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Brain–Gut Microbiome Interactions and Functional Bowel Disorders

  • Emeran A. Mayer
    Correspondence
    Reprint requests Address requests for reprints to: Emeran A. Mayer, MD, Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, CHS 42-210, MC737818, Los Angeles, California.
    Affiliations
    Oppenheimer Center for Neurobiology of Stress, Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
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  • Tor Savidge
    Affiliations
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas

    Texas Children's Microbiome Center, Department of Pathology, Houston, Texas

    Texas Children's Hospital, Houston, Texas
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  • Robert J. Shulman
    Affiliations
    Department of Pediatrics, Baylor College of Medicine, Houston, Texas

    Children's Nutrition Research Center, Houston, Texas

    Texas Children's Hospital, Houston, Texas
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      Alterations in the bidirectional interactions between the intestine and the nervous system have important roles in the pathogenesis of irritable bowel syndrome (IBS). A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. A small and poorly defined role for dysbiosis in the development of IBS symptoms has been established through characterization of altered intestinal microbiota in IBS patients and reported improvement of subjective symptoms after its manipulation with prebiotics, probiotics, or antibiotics. It remains to be determined whether IBS symptoms are caused by alterations in brain signaling from the intestine to the microbiota or primary disruption of the microbiota, and whether they are involved in altered interactions between the brain and intestine during development. We review the potential mechanisms involved in the pathogenesis of IBS in different groups of patients. Studies are needed to better characterize alterations to the intestinal microbiome in large cohorts of well-phenotyped patients, and to correlate intestinal metabolites with specific abnormalities in gut–brain interactions.

      Keywords

      Abbreviations used in this paper:

      ANS (autonomic nervous system), CNS (central nervous system), ENS (enteric nervous system), FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyol), GI (gastrointestinal), HPA (hypothalamus–pituitary–adrenal), IBS (irritable bowel syndrome), IBS-C (constipation subtype of irritable bowel syndrome), IBS-D (diarrhea subtype of irritable bowel syndrome), SCFA (short-chain fatty acid)
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      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
        • Frazier T.H.
        • DiBaise J.K.
        • McClain C.J.
        Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury.
        JPEN J Parenter Enteral Nutr. 2011; 35: 14S-20S
        • Round J.L.
        • Mazmanian S.K.
        The gut microbiota shapes intestinal immune responses during health and disease.
        Nat Rev Immunol. 2009; 9: 313-323
        • Forsythe P.
        • Kunze W.A.
        Voices from within: gut microbes and the CNS.
        Cell Mol Life Sci. 2013; 70: 55-69
        • Sudo N.
        • Chida Y.
        • Aiba Y.
        • et al.
        Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.
        J Physiol. 2004; 558: 263-275
        • Amaral F.A.
        • Sachs D.
        • Costa V.V.
        • et al.
        Commensal microbiota is fundamental for the development of inflammatory pain.
        Proc Natl Acad Sci U S A. 2008; 105: 2193-2197
        • 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
        • Bercik P.
        • Collins S.M.
        • Verdu E.F.
        Microbes and the gut-brain axis.
        Neurogastroenterol Motil. 2012; 24: 405-413
        • Camilleri M.
        • Lasch K.
        • Zhou W.
        Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome.
        Am J Physiol Gastrointest Liver Physiol. 2012; 303: G775-G785
        • Matricon J.
        • Meleine M.
        • Gelot A.
        • et al.
        Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome.
        Aliment Pharmacol Ther. 2012; 36: 1009-1031
        • Simren M.
        • Barbara G.
        • Flint H.J.
        • et al.
        Intestinal microbiota in functional bowel disorders: a Rome foundation report.
        Gut. 2013; 62: 159-176
        • Ringel Y.
        • Maharshak N.
        Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome.
        Am J Physiol Gastrointest Liver Physiol. 2013; 305: G529-G541
        • Hughes P.A.
        • Zola H.
        • Penttila I.A.
        • et al.
        Immune activation in irritable bowel syndrome: can neuroimmune interactions explain symptoms?.
        Am J Gastroenterol. 2013; 108: 1066-1074
        • Valdez-Morales E.E.
        • Overington J.
        • Guerrero-Alba R.
        • et al.
        Sensitization of peripheral sensory nerves by mediators from colonic biopsies of diarrhea-predominant irritable bowel syndrome patients: a role for PAR2.
