We therefore review the literature on the role of gut microbiota in gut homeostasis and link it with mechanisms that could influence behaviour. We discuss the association of dysbiosis with disease, with particular focus on functional bowel disorders and their relationship to psychological stress. This is of particular interest because exposure to stressors has long been known to increase susceptibility to and severity of gastrointestinal diseases.

[1]  D. Fuchs,et al.  Lactose Malabsorption Is Associated with Early Signs of Mental Depression in Females (A Preliminary Report) , 1998, Digestive Diseases and Sciences.

[2]  H. Szechtman,et al.  Antidepressants attenuate increased susceptibility to colitis in a murine model of depression. , 2006, Gastroenterology.

[3]  P. Bercik,et al.  Altered colonic function and microbiota profile in a mouse model of chronic depression , 2013, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[4]  M. Gareau,et al.  Pathophysiological mechanisms of stress-induced intestinal damage. , 2008, Current molecular medicine.

[5]  J. Söderholm,et al.  Stress and gastrointestinal tract. II. Stress and intestinal barrier function. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[6]  T. Dinan,et al.  Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour , 2010, Stress.

[7]  Y. Benno,et al.  Cerebral Low-Molecular Metabolites Influenced by Intestinal Microbiota: A Pilot Study , 2013, Front. Syst. Neurosci..

[8]  R. Shulman,et al.  Brain-gut microbiome interactions and functional bowel disorders. , 2014, Gastroenterology.

[9]  T. Dinan,et al.  Bifidobacterium breve with α-Linolenic Acid and Linoleic Acid Alters Fatty Acid Metabolism in the Maternal Separation Model of Irritable Bowel Syndrome , 2012, PloS one.

[10]  C P Buchanan,et al.  Short-Term Benefit From Oral Vancomycin Treatment of Regressive-Onset Autism , 2000, Journal of child neurology.

[11]  K. Strandberg,et al.  Effects of microbial contamination on the cecum enlargement of germfree rats. , 1970, Scandinavian journal of gastroenterology.

[12]  H. Eutamene,et al.  Role of probiotics in correcting abnormalities of colonic flora induced by stress , 2007, Gut.

[13]  Kazufumi Yoshihara,et al.  Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[14]  J. Petrosino,et al.  Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders , 2013, Cell.

[15]  H. Sternbach,et al.  Antibiotics: Neuropsychiatric Effects and Psychotropic Interactions , 1997, Harvard review of psychiatry.

[16]  Frederic D Bushman,et al.  Rapid evolution of the human gut virome , 2013, Proceedings of the National Academy of Sciences.

[17]  Justin C.Y. Wu Psychological Co-morbidity in Functional Gastrointestinal Disorders: Epidemiology, Mechanisms and Management , 2012, Journal of neurogastroenterology and motility.

[18]  M. Angley,et al.  Low Relative Abundances of the Mucolytic Bacterium Akkermansia muciniphila and Bifidobacterium spp. in Feces of Children with Autism , 2011, Applied and Environmental Microbiology.

[19]  T. Dinan,et al.  Early-life stress induces visceral hypersensitivity in mice , 2012, Neuroscience Letters.

[20]  S. Dowd,et al.  Exposure to a social stressor alters the structure of the intestinal microbiota: Implications for stressor-induced immunomodulation , 2011, Brain, Behavior, and Immunity.

[21]  Y. Sanz,et al.  Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children , 2010, BMC Microbiology.

[22]  L. Desbonnet,et al.  Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression , 2010, Neuroscience.

[23]  F. Bäckhed,et al.  The gut microbiota — masters of host development and physiology , 2013, Nature Reviews Microbiology.

[24]  Joshua LaBaer,et al.  Reduced Incidence of Prevotella and Other Fermenters in Intestinal Microflora of Autistic Children , 2013, PloS one.

[25]  E. Quigley,et al.  Hepatic encephalopathy involves interactions among the microbiota, gut, brain. , 2014, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[26]  W. Whitehead,et al.  Which psychological factors exacerbate irritable bowel syndrome? Development of a comprehensive model. , 2013, Journal of psychosomatic research.

[27]  J. Pruessner,et al.  Neuropathology of stress , 2013, Acta Neuropathologica.

[28]  S. Finegold,et al.  Microbiology of regressive autism. , 2012, Anaerobe.

[29]  John F. Cryan,et al.  Maternal separation as a model of brain–gut axis dysfunction , 2011, Psychopharmacology.

