The microbiota is increasingly recognized for its ability to influence the development and function of the nervous system and several complex host behaviors. In this review, we discuss emerging roles for the gut microbiota in modulating host social and communicative behavior, stressor-induced behavior, and performance in learning and memory tasks. We summarize effects of the microbiota on host neurophysiology, including brain microstructure, gene expression, and neurochemical metabolism across regions of the amygdala, hippocampus, frontal cortex, and hypothalamus. We further assess evidence linking dysbiosis of the gut microbiota to neurobehavioral diseases, such as autism spectrum disorder and major depression, drawing upon findings from animal models and human trials. Finally, based on increasing associations between the microbiota, neurophysiology, and behavior, we consider whether investigating mechanisms underlying the microbiota-gut-brain axis could lead to novel approaches for treating particular neurological conditions.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Aguilera M, Vergara P, Martinez V. 2013. Stress and antibiotics alter luminal and wall-adhered microbiota and enhance the local expression of visceral sensory-related systems in mice. Neurogastroenterol. Motil. 25:e515–29 [Google Scholar]
  2. Ait-Belgnaoui A, Durand H, Cartier C, Chaumaz G, Eutamene H. et al. 2012. Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. Psychoneuroendocrinology 37:1885–95 [Google Scholar]
  3. Ait-Belgnaoui A, Colom A, Braniste V, Ramalho L, Marrot A. et al. 2014. Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice. Neurogastroenterol. Motil. 26:510–20 [Google Scholar]
  4. Amaral FA, Sachs D, Costa VV, Fagundes CT, Cisalpino D. et al. 2008. Commensal microbiota is fundamental for the development of inflammatory pain. PNAS 105:2193–97 [Google Scholar]
  5. Arentsen T, Raith H, Qian Y, Forssberg H, Diaz Heijtz R. 2015. Host microbiota modulates development of social preference in mice. Microb. Ecol. Health Dis. 26:29719 [Google Scholar]
  6. Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. 2011. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav. Immun. 25:397–407 [Google Scholar]
  7. Bendtsen KMB, Krych L, Sørensen DB, Pang W, Nielsen DS. et al. 2012. Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse. PLOS ONE 7:e46231 [Google Scholar]
  8. Bercik P, Denou E, Collins J, Jackson W, Lu J. et al. 2011. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141:599–609.e3 [Google Scholar]
  9. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A. et al. 2014. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6:263ra158 [Google Scholar]
  10. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM. et al. 2011. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAS 108:16050–55 [Google Scholar]
  11. Bruch JD. 2016. Intestinal infection associated with future onset of an anxiety disorder: results of a nationally representative study. Brain Behav. Immun. 57:222–26 [Google Scholar]
  12. Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. 2016. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165:1762–75 [Google Scholar]
  13. Campos AC, Rocha NP, Nicoli JR, Vieira LQ, Teixeira MM, Teixeira AL. 2016. Absence of gut microbiota influences lipopolysaccharide-induced behavioral changes in mice. Behav. Brain Res. 312:186–94 [Google Scholar]
  14. Castro-Nallar E, Bendall ML, Pérez-Losada M, Sabuncyan S, Severance EG. et al. 2015. Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls. PeerJ 3:e1140 [Google Scholar]
  15. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F. et al. 2013. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501:52–57 [Google Scholar]
  16. Christian LM, Galley JD, Hade EM, Schoppe-Sullivan S, Kamp-Dush C. et al. 2015. Gut microbiome composition is associated with temperament during early childhood. Brain Behav. Immun. 45:118–27 [Google Scholar]
  17. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD. et al. 2013. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18:666–73 [Google Scholar]
  18. Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A. et al. 2014. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 42:207–17 [Google Scholar]
  19. Dash S, Clarke G, Berk M, Jacka FN. 2015. The gut microbiome and diet in psychiatry: focus on depression. Curr. Opin. Psychiatry 28:1–6 [Google Scholar]
  20. Davis DJ, Bryda EC, Gillespie CH, Ericsson AC. 2016. Microbial modulation of behavior and stress responses in zebrafish larvae. Behav. Brain Res. 311:219–27 [Google Scholar]
  21. De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ. et al. 2015. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat. Commun. 6:7735 [Google Scholar]
  22. de Theije CG, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J. et al. 2014. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav. Immun. 37:197–206 [Google Scholar]