        Am J Gastroenterol. 2013; 108: 1634-1643
        • Cani P.D.
        • Everard A.
        • Duparc T.
        Gut microbiota, enteroendocrine functions and metabolism.
        Curr Opin Pharmacol. 2013; 13: 935-940
        • Diaz Heijtz R.
        • Wang S.
        • Anuar F.
        • et al.
        Normal gut microbiota modulates brain development and behavior.
        Proc Natl Acad Sci U S A. 2011; 108: 3047-3052
        • Neufeld K.M.
        • Kang N.
        • Bienenstock J.
        • et al.
        Reduced anxiety-like behavior and central neurochemical change in germ-free mice.
        Neurogastroenterol Motil. 2011; 23 (e119): 255-264
        • Gareau M.G.
        • Wine E.
        • Rodrigues D.M.
        • et al.
        Bacterial infection causes stress-induced memory dysfunction in mice.
        Gut. 2011; 60: 307-317
        • Tillisch K.
        • Labus J.
        • Kilpatrick L.
        • et al.
        Consumption of fermented milk product with probiotic modulates brain activity.
        Gastroenterology. 2013; 144 (1401 e1–e4): 1394-1401
        • Backhed F.
        • Fraser C.M.
        • Ringel Y.
        • et al.
        Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications.
        Cell Host Microbe. 2012; 12: 611-622
        • Le Chatelier E.
        • Nielsen T.
        • Qin J.
        • et al.
        Richness of human gut microbiome correlates with metabolic markers.
        Nature. 2013; 500: 541-546
        • Methe B.A.
        • Nelson K.E.
        • Pop M.
        • et al.
        A framework for human microbiome research.
        Nature. 2012; 486: 215-221
        • Li K.
        • Bihan M.
        • Yooseph S.
        • et al.
        Analyses of the microbial diversity across the human microbiome.
        PLoS One. 2012; 7: e32118
        • Wang Z.K.
        • Yang Y.S.
        Upper gastrointestinal microbiota and digestive diseases.
        World J Gastroenterol. 2013; 19: 1541-1550
        • Kerckhoffs A.P.
        • Ben-Amor K.
        • Samsom M.
        • et al.
        Molecular analysis of faecal and duodenal samples reveals significantly higher prevalence and numbers of Pseudomonas aeruginosa in irritable bowel syndrome.
        J Med Microbiol. 2011; 60: 236-245
        • Pimentel M.F.
        • Giamarellos-Bourboulis E.J.
        • Pyleris E.
        • et al.
        The first large scale deep sequencing of the duodenal microbiome in irritable bowel syndrome reveals striking differences compared to healthy controls.
        Gastroenterology. 2013; 144: S59
        • Bailey M.T.
        • Coe C.L.
        Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys.
        Dev Psychobiol. 1999; 35: 146-155
        • Bailey M.T.
        • Karaszewski J.W.
        • Lubach G.R.
        • et al.
        In vivo adaptation of attenuated Salmonella typhimurium results in increased growth upon exposure to norepinephrine.
        Physiol Behav. 1999; 67: 359-364
        • Bailey M.T.
        • Lubach G.R.
        • Coe C.L.
        Prenatal stress alters bacterial colonization of the gut in infant monkeys.
        J Pediatr Gastroenterol Nutr. 2004; 38: 414-421
        • De Filippo C.
        • Cavalieri D.
        • Di Paola M.
        • et al.
        Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.
        Proc Natl Acad Sci U S A. 2010; 107: 14691-14696
        • Wu G.D.
        • Chen J.
        • Hoffmann C.
        • et al.
        Linking long-term dietary patterns with gut microbial enterotypes.
        Science. 2011; 334: 105-108
        • David L.A.
        • Maurice C.F.
        • Carmody R.N.
        • et al.
        Diet rapidly and reproducibly alters the human gut microbiome.
        Nature. 2014; 505: 559-563
        • Jeffery I.B.
        • O'Toole P.W.
        Diet-microbiota interactions and their implications for healthy living.
        Nutrients. 2013; 5: 234-252
        • Gwee K.A.
        Irritable bowel syndrome in developing countries–a disorder of civilization or colonization?.
        Neurogastroenterol Motil. 2005; 17: 317-324
        • Williams E.A.
        • Nai X.
