The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems

Marilia Carabotti, Annunziata Scirocco, Maria Antonietta Maselli, Carola Severi, Marilia Carabotti, Annunziata Scirocco, Maria Antonietta Maselli, Carola Severi

Abstract

The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent advances in research have described the importance of gut microbiota in influencing these interactions. This interaction between microbiota and GBA appears to be bidirectional, namely through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved. Most of the data have been acquired using technical strategies consisting in germ-free animal models, probiotics, antibiotics, and infection studies. In clinical practice, evidence of microbiota-GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety-depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel syndrome can be considered an example of the disruption of these complex relationships, and a better understanding of these alterations might provide new targeted therapies.

Keywords: Gut-brain axis; central nervous system; enteric microbiota; enteric nervous system; irritable bowel syndrome.

Conflict of interest statement

Conflict of Interest: None

Figures

Figure 1
Figure 1
Microbiome gut-brain axis structure The central nervous system and in particular hypothalamic pituitary adrenal (HPA) axis (in dashed line) can be activated in response to environmental factors, such as emotion or stress. HPA is finalized to cortisol release and is driven by a complex interaction between amygdala (AMG), hippocampus (HIPP), and hypothalamus (HYP), constituting the limbic system. HYP secretion of the corticotropin-releasing factor (CRF) stimulates adrenocorticotropic hormone (ACTH) secretion from pituitary gland that, in turn, leads to cortisol release from the adrenal glands. In parallel, central nervous system communicate along both afferent and efferent autonomic pathways (SNA) with different intestinal targets such as enteric nervous system (ENS), muscle layers and gut mucosa, modulating motility, immunity, permeability and secretion of mucus. The enteric microbiota has a bidirectional communication with these intestinal targets, modulating gastrointestinal functions and being itself modulated by brain-gut interactions