  23. Degroote S, Hunting DJ, Baccarelli AA, Takser L. 2016. Maternal gut and fetal brain connection: increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 71:76–82 [Google Scholar]
  24. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF. et al. 2010. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170:1179–88 [Google Scholar]
  25. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF. 2014. Microbiota is essential for social development in the mouse. Mol. Psychiatry 19:146–48 [Google Scholar]
  26. Desbonnet L, Clarke G, Traplin A, O'Sullivan O, Crispie F. et al. 2015. Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav. Immun. 48:165–73 [Google Scholar]
  27. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B. et al. 2011. Normal gut microbiota modulates brain development and behavior. PNAS 108:3047–52 [Google Scholar]
  28. Dillon RJ, Vennard CT, Charnley AK. 2000. Exploitation of gut bacteria in the locust. Nature 403:851 [Google Scholar]
  29. Dinan TG, Cryan JF. 2013. Melancholic microbes: a link between gut microbiota and depression. ? Neurogastroenterol. Motil. 25:713–19 [Google Scholar]
  30. Dosmann A, Bahet N, Gordon DM. 2016. Experimental modulation of external microbiome affects nestmate recognition in harvester ants (Pogonomyrmex barbatus). PeerJ 4:e1566 [Google Scholar]
  31. Emge JR, Huynh K, Miller EN, Kaur M, Reardon C. et al. 2016. Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease. Am. J. Physiol. Gastrointest. Liver Physiol. 310:G989–98 [Google Scholar]
  32. Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O. et al. 2015. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18:965–77 [Google Scholar]
  33. Ezenwa VO, Williams AE. 2014. Microbes and animal olfactory communication: Where do we go from here. ? BioEssays 36:847–54 [Google Scholar]
  34. Fernandez-Real JM, Serino M, Blasco G, Puig J, Daunis-i-Estadella J. et al. 2015. Gut microbiota interacts with brain microstructure and function. J. Clin. Endocrinol. Metab. 100:4505–13 [Google Scholar]
  35. Frohlich EE, Farzi A, Mayerhofer R, Reichmann F, Jacan A. et al. 2016. Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav. Immun. 56:140–55 [Google Scholar]
  36. Gacias M, Gaspari S, Santos PMG, Tamburini S, Andrade M. et al. 2016. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife 5:e13442 [Google Scholar]
  37. Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT. et al. 2011. Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60:307–17 [Google Scholar]
  38. Ghasemlou N, Chiu IM, Julien JP, Woolf CJ. 2015. CD11b+Ly6G myeloid cells mediate mechanical inflammatory pain hypersensitivity. PNAS 112:E6808–17 [Google Scholar]
  39. Goodson JL. 2005. The vertebrate social behavior network: evolutionary themes and variations. Horm. Behav. 48:11–22 [Google Scholar]
  40. Hoban AE, Stilling RM, Ryan FJ, Shanahan F, Dinan TG. et al. 2016. Regulation of prefrontal cortex myelination by the microbiota. Transl. Psychiatry 6:e774 [Google Scholar]
  41. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER. et al. 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–63 [Google Scholar]
  42. Humann J, Mann B, Gao G, Moresco P, Ramahi J. et al. 2016. Bacterial peptidoglycan traverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior. Cell Host Microbe 19:901 [Google Scholar]
  43. Janik R, Thomason LA, Stanisz AM, Forsythe P, Bienenstock J, Stanisz GJ. 2016. Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate. NeuroImage 125:988–95 [Google Scholar]
  44. Jasarevic E, Howerton CL, Howard CD, Bale TL. 2015. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology 156:3265–76 [Google Scholar]
  45. Kai M, Haustein M, Molina F, Petri A, Scholz B, Piechulla B. 2009. Bacterial volatiles and their action potential. Appl. Microbiol. Biotechnol. 81:1001–12 [Google Scholar]
  46. Koch H, Schmid-Hempel P. 2011. Socially transmitted gut microbiota protect bumble bees against an intestinal parasite. PNAS 108:19288–92 [Google Scholar]
  47. Krajmalnik-Brown R, Lozupone C, Kang DW, Adams JB. 2015. Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease. Microb. Ecol. Health Dis. 26:26914 [Google Scholar]
  48. Lax S, Smith DP, Hampton-Marcell J, Owens SM, Handley KM. et al. 2014. Longitudinal analysis of microbial interaction between humans and the indoor environment. Science 345:1048–52 [Google Scholar]
  49. Leclaire S, Nielsen JF, Drea CM. 2014. Bacterial communities in meerkat and scent secretions vary with host sex, age and group membership. Behav. Ecol. 25:996–1004 [Google Scholar]
  50. Li L, Su Q, Xie B, Duan L, Zhao W. et al. 2016. Gut microbes in correlation with mood: case study in a closed experimental human life support system. Neurogastroenterol. Motil. 28:1233–40 [Google Scholar]
  51. Liang S, Wang T, Hu X, Luo J, Li W. et al. 2015. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience 310:561–77 [Google Scholar]
