Through the gut-brain axis, the microorganisms that reside in the gut are able to exert an important influence on the central nervous system. Preclinical and clinical evidence suggests that alterations in the composition of the gut microbiota are involved in gastrointestinal and neurological disorders. During critical neurodevelopmental time periods, such as the early life, changes in gut microbial composition may detrimentally impact neurodevelopment, and subsequently lead to neurological disorders in later life. The finding that neurological disorders persist suggests that epigenetic modifications may be involved in response to disruption of the microbiota-gut-brain axis. Through establishing epigenetic modifications, environmental (microbial) signals can interfere with the cellular gene expression patterns. These long-lasting modifications exert their effects even when the initial stimulus is removed. In this review, we discuss the pathways that provide bidirectional communication between the microbiota and the central and peripheral nervous systems. Furthermore, we summarize how these microorganisms in the gut exert their influence through changing the epigenome in the brain-gut axis.
Impact statement
Alterations in the composition of gut microbiota may influence the etiology of gastrointestinal and neurological disorders by disturbing the communication in the gut-brain axis. Epigenetic changes in the gut-brain axis may perpetuate these phenotypes even when the gut microbiota has been restored. The studies reviewed in this article provide an overview of the influence the microbiota exerts onto its host’s epigenome. First, we summarize the bidirectional pathways through which the microbiota and the gut-brain axis communicate. Second, we provide evidence for the epigenome-altering capacity of the gut microbiota. Finally, we address the existing knowledge gaps and highlight the potential role of the epigenome in the microbiota-gut-brain axis.
SchemannM.Control of gastrointestinal motility by the “gut brain” – the enteric nervous system. J Pediatr Gastroenterol Nutr2005;
41: S4–6
4.
QinJLiRRaesJArumugamMBurgdorfKSManichanhCNielsenTPonsNLevenezFYamadaTMendeDRLiJXuJLiSLiDCaoJWangBLiangHZhengHXieYTapJLepagePBertalanMBattoJMHansenTLe PaslierDLinnebergANielsenHBPelletierERenaultPSicheritz-PontenTTurnerKZhuHYuCLiSJianMZhouYLiYZhangXLiSQinNYangHWangJBrunakSDoreJGuarnerFKristiansenKPedersenOParkhillJWeissenbachJMeta Hitc BorkPEhrlichSDWangJ.A human gut microbial gene catalogue established by metagenomic sequencing. Nature2010;
464:59–65
5.
AllenAPDinanTGClarkeGCryanJF.A psychology of the human brain-gut-microbiome axis. Soc Personal Psychol Compass2017;
11:e12309
6.
BercikPDenouECollinsJJacksonWLuJJuryJDengYBlennerhassettPMacriJMcCoyKDVerduEFCollinsSM.The intestinal microbiota affect Central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology2011;
141:599–609, 09 e1-3
7.
CryanJFDinanTG.Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci2012;
13:701–12
8.
FosterJAMcVey NeufeldKA.Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci2013;
36:305–12
9.
AdamsJBJohansenLJPowellLDQuigDRubinRA.Gastrointestinal flora and gastrointestinal status in children with autism – comparisons to typical children and correlation with autism severity. BMC Gastroenterol2011;
11:22
10.
JiangHLingZZhangYMaoHMaZYinYWangWTangWTanZShiJLiLRuanB.Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun2015;
48:186–94
11.
ParrachoHMBinghamMOGibsonGRMcCartneyAL.Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol2005;
54:987–91
12.
Rajilic-StojanovicMBiagiEHeiligHGKajanderKKekkonenRATimsSde VosWM.Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology2011;
141:1792–801
13.
SalonenAde VosWMPalvaA.Gastrointestinal microbiota in irritable bowel syndrome: present state and perspectives. Microbiology2010;
156:3205–15
14.
SongYLiuCFinegoldSM.Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol2004;
70:6459–65
15.
CrouzetLGaultierEDel'HommeCCartierCDelmasEDapoignyMFioramontiJBernalier-DonadilleA.The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogastroenterol Motil2013;
25:e272–82
16.
KellyJRBorreY, COPattersonEEl AidySDeaneJKennedyPJBeersSScottKMoloneyGHobanAEScottLFitzgeraldPRossPStantonCClarkeGCryanJFDinanTG.Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res2016;
82:109–18
17.
JohnsonACGreenwood-Van MeerveldBMcRorieJ.Effects of Bifidobacterium infantis 35624 on post-inflammatory visceral hypersensitivity in the rat. Dig Dis Sci2011;
56:3179–86
18.
KajanderKHatakkaKPoussaTFarkkilaMKorpelaR.A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention. Aliment Pharmacol Ther2005;
22:387–94
19.