        • Corfe B.M.
        Dietary intakes in people with irritable bowel syndrome.
        BMC Gastroenterol. 2011; 11: 9
        • Bohn L.
        • Storsrud S.
        • Simren M.
        Nutrient intake in patients with irritable bowel syndrome compared with the general population.
        Neurogastroenterol Motil. 2013; 25: 23-30.e1
        • El-Salhy M.
        • Ostgaard H.
        • Gundersen D.
        • et al.
        The role of diet in the pathogenesis and management of irritable bowel syndrome (review).
        Int J Mol Med. 2012; 29: 723-731
        • Jarrett M.
        • Heitkemper M.M.
        • Bond E.F.
        • et al.
        Comparison of diet composition in women with and without functional bowel disorder.
        Gastroenterol Nurs. 1994; 16: 253-258
        • Durban A.
        • Abellan J.J.
        • Jimenez-Hernandez N.
        • et al.
        Assessing gut microbial diversity from feces and rectal mucosa.
        Microb Ecol. 2011; 61: 123-133
        • Carroll I.M.
        • Ringel-Kulka T.
        • Keku T.O.
        • et al.
        Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome.
        Am J Physiol Gastrointest Liver Physiol. 2011; 301: G799-G807
        • Durban A.
        • Abellan J.J.
        • Jimenez-Hernandez N.
        • et al.
        Structural alterations of faecal and mucosa-associated bacterial communities in irritable bowel syndrome.
        Environ Microbiol Rep. 2012; 4: 242-247
        • Jeffery I.B.
        • O'Toole P.W.
        • Ohman L.
        • et al.
        An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota.
        Gut. 2012; 61: 997-1006
        • McNulty N.P.
        • Yatsunenko T.
        • Hsiao A.
        • et al.
        The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins.
        Sci Transl Med. 2011; 3 (106ra106)
        • Kashyap P.C.
        • Marcobal A.
        • Ursell L.K.
        • et al.
        Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota.
        Proc Natl Acad Sci U S A. 2013; 110: 17059-17064
        • Kopečný J.
        • Šimůnek J.
        Cellulolytic bacteria in the human gut and irritable bowel syndrome.
        Acta Vet Brno. 2002; 71: 421-427
        • Le Gall G.
        • Noor S.O.
        • Ridgway K.
        • et al.
        Metabolomics of fecal extracts detects altered metabolic activity of gut microbiota in ulcerative colitis and irritable bowel syndrome.
        J Proteome Res. 2011; 10: 4208-4218
        • Mortensen P.B.
        • Andersen J.R.
        • Arffmann S.
        • et al.
        Short-chain fatty acids and the irritable bowel syndrome: the effect of wheat bran.
        Scand J Gastroenterol. 1987; 22: 185-192
        • Tana C.
        • Umesaki Y.
        • Imaoka A.
        • et al.
        Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome.
        Neurogastroenterol Motil. 2010; 22: 512-515
        • Treem W.R.
        • Ahsan N.
        • Kastoff G.
        • et al.
        Fecal short-chain fatty acids in patients with diarrhea-predominant irritable bowel syndrome: in vitro studies of carbohydrate fermentation.
        J Pediatr Gastroenterol Nutr. 1996; 23: 280-286
        • Kajander K.
        • Myllyluoma E.
        • Kyronpalo S.
        • et al.
        Elevated pro-inflammatory and lipotoxic mucosal lipids characterise irritable bowel syndrome.
        World J Gastroenterol. 2009; 15: 6068-6074
        • Ahmed I.
        • Greenwood R.
        • Costello Bde L.
        • et al.
        An investigation of fecal volatile organic metabolites in irritable bowel syndrome.
        PLoS One. 2013; 8: e58204
        • Halmos E.P.
        • Power V.A.
        • Shepherd S.J.
        • et al.
        A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.
        Gastroenterology. 2014; 146: 67-75
        • Biesiekierski J.R.
        • Peters S.L.
        • Newnham E.D.
        • et al.
        No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.
        Gastroenterology. 2013; 145 (320–328 e1–e3)
        • Whelan K.
        Probiotics and prebiotics in the management of irritable bowel syndrome: a review of recent clinical trials and systematic reviews.
        Curr Opin Clin Nutr Metab Care. 2011; 14: 581-587
        • Olesen M.