References

    1. Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 2009;6:306–314.
    1. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865–871.
    1. Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology. 2014;146:1500–1512.
    1. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–1638.
    1. Morgan MY. The treatment of chronic hepatic encephalopathy. Hepatogastroenterology. 1991;38:377–387.
    1. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–312.
    1. Naseribafrouei A, Hestad K, Avershina E, et al. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil. 2014;26:1155–1162.
    1. Mayer EA, Padua D, Tillisch K. Altered brain-gut axis in autism: comorbidity or causative mechanisms? Bioessays. 2014;36:933–999.
    1. Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol. 2004;70:6459–6465.
    1. Simrén M, Barbara G, Flint HJ, et al. Rome Foundation Committee. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62:159–176.
    1. Mayer EA, Tillisch K. The brain-gut axis in abdominal pain syndromes. Annu Rev Med. 2011;62:381–396.
    1. Berrill JW, Gallacher J, Hood K, et al. An observational study of cognitive function in patients with irritable bowel syndrome and inflammatory bowel disease. Neurogastroenterol Motil. 2013;25:918–e704.
    1. Koloski NA, Jones M, Kalantar J, Weltman M, Zaguirre J, Talley NJ. The brain-gut pathway in functional gastrointestinal disorders is bidirectional: a 12-year prospective population-based study. Gut. 2012;61:1284–1290.
    1. Dupont HL. Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Ther. 2014;39:1033–1042.
    1. Spiller R, Lam C. An Update on Post-infectious Irritable Bowel Syndrome: Role of Genetics, Immune Activation, Sero- tonin and Altered Microbiome. J Neurogastroenterol Motil. 2012;18:258–268.
    1. Quigley EM. Small intestinal bacterial overgrowth: what it 77 is and what it is not. Curr Opin Gastroenterol. 2014;30:141–146.
    1. Pimentel M, Lembo A, Chey WD, et al. TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364:22–32.
    1. Crouzet L, Gaultier E, Del’Homme C, et al. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogastroenterol Motil. 2013;25:e272–e282.
    1. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Irritable bowel syndrome: A microbiome-gut-brain axis disorder? World J Gastroenterol. 2014;20:14105–14125.
    1. Bravo JA, Julio-Pieper M, Forsythe P, et al. Communication between gastrointestinal bacteria and the nervous system. Curr Opin Pharmacol. 2012;12:667–672.
    1. Barbara G, Stanghellini V, Brandi G, et al. Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol. 2005;100:2560–2568.
    1. Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain and behaviour - epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014;13:69–86.
    1. Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18:666–673.
    1. 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.
    1. Abrams GD, Bishop JE. Effect of the normal microbial flora on gastrointestinal motility. Proc Soc Exp Biol Med. 1967;126:301–304.
    1. Iwai H, Ishihara Y, Yamanaka J, Ito T. Effects of bacterial flora on cecal size and transit rate of intestinal contents in mice. Jpn J Exp Med. 1973;43:297–305.
    1. Caenepeel P, Janssens J, Vantrappen G, Eyssen H, Coremans G. Interdigestive myoelectric complex in germ-free rats. Dig Dis Sci. 1989;34:1180–1184.
    1. Husebye E, Hellström PM, Sundler F, Chen J, Midtvedt T. Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats. Am J Physiol Gastrointest Liver Physiol. 2001;280:G368–G380.
    1. Wostmann E, Bruckner-Kardoss E. Development of cecal distention in germ-free baby rats. Am J Physiol. 1959;197:1345–1346.
    1. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science. 2001;291:881–884.
    1. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011;23:255–264.
    1. Neufeld KA, Kang N, Bienenstock J, Foster JA. Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol. 2011;4:492–494.
    1. Nishino, Mikami K, Takahashi H, et al. Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods. Neurogastroenterol Motil. 2013;25:521–528.
    1. 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.
    1. Gareau MG, Wine E, Rodrigues DM, et al. Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 2011;60:307–317.
    1. Al-Qudah M, Anderson CD, Mahavadi S, et al. Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C. Am J Physiol Gastrointest Liver Physiol. 2014;306:G328–G337.
    1. Saulnier DM, Ringel Y, Heyman MB, et al. The intestinal microbiome, probiotics and prebiotics in neurogastroenterology. Gut Microbes. 2013;4:17–27.
    1. Bravo JA, Forsythe P, Chew MV, 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.
    1. Bercik P, Denou E, Collins J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141:599–609.
    1. Distrutti E, O’Reilly JA, McDonald C, et al. Modulation of intestinal microbiota by the probiotic VSL#3 resets brain gene expression and ameliorates the age-related deficit in LTP. PLoS One. 2014;9:e106503.
    1. Distrutti E, Cipriani S, Mencarelli A, Renga B, Fiorucci S. Probiotics VSL#3 protect against development of visceral pain in murine model of irritable bowel syndrome. PLoS One. 2013;8:e63893.
    1. Bercik P, Park AJ, Sinclair D, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain Communication. Neurogastroenterol Motil. 2011;23:1132–1139.
    1. Ait-Belgnaoui A, Colom A, Braniste V, et al. Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterol Motil. 2014;26:510–520.
    1. Kunze WA, Mao YK, Wang B, et al. Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening. J Cell Mol Med. 2009;13:2261–2270.