KajanderKMyllyluomaERajilic-StojanovicMKyronpaloSRasmussenMJarvenpaaSZoetendalEGde VosWMVapaataloHKorpelaR.Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota. Aliment Pharmacol Ther2008;
27:48–57
20.
KamiyaTWangLForsythePGoettscheGMaoYWangYTougasGBienenstockJ.Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut2006;
55:191–6
21.
BurokasAArboleyaSMoloneyRDPetersonVLMurphyKClarkeGStantonCDinanTGCryanJF.Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol Psychiatry2017;
82:472–87
22.
HobanAEMoloneyRDGolubevaAVMcVey NeufeldKAO'SullivanOPattersonEStantonCDinanTGClarkeGCryanJF.Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat. Neuroscience2016;
339:463–77
23.
MessaoudiMLalondeRViolleNJavelotHDesorDNejdiABissonJFRougeotCPichelinMCazaubielMCazaubielJM.Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacteria longum R0175) in rats and human subjects. Br J Nutr2011;
105:755–64
24.
SavignacHMTramullasMKielyBDinanTGCryanJF.Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res2015;
287:59–72
25.
TarrAJGalleyJDFisherSEChichlowskiMBergBMBaileyMT.The prebiotics 3'Sialyllactose and 6'Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut-brain axis. Brain Behav Immun2015;
50:166–77
26.
ForsythePSudoNDinanTTaylorVHBienenstockJ.Mood and gut feelings. Brain Behav Immun2010;
24:9–16
27.
FurnessJBCallaghanBPRiveraLRChoHJ.The enteric nervous system and gastrointestinal innervation: integrated local and central control. Adv Exp Med Biol2014;
817:39–71
28.
BonazBBazinTPellissierS.The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci2018;
12:49
29.
LyteM.Microbial endocrinology and infectious disease in the 21st century. Trends Microbiol2004;
12:14–20
30.
ClarkeGGrenhamSScullyPFitzgeraldPMoloneyRDShanahanFDinanTGCryanJF.The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry2013;
18:666–73
31.
GuthrieGDNicholson-GuthrieCS.gamma-Aminobutyric acid uptake by a bacterial system with neurotransmitter binding characteristics. Proc Natl Acad Sci USA1989;
86:7378–81
32.
HughesDTSperandioV.Inter-kingdom signalling: communication between bacteria and their hosts. Nat Rev Microbiol2008;
6:111–20
33.
StephensRLTacheY.Intracisternal injection of a TRH analogue stimulates gastric luminal serotonin release in rats. Am J Physiol1989;
256:G377–83
34.
YanoJMYuKDonaldsonGPShastriGGAnnPMaLNaglerCRIsmagilovRFMazmanianSKHsiaoEY.Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell2015;
161:264–76
35.
WikoffWRAnforaATLiuJSchultzPGLesleySAPetersECSiuzdakG.Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA2009;
106:3698–703
36.
MorrisCRKimHYTrachtenbergFWoodJQuinnCTSweetersNKwiatkowskiJLThompsonAAGiardinaPJBoudreauxJOlivieriNFPorterJBNeufeldEJVichinskyEP.Thalassemia clinical research N. Risk factors and mortality associated with an elevated tricuspid regurgitant jet velocity measured by Doppler-echocardiography in thalassemia: a thalassemia clinical research network report. Blood2011;
118:3794–802
37.
Diaz HeijtzRWangSAnuarFQianYBjorkholmBSamuelssonAHibberdMLForssbergHPetterssonS.Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA2011;
108:3047–52
38.
MaoYKKasperDLWangBForsythePBienenstockJKunzeWA.Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons. Nat Commun2013;
4:1465
39.
BravoJAForsythePChewMVEscaravageESavignacHMDinanTGBienenstockJCryanJF.Ingestion of lactobacillus strain regulates emotional behavior and Central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA2011;
108:16050–5
40.
SmithSMValeWW.The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci2006;
8:383–95
41.
Greenwood-Van MeerveldBJohnsonAC.Mechanisms of stress-induced visceral pain. J Neurogastroenterol Motil2018;
24:7–18
42.
OkumuraRTakedaK.Maintenance of gut homeostasis by the mucosal immune system. Proc Jpn Acad Ser B2016;
92:423–35
43.
van WijkFCheroutreH.Mucosal T cells in gut homeostasis and inflammation. Exp Rev Clin Immunol2010;
6:559–66
44.
GalleyJDNelsonMCYuZDowdSEWalterJKumarPSLyteMBaileyMT.Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota. BMC Microbiol2014;
14:189
45.
Martin-HernandezDCasoJRBrisAGMausSRMadrigalJLGarcia-BuenoBMacDowellKSAlouLGomez-LusMLLezaJC.Bacterial translocation affects intracellular neuroinflammatory pathways in a depression-like model in rats. Neuropharmacology2016;
103:122–33
46.