        • Gudmand-Hoyer E.
        Efficacy, safety, and tolerability of fructooligosaccharides in the treatment of irritable bowel syndrome.
        Am J Clin Nutr. 2000; 72: 1570-1575
        • Silk D.B.
        • Davis A.
        • Vulevic J.
        • et al.
        Clinical trial: the effects of a trans-galactooligosaccharide prebiotic on faecal microbiota and symptoms in irritable bowel syndrome.
        Aliment Pharmacol Ther. 2009; 29: 508-518
        • Sanders M.E.
        • Guarner F.
        • Guerrant R.
        • et al.
        An update on the use and investigation of probiotics in health and disease.
        Gut. 2013; 62: 787-796
        • Ortiz-Lucas M.
        • Tobias A.
        • Saz P.
        • et al.
        Effect of probiotic species on irritable bowel syndrome symptoms: a bring up to date meta-analysis.
        Rev Esp Enferm Dig. 2013; 105: 19-36
        • Horvath A.
        • Dziechciarz P.
        • Szajewska H.
        Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood.
        Aliment Pharmacol Ther. 2011; 33: 1302-1310
        • Menees S.B.
        • Maneerattannaporn M.
        • Kim H.M.
        • et al.
        The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis.
        Am J Gastroenterol. 2012; 107 (quiz 36): 28-35
        • Enck P.
        • Junne F.
        • Klosterhalfen S.
        • et al.
        Therapy options in irritable bowel syndrome.
        Eur J Gastroenterol Hepatol. 2010; 22: 1402-1411
        • Collins B.S.
        • Lin H.C.
        Double-blind, placebo-controlled antibiotic treatment study of small intestinal bacterial overgrowth in children with chronic abdominal pain.
        J Pediatr Gastroenterol Nutr. 2011; 52: 382-386
        • Sachdev A.H.
        • Pimentel M.
        Antibiotics for irritable bowel syndrome: rationale and current evidence.
        Curr Gastroenterol Rep. 2012; 14: 439-445
        • DuPont H.L.
        • Jiang Z.D.
        • Okhuysen P.C.
        • et al.
        A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers' diarrhea.
        Ann Intern Med. 2005; 142: 805-812
        • Cheng J.
        • Shah Y.M.
        • Gonzalez F.J.
        Pregnane X receptor as a target for treatment of inflammatory bowel disorders.
        Trends Pharmacol Sci. 2012; 33: 323-330
        • Xu D.
        • Gao J.
        • Gillilland 3rd, M.
        • et al.
        Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.
        Gastroenterology. 2014; 146: 484-496.e4
        • Spiller R.C.
        Postinfectious irritable bowel syndrome.
        Gastroenterology. 2003; 124: 1662-1671
        • Mendall M.A.
        • Kumar D.
        Antibiotic use, childhood affluence and irritable bowel syndrome (IBS).
        Eur J Gastroenterol Hepatol. 1998; 10: 59-62
        • Maxwell P.R.
        • Rink E.
        • Kumar D.
        • et al.
        Antibiotics increase functional abdominal symptoms.
        Am J Gastroenterol. 2002; 97: 104-108
        • Villarreal A.A.
        • Aberger F.J.
        • Benrud R.
        • et al.
        Use of broad-spectrum antibiotics and the development of irritable bowel syndrome.
        WMJ. 2012; 111: 17-20
        • Barbara G.
        • Stanghellini V.
        • Berti-Ceroni C.
        • et al.
        Role of antibiotic therapy on long-term germ excretion in faeces and digestive symptoms after Salmonella infection.
        Aliment Pharmacol Ther. 2000; 14: 1127-1131
        • Marild K.
        • Ye W.
        • Lebwohl B.
        • et al.
        Antibiotic exposure and the development of coeliac disease: a nationwide case-control study.
        BMC Gastroenterol. 2013; 13: 109
        • Trasande L.
        • Blustein J.
        • Liu M.
        • et al.
        Infant antibiotic exposures and early-life body mass.
        Int J Obes (Lond). 2013; 37: 16-23
        • Mayer E.A.
        The neurobiology of stress and gastrointestinal disease.
        Gut. 2000; 47: 861-869
        • Van Felius I.D.
        • Akkermans L.M.
        • Bosscha K.
        • et al.
        Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis.
        Neurogastroenterol Motil. 2003; 15: 267-276
        • Lembo A.