    1. Iyer LM, Aravind L, Coon SL, Klein DC, Koonin EV. Evolution of cell-cell signaling in animals: did late horizontal gene transfer from bacteria have a role? Trends Genet. 2004;20:292–299.
    1. 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.
    1. Sobko T, Huang L, Midtvedt T, et al. Generation of NO by probiotic bacteria in the gastrointestinal Tract. Free Radic Biol Med. 2006;41:985–991.
    1. Schicho R, Krueger D, Zeller F, et al. Hydrogen sulfide is a novel prosecretory neuromodulator in the Guinea-pig and human colon. Gastroenterology. 2006;131:1542–1552.
    1. Kimura I, Inoue D, Maeda T, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41) Proc Natl Acad Sci U S A. 2011;108:8030–8035.
    1. Grider JR, Piland BE. The peristaltic reflex induced by short-chain fatty acids is mediated by sequential release of 5-HT and neuronal CGRP but not BDNF. Am J Physiol Gastrointest Liver Physiol. 2007;292:G429–G437.
    1. Vecsey CG, Hawk JD, Lattal KM, et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. J Neurosci. 2007;27:6128–6140.
    1. Stefanko DP, Barrett RM, Ly AR, Reolon GK, Wood MA. Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci U S A. 2009;106:9447–9452.
    1. Li W, Dowd SE, Scurlock B, Acosta-Martinez V, Lyte M. Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria. Physiol Behav. 2009;96:557–567.
    1. Uribe A, Alam M, Johansson O, Midtvedt T, Theodorsson E. Microflora modulates endocrine cells in the gastrointestinal mucosa of the rat. Gastroenterology. 1994;107:1259–1269.
    1. Tortorella C, Neri G, Nussdorfer GG. Galanin in the regulation of the hypothalamic-pituitary-adrenal axis (Review) Int J Mol Med. 2007;19:639–647.
    1. Giordano R, Pellegrino M, Picu A, et al. Neuroregulation of the hypothalamus-pituitary-adrenal (HPA) axis in humans: effects of GABA-, mineralocorticoid-, and GH-Secretagogue-receptor modulation. Sci World J. 2006;17:1–11.
    1. Verdú EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55:182–190.
    1. Saito T, Bunnett NW. Protease-activated receptors: regulation of neuronal function. Neuromolecular Med. 2005;7:79–99.
    1. Biancheri P, Di Sabatino A, Corazza GR, MacDonald TT. Proteases and the gut barrier. Cell Tissue Res. 2013;351:269–280.
    1. Gecse K, Róka 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.
    1. Carroll IM, Ringel-Kulka T, Ferrier L, et al. Fecal protease activity is associated with compositional alterations in the intestinal microbiota. PLoS One. 2013;8:e78017.
    1. Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. 2009;136:2003–2014.
    1. Theodorou V, Ait Belgnaoui A, Agostini S, Eutamene H. Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome. Gut Microbes. 2014;5:430–436.
    1. Budzyński J, Kłopocka M. Brain-gut axis in the pathogenesis of Helicobacter pylori infection. World J Gastroenterol. 2014;20:5212–5225.
    1. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcerdyspepsia. Cochrane Database Syst Rev. 2006 Apr 19;2:CD002096. Review. Update in: Cochrane Database Syst Rev 2011;(2): CD002096.
    1. Galley JD, Nelson MC, Yu Z, et al. Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota. BMC Microbiol. 2014;14:189.
    1. Hughes DT, Sperandio V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Microbiol. 2008;6:111–120.
    1. Guthrie GD, Nicholson-Guthrie CS. Gamma-Aminobutyric acid uptake by a bacterial system with neurotransmitter binding characteristics. Proc Natl Acad Sci U S A. 1989;86:7378–7381.
    1. Clarke MB, Hughes DT, Zhu C, Boedeker EC, Sperandio V. The QseC sensor kinase: a bacterial adrenergic receptor. Proc Natl Acad Sci U S A. 2006;103:10420–10425.
    1. Macfarlane S, Dillon JF. Microbial biofilms in the human gastrointestinal Tract. J Appl Microbiol. 2007;102:1187–1196.
    1. Rubio CA, Huang CB. Quantification of the sulphomucin-producing cell population of the colonic mucosa during protracted stress in rats. In Vivo. 1992;6:81–84.
    1. Gué M, Peeters T, Depoortere I, Vantrappen G, Buéno L. Stress-induced changes in gastric emptying, postprandial motility, and plasma gut hormone levels in dogs. Gastroenterology. 1989;97:1101–1107.
    1. Gué M, Junien JL, Bueno L. Conditioned emotional response in rats enhances colonic motility through the central release of corticotropin-releasing factor. Gastroenterology. 1991;100:964–970.
    1. 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. Gut. 2006;55:655–661.
    1. 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.
    1. Söderholm JD, Yates DA, Gareau MG, Yang PC, MacQueen G, Perdue MH. 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.
    1. Varghese AK, Verdú EF, Bercik P, et al. Antidepressants attenuate increased susceptibility to colitis in a murine model of depression. Gastroenterology. 2006;130:1743–1753.
    1. Park AJ, Collins J, Blennerhassett PA, et al. Altered colonic function and microbiota profile in a mouse model of chronic depression. Neurogastroenterol Motil. 2013;25:733–e575.
    1. 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.
    1. 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.
    1. Cogan TA, Thomas AO, Rees LE, et al. Norepinephrine increases the pathogenic potential of Campylobacter jejuni. Gut. 2007;56:1060–1065.
    1. Freestone PP, Williams PH, Haigh RD, Maggs AF, Neal CP, Lyte M. Growth stimulation of intestinal commensal Escherichia coli by catecholamines: a possible contributory factor in trauma-induced sepsis. Shock. 2002;18:465–470.
    1. Freestone PP, Haigh RD, Williams PH, Lyte M. Involvement of enterobactin in norepinephrine-mediated iron supply from transferrin to enterohaemorrhagic Escherichia coli. FEMS Microbiol Lett. 2003;222:39–43.

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