ZhangJSongLWangYLiuCZhangLZhuSLiuSDuanL.Beneficial effect of butyrate-producing Lachnospiraceae on stress-induced visceral hypersensitivity in rats. J Gastroenterol Hepatol2019;
34:1368–76
47.
SudoNChidaYAibaYSonodaJOyamaNYuX-NKuboCKogaY.Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J Physiol2004;
558:263–75
48.
BaileyMTLubachGRCoeCL.Prenatal stress alters bacterial colonization of the gut in infant monkeys. J Pediatr Gastroenterol Nutr2004;
38:414–21
49.
BaileyMTCoeCL.Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol1999;
35:146–55
50.
LeeCKimBGKimJHChunJImJPKimJS.Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner. Int Immunopharmacol2017;
51:47–56
51.
JiangNMCowanMMoonahSNPetriWA.Jr.The impact of systemic inflammation on neurodevelopment. Trends Mol Med2018;
24:794–804
52.
SoretRChevalierJDe CoppetPPoupeauGDerkinderenPSegainJPNeunlistM.Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology2010;
138:1772–82
53.
ChangPVHaoLOffermannsSMedzhitovR.The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA2014;
111:2247–52
54.
BrownAJGoldsworthySMBarnesAAEilertMMTcheangLDanielsDMuirAIWigglesworthMJKinghornIFraserNJPikeNBStrumJCSteplewskiKMMurdockPRHolderJCMarshallFHSzekeresPGWilsonSIgnarDMFoordSMWiseADowellSJ.The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem2003;
278:11312–9
55.
KimuraIInoueDMaedaTHaraTIchimuraAMiyauchiSKobayashiMHirasawaATsujimotoG.Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA2011;
108:8030–5
56.
PudduASanguinetiRMontecuccoFVivianiGL.Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediat Inflamm2014;
2014:162021
57.
KrautkramerKAKreznarJHRomanoKAVivasEIBarrett-WiltGARabagliaMEKellerMPAttieADReyFEDenuJM.Diet-microbiota interactions mediate global epigenetic programming in multiple host tissues. Mol Cell2016;
64:982–92
58.
WeiYMelasPAWegenerGMatheAALavebrattC.Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene. Int J Neuropsychopharmacol2014;
18:pii:pyu032
59.
SepulvedaARYaoYYanWParkDIKimJJGoodingWAbudayyehSGrahamDY.CpG methylation and reduced expression of O6-methylguanine DNA methyltransferase is associated with Helicobacter pylori infection. Gastroenterology2010;
138:1836–44
60.
JoseLRamachandranRBhagavatRGomezRLChandranARaghunandananSOmkumarRVChandraNMundayoorSKumarRA.Hypothetical protein Rv3423.1 of Mycobacterium tuberculosis is a histone acetyltransferase. FEBS J2016;
283:265–81
61.
YaseenIKaurPNandicooriVKKhoslaS.Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3. Nat Commun2015;
6:8922
62.
PaulBBarnesSDemark-WahnefriedWMorrowCSalvadorCSkibolaCTollefsbolTO.Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin Epigenet2015;
7:112
63.
NeufeldKAKangNBienenstockJFosterJA.Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol2011;
4:492–4
64.
HobanAEStillingRMMoloneyGShanahanFDinanTGClarkeGCryanJF.The microbiome regulates amygdala-dependent fear recall. Mol Psychiatry2018;
23:1134–44
65.
StillingRMRyanFJHobanAEShanahanFClarkeGClaessonMJDinanTGCryanJF.Microbes & neurodevelopment – absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav Immun2015;
50:209–20
66.
HobanAEStillingRM, GMMMoloneyRDShanahanFDinanTGCryanJFClarkeG.Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. Microbiome2017;
5:102
67.
ChenJJZengBHLiWWZhouCJFanSHChengKZengLZhengPFangLWeiHXieP.Effects of gut microbiota on the microRNA and mRNA expression in the hippocampus of mice. Behav Brain Res2017;
322:34–41
68.
Berni Canani, R, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics 2012;4,4
69.
FofanovaTYPetrosinoJFKellermayerR.Microbiome-Epigenome interactions and the environmental origins of inflammatory bowel diseases. J Pediatr Gastroenterol Nutr2016;
62:208–19
70.
TranLChalonerASawalhaAHGreenwood Van-MeerveldB.Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress. Psychoneuroendocrinology2013;
38:898–906
71.
WatanabeYAraseSNagaokaNKawaiMMatsumotoS.Chronic psychological stress disrupted the composition of the murine colonic microbiota and accelerated a murine model of inflammatory bowel disease. PLoS One2016;
11:e0150559
72.