        • Camilleri M.
        Chronic constipation.
        N Engl J Med. 2003; 349: 1360-1368
        • Chey W.Y.
        • Jin H.O.
        • Lee M.H.
        • et al.
        Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea.
        Am J Gastroenterol. 2001; 96: 1499-1506
        • Macfarlane S.
        • Dillon J.F.
        Microbial biofilms in the human gastrointestinal tract.
        J Appl Microbiol. 2007; 102: 1187-1196
        • Alonso C.
        • Guilarte M.
        • Vicario M.
        • et al.
        Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation.
        Gastroenterology. 2008; 135: 163-172.e1
        • Groot J.
        • Bijlsma P.
        • Van Kalkeren A.
        • et al.
        Stress-induced decrease of the intestinal barrier function. The role of muscarinic receptor activation.
        Ann N Y Acad Sci. 2000; 915: 237-246
        • Jacob C.
        • Yang P.C.
        • Darmoul D.
        • et al.
        Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins.
        J Biol Chem. 2005; 280: 31936-31948
        • Kiliaan A.J.
        • Saunders P.R.
        • Bijlsma P.B.
        • et al.
        Stress stimulates transepithelial macromolecular uptake in rat jejunum.
        Am J Physiol. 1998; 275: G1037-G1044
        • Soderholm J.D.
        • Yates D.A.
        • Gareau M.G.
        • et al.
        Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress.
        Am J Physiol Gastrointest Liver Physiol. 2002; 283: G1257-G1263
        • Yates D.A.
        • Santos J.
        • Söderholm J.D.
        • et al.
        Adaptation of stress-induced mucosal pathophysiology in rat colon involves opioid pathways.
        Am J Physiol Gastrointest Liver Physiol. 2001; 281: G124-G128
        • Keita A.V.
        • Soderholm J.D.
        The intestinal barrier and its regulation by neuroimmune factors.
        Neurogastroenterol Motil. 2010; 22: 718-733
        • Bailey M.T.
        • Dowd S.E.
        • Parry N.M.
        • et al.
        Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium.
        Infect Immun. 2010; 78: 1509-1519
        • Tannock G.W.
        • Savage D.C.
        Influences of dietary and environmental stress on microbial populations in the murine gastrointestinal tract.
        Infect Immun. 1974; 9: 591-598
        • Bailey M.T.
        • Dowd S.E.
        • Galley J.D.
        • et al.
        Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation.
        Brain Behav Immun. 2011; 25: 397-407
        • Lyte M.
        • Freestone P.P.E.E.
        Microbial endocrinology: interkingdom signaling in health and disease.
        Springer Publishers, New York2010
        • Santos J.
        • Saperas E.
        • Nogueiras C.
        • et al.
        Release of mast cell mediators into the jejunum by cold pain stress in humans.
        Gastroenterology. 1998; 114: 640-648
        • Stephens R.L.
        • Tache Y.
        Intracisternal injection of a TRH analogue stimulates gastric luminal serotonin release in rats.
        Am J Physiol. 1989; 256: G377-G383
        • Yang H.
        • Stephens R.L.
        • Tache Y.
        TRH analogue microinjected into specific medullary nuclei stimulates gastric serotonin secretion in rats.
        Am J Physiol. 1992; 262: G216-G222
        • Alverdy J.
        • Holbrook C.
        • Rocha F.
        • et al.
        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.
        Ann Surg. 2000; 232: 480-489
        • Hughes D.T.
        • Sperandio V.
        Inter-kingdom signalling: communication between bacteria and their hosts.
        Nat Rev Microbiol. 2008; 6: 111-120
        • Asano Y.
        • Hiramoto T.
        • Nishino R.
        • et al.
        Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice.
        Am J Physiol Gastrointest Liver Physiol. 2012; 303: G1288-G1295
        • Lyte M.
        Microbial endocrinology and infectious disease in the 21st century.
        Trends Microbiol. 2004; 12: 14-20
        • Cogan T.A.
        • Thomas A.O.
        • Rees L.E.
        • et al.
        Norepinephrine increases the pathogenic potential of Campylobacter jejuni.
        Gut. 2007; 56: 1060-1065
        • Fish E.W.
        • Shahrokh D.
        • Bagot R.
        • et al.