[30]  D. Raoult,et al.  Human Gut Microbiota: Repertoire and Variations , 2012, Front. Cell. Inf. Microbio..

[31]  F. Shanahan,et al.  Categorization of the gut microbiota: enterotypes or gradients? , 2012, Nature Reviews Microbiology.

[32]  R. Sapolsky,et al.  How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. , 2000, Endocrine reviews.

[33]  S. Dowd,et al.  Stressor Exposure Disrupts Commensal Microbial Populations in the Intestines and Leads to Increased Colonization by Citrobacter rodentium , 2010, Infection and Immunity.

[34]  G. Bergonzelli,et al.  Nutritional Approach to Restore Impaired Intestinal Barrier Function and Growth After Neonatal Stress in Rats , 2006, Journal of pediatric gastroenterology and nutrition.

[35]  S. Collins,et al.  The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications. , 2013, Current opinion in microbiology.

[36]  Tanmay Parekh,et al.  Application of Novel PCR-Based Methods for Detection, Quantitation, and Phylogenetic Characterization of Sutterella Species in Intestinal Biopsy Samples from Children with Autism and Gastrointestinal Disturbances , 2012, mBio.

[37]  S. Collins,et al.  The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. , 2009, Gastroenterology.

[38]  J. Cubells,et al.  The Gut Microbiome: A New Frontier in Autism Research , 2013, Current Psychiatry Reports.

[39]  D. Fuchs,et al.  Carbohydrate Malabsorption Syndromes and Early Signs of Mental Depression in Females , 2000, Digestive Diseases and Sciences.

[40]  T. Dinan,et al.  Differential activation of the prefrontal cortex and amygdala following psychological stress and colorectal distension in the maternally separated rat , 2014, Neuroscience.

[41]  B. Wostmann The germfree animal in nutritional studies. , 1981, Annual review of nutrition.

[42]  Z. Bian,et al.  Neonatal maternal separation enhances central sensitivity to noxious colorectal distention in rat , 2007, Brain Research.

[43]  F. Bäckhed Programming of Host Metabolism by the Gut Microbiota , 2011, Annals of Nutrition and Metabolism.

[44]  E. Zoetendal,et al.  High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota , 2008, Gut.

[45]  S. Rabot,et al.  Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  F. Barreau,et al.  New Insights in the Etiology and Pathophysiology of Irritable Bowel Syndrome: Contribution of Neonatal Stress Models , 2007, Pediatric Research.

[47]  W. Jackson,et al.  Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. , 2010, Gastroenterology.

[48]  T. Dinan,et al.  Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders. , 2011, The international journal of neuropsychopharmacology.

[49]  M. Heikenwalder,et al.  Reversible Microbial Colonization of Germ-Free Mice Reveals the Dynamics of IgA Immune Responses , 2010, Science.

[50]  Y. Sanz,et al.  Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease , 2008, Journal of Clinical Pathology.

[51]  P. Lundberg,et al.  Brain responses to visceral stimuli reflect visceral sensitivity thresholds in patients with irritable bowel syndrome. , 2012, Gastroenterology.

[52]  C. Nemeroff,et al.  Long-term behavioral and neuroendocrine adaptations to adverse early experience. , 2000, Progress in brain research.

[53]  M. Angley,et al.  Elevated Fecal Short Chain Fatty Acid and Ammonia Concentrations in Children with Autism Spectrum Disorder , 2012, Digestive Diseases and Sciences.

[54]  E R Bolte,et al.  Autism and Clostridium tetani. , 1998, Medical hypotheses.

[55]  C. Coe,et al.  Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. , 1999, Developmental psychobiology.

[56]  M. Ramírez,et al.  Effects of maternal separation on hypothalamic–pituitary–adrenal responses, cognition and vulnerability to stress in adult female rats , 2008, Neuroscience.

[57]  G. MacQueen,et al.  Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation , 2007, Gut.

[58]  J. Nicholson,et al.  Host-Gut Microbiota Metabolic Interactions , 2012, Science.

[59]  M. Teixeira,et al.  Commensal microbiota is fundamental for the development of inflammatory pain , 2008, Proceedings of the National Academy of Sciences.

[60]  Peer Bork,et al.  Enterotypes of the human gut microbiome , 2011, Nature.

[61]  G. Tannock,et al.  The effect of food and water deprivation (stress) on Salmonella-carrier mice. , 1972, Journal of medical microbiology.