YuLMZhaoKJWangSSWangXLuB.Corticotropin-releasing factor induces inflammatory cytokines via the NLRP6-inflammatory cytokine axis in a murine model of irritable bowel syndrome. J Dig Dis2019;
20:143–51
73.
ZhaoKYuLWangXHeYLuB.Clostridium butyricum regulates visceral hypersensitivity of irritable bowel syndrome by inhibiting colonic mucous low grade inflammation through its action on NLRP6. Acta Biochim Biophys Sin2018;
50:216–23
74.
Amini-KhoeiHHaghani-SamaniEBeigiMSoltaniAMobiniGRBalali-DehkordiSHaj-MirzaianARafieian-KopaeiMAlizadehAHojjatiMRValidiM.On the role of corticosterone in behavioral disorders, microbiota composition alteration and neuroimmune response in adult male mice subjected to maternal separation stress. Int Immunopharmacol2019;
66:242–50
75.
MoloneyRDStillingRMDinanTGCryanJF.Early-life stress-induced visceral hypersensitivity and anxiety behavior is reversed by histone deacetylase inhibition. Neurogastroenterol Motil2015;
27:1831–6
76.
MoussaouiNBranisteVAit-BelgnaouiAGabanouMSekkalSOlierMTheodorouVMartinPGHoudeauE.Changes in intestinal glucocorticoid sensitivity in early life shape the risk of epithelial barrier defect in maternal-deprived rats. PLoS One2014;
9:e88382
77.
McCoyCRRanaSStringfellowSADayJJWyssJMClintonSMKermanIA.Neonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress-reactive Wistar Kyoto rats. Eur J Neurosci2016;
44:2829–45
78.
ParkSWLeeJGSeoMKLyNNLeeCHChoHYHeinLTChoiAJKimGMKimYH.Epigenetic modification of glucocorticoid receptor promoter I7 in maternally separated and restraint-stressed rats. Neurosci Lett2017;
650:38–44
79.
ParkSWSeoMKLeeJGHienLTKimYH.Effects of maternal separation and antidepressant drug on epigenetic regulation of the brain-derived neurotrophic factor exon I promoter in the adult rat hippocampus. Psychiatry Clin Neurosci2018;
72:255–65
80.
SeoMKLyNNLeeCHChoHYChoiCMNhuLHLeeJGLeeBJKimGMYoonBJParkSWKimYH.Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus. Neuropharmacology2016;
105:388–97
81.
TodaHBokuSNakagawaSInoueTKatoATakamuraNSongNNibuyaMKoyamaTKusumiI.Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala. PLoS One2014;
9:e97421
PaternainLMartisovaECampionJMartinezJARamirezMJMilagroFI.Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour. Behav Brain Res2016;
299:51–8
84.
BaroueiJMoussaviMHodgsonDM.Effect of maternal probiotic intervention on HPA axis, immunity and gut microbiota in a rat model of irritable bowel syndrome. PLoS One2012;
7:e46051
85.
MurakamiTKamadaKMizushimaKHigashimuraYKatadaKUchiyamaKHandaOTakagiTNaitoYItohY.Changes in intestinal motility and gut microbiota composition in a rat stress model. Digestion2017;
95:55–60
86.
CowanCSMStylianakisAARichardsonR.Early-life stress, microbiota, and brain development: probiotics reverse the effects of maternal separation on neural circuits underpinning fear expression and extinction in infant rats. Dev Cogn Neurosci2019;
37:100627
87.
FukuiHOshimaTTanakaYOikawaYMakizakiYOhnoHTomitaTWatariJMiwaH.Effect of probiotic Bifidobacterium bifidum G9-1 on the relationship between gut microbiota profile and stress sensitivity in maternally separated rats. Sci Rep2018;
8:12384
88.
Moya-PerezAPerez-VillalbaABenitez-PaezACampilloISanzY.Bifidobacterium CECT 7765 modulates early stress-induced immune, neuroendocrine and behavioral alterations in mice. Brain Behav Immun2017;
65:43–56
89.
O'MahonySMMcVey NeufeldKAWaworuntuRVPuscedduMMManurungSMurphyKStrainCLagunaMCPetersonVLStantonCBergBMDinanTGCryanJF.The enduring effects of early-life stress on the microbiota-gut-brain axis are buffered by dietary supplementation with milk fat globule membrane and a prebiotic blend. Eur J Neurosci2019;
00:1–17
90.
RincelMOlierMMinniAde OliveiraCMMatimeYGaultierEGritIHelblingJCCostaAMLepinayAMoisanMPLayeSFerrierLParnetPTheodorouVDarnauderyM.Pharmacological restoration of gut barrier function in stressed neonates partially reverses long-term alterations associated with maternal separation. Psychopharmacology2019;
236:1583–96