        Epigenetic programming of stress responses through variations in maternal care.
        Ann N Y Acad Sci. 2004; 1036: 167-180
        • Meaney M.J.
        Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations.
        Ann Rev Neurosci. 2001; 24: 1161-1192
        • Cummings J.H.
        • Pomare E.W.
        • Branch W.J.
        • et al.
        Short chain fatty acids in human large intestine, portal, hepatic and venous blood.
        Gut. 1987; 28: 1221-1227
        • Smith P.M.
        • Howitt M.R.
        • Panikov N.
        • et al.
        The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.
        Science. 2013; 341: 569-573
        • Vinolo M.A.
        • Ferguson G.J.
        • Kulkarni S.
        • et al.
        SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor.
        PLoS One. 2011; 6: e21205
        • Layden B.T.
        • Angueira A.R.
        • Brodsky M.
        • et al.
        Short chain fatty acids and their receptors: new metabolic targets.
        Transl Res. 2013; 161: 131-140
        • Nepelska M.
        • Cultrone A.
        • Beguet-Crespel F.
        • et al.
        Butyrate produced by commensal bacteria potentiates phorbol esters induced AP-1 response in human intestinal epithelial cells.
        PLoS One. 2012; 7: e52869
        • Ganapathy V.
        • Thangaraju M.
        • Prasad P.D.
        • et al.
        Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host.
        Curr Opin Pharmacol. 2013; 13: 869-874
        • Bindels L.B.
        • Dewulf E.M.
        • Delzenne N.M.
        GPR43/FFA2: physiopathological relevance and therapeutic prospects.
        Trends Pharmacol Sci. 2013; 34: 226-232
        • Cresci G.A.
        • Thangaraju M.
        • Mellinger J.D.
        • et al.
        Colonic gene expression in conventional and germ-free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8.
        J Gastrointest Surg. 2010; 14: 449-461
        • Karaki S.
        • Mitsui R.
        • Hayashi H.
        • et al.
        Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine.
        Cell Tissue Res. 2006; 324: 353-360
        • Nohr M.K.
        • Pedersen M.H.
        • Gille A.
        • et al.
        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.
        Endocrinology. 2013; 154: 3552-3564
        • Vanhoutvin S.A.
        • Troost F.J.
        • Kilkens T.O.
        • et al.
        The effects of butyrate enemas on visceral perception in healthy volunteers.
        Neurogastroenterol Motil. 2009; 21 (952–e76)
        • Banasiewicz T.
        • Krokowicz L.
        • Stojcev Z.
        • et al.
        Microencapsulated sodium butyrate reduces the frequency of abdominal pain in patients with irritable bowel syndrome.
        Colorectal Dis. 2013; 15: 204-209
        • Camilleri M.
        Peripheral mechanisms in irritable bowel syndrome.
        N Engl J Med. 2012; 367: 1626-1635
        • Abrahamsson H.
        • Ostlund-Lindqvist A.M.
        • Nilsson R.
        • et al.
        Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation.
        Scand J Gastroenterol. 2008; 43: 1483-1488
        • Gecse K.
        • Roka R.
        • Ferrier L.
        • et al.
        Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity.
        Gut. 2008; 57: 591-599
        • Cenac N.
        • Andrews C.N.
        • Holzhausen M.
        • et al.
        Role for protease activity in visceral pain in irritable bowel syndrome.
        J Clin Invest. 2007; 117: 636-647
        • Annahazi A.
        • Ferrier L.
        • Bezirard V.
        • et al.
        Luminal cysteine-proteases degrade colonic tight junction structure and are responsible for abdominal pain in constipation-predominant IBS.
        Am J Gastroenterol. 2013; 108: 1322-1331
        • Saito T.
        • Bunnett N.W.
        Protease-activated receptors: regulation of neuronal function.
        Neuromolecular Med. 2005; 7: 79-99
        • Carroll I.M.
        • Ringel-Kulka T.
        • Ferrier L.
        • et al.
        Fecal protease activity is associated with compositional alterations in the intestinal microbiota.
        PLoS One. 2013; 8: e78017
        • Steck N.
        • Mueller K.
        • Schemann M.
        • et al.
        Bacterial proteases in IBD and IBS.
        Gut. 2012; 61: 1610-1618
        • Tooth D.
        • Garsed K.
        • Singh G.
        • et al.
        Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit.