[62]  F. Bushman,et al.  The human gut virome: inter-individual variation and dynamic response to diet. , 2011, Genome research.

[63]  B. Berger,et al.  The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut–brain communication , 2011, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[64]  S. Hapfelmeier,et al.  Intestinal bacterial colonization induces mutualistic regulatory T cell responses. , 2011, Immunity.

[65]  S. Collins Stress and the Gastrointestinal Tract IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[66]  M. Angley,et al.  Increased abundance of Sutterella spp. and Ruminococcus torques in feces of children with autism spectrum disorder , 2013, Molecular Autism.

[67]  A. K. Hansen,et al.  Patterns of Early Gut Colonization Shape Future Immune Responses of the Host , 2012, PloS one.

[68]  G. Abrams,et al.  Effect of the Normal Microbial Flora on Gastrointestinal Motility.∗ , 1967, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[69]  J. Foster,et al.  The role of luminal factors in the recovery of gastric function and behavioral changes after chronic Helicobacter pylori infection , 2008 .

[70]  N. Track The gastrointestinal endocrine system. , 1980, Canadian Medical Association journal.

[71]  H. Abelaira,et al.  Animal models as tools to study the pathophysiology of depression. , 2013, Revista brasileira de psiquiatria.

[72]  M. Icaza-Chávez Gut microbiota in health and disease , 2013 .

[73]  C. Cartier,et al.  Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats. , 2004, Gastroenterology.

[74]  Thomas F. Tedder,et al.  Innate and Adaptive Immunity Cooperate Flexibly to Maintain Host-Microbiota Mutualism , 2009, Science.

[75]  Dan J Stein,et al.  Maternal Separation in Rats Leads to Anxiety-Like Behavior and a Blunted ACTH Response and Altered Neurotransmitter Levels in Response to a Subsequent Stressor , 2004, Metabolic Brain Disease.

[76]  John C. Lindon,et al.  Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. , 2010, Journal of proteome research.

[77]  J. Neu Normal gut microbiota modulates brain development and behavior , 2012 .

[78]  R. Knight,et al.  Evolution of Mammals and Their Gut Microbes , 2008, Science.

[79]  Kirsten Tillisch,et al.  Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. , 2011, Gastroenterology.

[80]  S. Cole,et al.  Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis , 2013, Proceedings of the National Academy of Sciences.

[81]  G. MacQueen,et al.  Neonatal Maternal Separation Causes Colonic Dysfunction in Rat Pups Including Impaired Host Resistance , 2006, Pediatric Research.

[82]  P. Scully,et al.  Early Life Stress Alters Behavior, Immunity, and Microbiota in Rats: Implications for Irritable Bowel Syndrome and Psychiatric Illnesses , 2009, Biological Psychiatry.

[83]  Mark Lyte,et al.  Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics , 2011, BioEssays : news and reviews in molecular, cellular and developmental biology.

[84]  J. Ochoa-Repáraz,et al.  Gut, bugs, and brain: Role of commensal bacteria in the control of central nervous system disease , 2011, Annals of neurology.

[85]  Andre Franke,et al.  Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function , 2012, Science.

[86]  R. Murison,et al.  Neonatal maternal separation in male rats increases intestinal permeability and affects behavior after chronic social stress , 2012, Physiology & Behavior.

[87]  C. Nemeroff,et al.  Long‐term behavioural and molecular alterations associated with maternal separation in rats , 2007, The European journal of neuroscience.

[88]  W. Hao Stress and intestinal barrier function , 2002 .

[89]  W. Vale,et al.  The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress , 2006, Dialogues in clinical neuroscience.

[90]  T. Brzozowski,et al.  STRESS AND THE GUT: PATHOPHYSIOLOGY, CLINICAL CONSEQUENCES, DIAGNOSTIC APPROACH AND TREATMENT OPTIONS , 2012 .

[91]  H. Eysenck Psychosomatic Research , 1965, Nature.

[92]  Jeffrey I. Gordon,et al.  Mechanisms underlying the resistance to diet-induced obesity in germ-free mice , 2007, Proceedings of the National Academy of Sciences.

[93]  Y. Sanz,et al.  Imbalance in the composition of the duodenal microbiota of children with coeliac disease. , 2007, Journal of medical microbiology.

[94]  S. Mehdi Antibiotic-induced psychosis: a link to D-alanine? , 2010, Medical hypotheses.

[95]  D. Hodgson,et al.  Effect of Maternal Probiotic Intervention on HPA Axis, Immunity and Gut Microbiota in a Rat Model of Irritable Bowel Syndrome , 2012, PloS one.

[96]  Emeran A. Mayer,et al.  Gut feelings: the emerging biology of gut–brain communication , 2011, Nature Reviews Neuroscience.

[97]  E. Distrutti,et al.  Probiotics VSL#3 Protect against Development of Visceral Pain in Murine Model of Irritable Bowel Syndrome , 2013, PloS one.

[98]  S. Collins IV. Modulation of intestinal inflammation by stress: basic mechanisms and clinical relevance , 2001 .

[99]  C. Olsson,et al.  Autonomic control of gut motility: A comparative view , 2011, Autonomic Neuroscience.

[100]  Eunseog Youn,et al.  Pyrosequencing study of fecal microflora of autistic and control children. , 2010, Anaerobe.

[101]  K. McCoy,et al.  Homeland security: IgA immunity at the frontiers of the body. , 2012, Trends in immunology.

[102]  J. Labus,et al.  Advances in imaging the brain-gut axis: functional gastrointestinal disorders. , 2011, Gastroenterology.

[103]  W. Lipkin,et al.  Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances , 2011, PloS one.

[104]  D. Fuchs,et al.  Fructose malabsorption is associated with early signs of mental depression. , 1998, European journal of medical research.

[105]  Weiwen Wang,et al.  Cognitive, emotional and neurochemical effects of repeated maternal separation in adolescent rats , 2013, Brain Research.

[106]  D. Fuchs,et al.  Fructose malabsorption is associated with decreased plasma tryptophan. , 1999, Advances in experimental medicine and biology.

[107]  J. Jury,et al.  Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[108]  M. Lyte,et al.  Stress at the intestinal surface: catecholamines and mucosa–bacteria interactions , 2010, Cell and Tissue Research.

[109]  R. Campos-Rodríguez,et al.  Stress modulates intestinal secretory immunoglobulin A , 2013, Front. Integr. Neurosci..

[110]  G. MacQueen,et al.  Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[111]  K. McCoy,et al.  The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. , 2011, Gastroenterology.

[112]  Vikram Bhatia,et al.  Stress and the gastrointestinal tract , 2005, Journal of gastroenterology and hepatology.

[113]  V. Théodorou,et al.  Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats. , 2007, The Journal of nutrition.

[114]  F. Barreau,et al.  Neonatal maternal deprivation triggers long term alterations in colonic epithelial barrier and mucosal immunity in rats , 2004, Gut.

[115]  J. Foster,et al.  Reduced anxiety‐like behavior and central neurochemical change in germ‐free mice , 2011, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[116]  D. Savage,et al.  Influences of Dietary and Environmental Stress on Microbial Populations in the Murine Gastrointestinal Tract , 1974, Infection and immunity.

[117]  Kyoko Takahashi,et al.  Commensal bacteria promote migration of mast cells into the intestine. , 2011, Immunobiology.

[118]  Marco Gobbetti,et al.  Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified , 2013, PloS one.

[119]  T. Dinan,et al.  Altered expression and secretion of colonic Interleukin-6 in a stress-sensitive animal model of brain-gut axis dysfunction , 2011, Journal of Neuroimmunology.

[120]  Elodie Ghedin,et al.  The human mycobiome in health and disease , 2013, Genome Medicine.

[121]  M. Surette,et al.  The interplay between the intestinal microbiota and the brain , 2012, Nature Reviews Microbiology.

[122]  Sebastian Tims,et al.  Long-term monitoring of the human intestinal microbiota composition. , 2013, Environmental microbiology.

[123]  Y. Ringel,et al.  Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome. , 2013, American journal of physiology. Gastrointestinal and liver physiology.

[124]  P. O’Toole,et al.  γ‐Aminobutyric acid production by culturable bacteria from the human intestine , 2012, Journal of applied microbiology.

[125]  S. Collins,et al.  Microbes and the gut‐brain axis , 2012, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[126]  E. Mayer,et al.  Principles and clinical implications of the brain–gut–enteric microbiota axis , 2009, Nature Reviews Gastroenterology &Hepatology.

[127]  M. Heitkemper,et al.  Is Childhood Abuse or Neglect Associated With Symptom Reports and Physiological Measures in Women With Irritable Bowel Syndrome? , 2011, Biological research for nursing.