        Gut. 2013; (Epub ahead of print)
        • Midtvedt T.
        • Zabarovsky E.
        • Norin E.
        • et al.
        Increase of faecal tryptic activity relates to changes in the intestinal microbiome: analysis of Crohn's disease with a multidisciplinary platform.
        PLoS One. 2013; 8: e66074
        • Barbara G.
        • Wang B.
        • Stanghellini V.
        • et al.
        Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome.
        Gastroenterology. 2007; 132: 26-37
        • Macfarlane G.T.
        • Allison C.
        • Gibson S.A.
        • et al.
        Contribution of the microflora to proteolysis in the human large intestine.
        J Appl Bacteriol. 1988; 64: 37-46
        • Roka R.
        • Rosztoczy A.
        • Leveque M.
        • et al.
        A pilot study of fecal serine-protease activity: a pathophysiologic factor in diarrhea-predominant irritable bowel syndrome.
        Clin Gastroenterol Hepatol. 2007; 5: 550-555
        • Balsari A.
        • Ceccarelli A.
        • Dubini F.
        • et al.
        The fecal microbial population in the irritable bowel syndrome.
        Microbiologica. 1982; 5: 185-194
        • Si J.M.
        • Yu Y.C.
        • Fan Y.J.
        • et al.
        Intestinal microecology and quality of life in irritable bowel syndrome patients.
        World J Gastroenterol. 2004; 10: 1802-1805
        • Matto J.
        • Maunuksela L.
        • Kajander K.
        • et al.
        Composition and temporal stability of gastrointestinal microbiota in irritable bowel syndrome–a longitudinal study in IBS and control subjects.
        FEMS Immunol Med Microbiol. 2005; 43: 213-222
        • Carroll I.M.
        • Chang Y.H.
        • Park J.
        • et al.
        Luminal and mucosal-associated intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome.
        Gut Pathog. 2010; 2: 19
        • Malinen E.
        • Rinttila T.
        • Kajander K.
        • et al.
        Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR.
        Am J Gastroenterol. 2005; 100: 373-382
        • Kerckhoffs A.P.
        • Samsom M.
        • van der Rest M.E.
        • et al.
        Lower Bifidobacteria counts in both duodenal mucosa-associated and fecal microbiota in irritable bowel syndrome patients.
        World J Gastroenterol. 2009; 15: 2887-2892
        • Rajilic-Stojanovic M.
        • Biagi E.
        • Heilig H.G.
        • et al.
        Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome.
        Gastroenterology. 2011; 141: 1792-1801
        • Saulnier D.M.
        • Riehle K.
        • Mistretta T.A.
        • et al.
        Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome.
        Gastroenterology. 2011; 141: 1782-1791
        • Krogius-Kurikka L.
        • Lyra A.
        • Malinen E.
        • et al.
        Microbial community analysis reveals high level phylogenetic alterations in the overall gastrointestinal microbiota of diarrhoea-predominant irritable bowel syndrome sufferers.
        BMC Gastroenterol. 2009; 9: 95
        • Moayyedi P.
        • Ford A.C.
        • Talley N.J.
        • et al.
        The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review.
        Gut. 2010; 59: 325-332
        • Hoveyda N.
        • Heneghan C.
        • Mahtani K.R.
        • et al.
        A systematic review and meta-analysis: probiotics in the treatment of irritable bowel syndrome.
        BMC Gastroenterol. 2009; 9: 15
        • McFarland L.V.
        • Dublin S.
        Meta-analysis of probiotics for the treatment of irritable bowel syndrome.
        World J Gastroenterol. 2008; 14: 2650-2661
        • Kamiya T.
        • Wang L.
        • Forsythe P.
        • et al.
        Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats.
        Gut. 2006; 55: 191-196
        • Rousseaux C.
        • Thuru X.
        • Gelot A.
        • et al.
        Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors.
        Nat Med. 2007; 13: 35-37
        • Verdu E.F.
        • Bercik P.
        • Verma-Gandhu M.
        • et al.
        Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice.
        Gut. 2006; 55: 182-190
        • Bercik P.
        • Verdu E.F.
        • Foster J.A.
        • et al.
        Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.
        Gastroenterology. 2010; 139: 2102-2112.e1
        • Bravo J.A.
        • Forsythe P.
        • Chew M.V.
        • et al.
        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