  52. Liu J, Dietz K, DeLoyht JM, Pedre X, Kelkar D. et al. 2012. Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat. Neurosci. 15:1621–23 [Google Scholar]
  53. Luczynski P, Whelan SO, O'Sullivan C, Clarke G, Shanahan F. et al. 2016. Adult microbiota-deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus. Eur. J. Neurosci. 44:2654–66 [Google Scholar]
  54. Macfabe DF. 2012. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb. Ecol. Health Dis. 23:19260 [Google Scholar]
  55. MacQueen G, Frodl T. 2011. The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research?. Mol. Psychiatry 16:252–64 [Google Scholar]
  56. Makinodan M, Rosen KM, Ito S, Corfas G. 2012. A critical period for social experience–dependent oligodendrocyte maturation and myelination. Science 337:1357–60 [Google Scholar]
  57. Matsuura K. 2001. Nestmate recognition mediated by intestinal bacteria in a termite. Reticulitermes speratus. Oikos 92:20–26 [Google Scholar]
  58. Matthews DM, Jenks SM. 2013. Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. Behav. Process. 96:27–35 [Google Scholar]
  59. Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D. et al. 2011. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longumR0175) in rats and human subjects. Br. J. Nutr. 105:755–64 [Google Scholar]
  60. Moeller AH, Foerster S, Wilson ML, Pusey AE, Hahn BH, Ochman H. 2016. Social behavior shapes the chimpanzee pan-microbiome. Sci. Adv. 2:e1500997 [Google Scholar]
  61. Möhle L, Mattei D, Heimesaat MM, Bereswill S, Fischer A. et al. 2016. Ly6Chi monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis. Cell Rep 15:1945–56 [Google Scholar]
  62. Moloney RD, Johnson AC, O'Mahony SM, Dinan TG, Greenwood-Van Meerveld B, Cryan JF. 2016. Stress and the microbiota-gut-brain axis in visceral pain: relevance to irritable bowel syndrome. CNS Neurosci. Ther. 22:102–17 [Google Scholar]
  63. Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linlokken A. et al. 2014. Correlation between the human fecal microbiota and depression. Neurogastroenterol. Motil. 26:1155–62 [Google Scholar]
  64. Neufeld KM, Kang N, Bienenstock J, Foster JA. 2011a. Effects of intestinal microbiota on anxiety-like behavior. Communicative Integr. Biol. 4:492–94 [Google Scholar]
  65. Neufeld KM, Kang N, Bienenstock J, Foster JA. 2011b. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23:255–e119 [Google Scholar]
  66. Nishino R, Mikami K, Takahashi H, Tomonaga S, Furuse M. et al. 2013. Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods. Neurogastroenterol. Motil. 25:521–28 [Google Scholar]
  67. Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O'Leary OF. 2015. Adult hippocampal neurogenesis is regulated by the microbiome. Biol. Psychiatry 78:e7–9 [Google Scholar]
  68. Ohland CL, Kish L, Bell H, Thiesen A, Hotte N. et al. 2013. Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology 38:1738–47 [Google Scholar]
  69. O'Mahony SM, Felice VD, Nally K, Savignac HM, Claesson MJ. et al. 2014. Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats. Neuroscience 277:885–901 [Google Scholar]
  70. Pärtty A, Luoto R, Kalliomaki M, Salminen S, Isolauri E. 2013. Effects of early prebiotic and probiotic supplementation on development of gut microbiota and fussing and crying in preterm infants: a randomized, double-blind, placebo-controlled trial. J. Pediatr. 163:1272–77.e2 [Google Scholar]
  71. Pokusaeva K, Johnson C, Luk B, Uribe G, Fu Y. et al. 2016. GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine. Neurogastroenterol. Motil. 29:e12904 [Google Scholar]
  72. Pyndt Jørgensen B, Krych L, Pedersen TB, Plath N, Redrobe JP. et al. 2015. Investigating the long-term effect of subchronic phencyclidine-treatment on novel object recognition and the association between the gut microbiota and behavior in the animal model of schizophrenia. Physiol. Behav. 141:32–39 [Google Scholar]
  73. Ritz NL, Burnett BJ, Setty P, Reinhart KM, Wilson MR. et al. 2016. Sulfate-reducing bacteria impairs working memory in mice. Physiol. Behav. 157:281–87 [Google Scholar]
  74. Savignac HM, Corona G, Mills H, Chen L, Spencer JPE. et al. 2013. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine. Neurochem. Int. 63:756–64 [Google Scholar]
  75. Savignac JM, Kiely B, Dinan TG, Cryan JF. 2014. Bifidobacteria exert sterain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol. Motil. 26:1615–27 [Google Scholar]
  76. Savignac HM, Tramullas M, Kiely B, Dinan TG, Cryan JF. 2015. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav. Brain Res. 287:59–72 [Google Scholar]
  77. Schmidt K, Cowen PJ, Harmer CJ, Tzortzis G, Errington S, Burnet PW. 2015. Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers. Psychopharmacology 232:1793–801 [Google Scholar]
  78. Sharon G, Segal D, Ringo JM, Hefetz A, Zilber-Rosenberg I, Rosenberg E. 2010. Commensal bacteria play a role in mating preference of Drosophila melanogaster. PNAS 107:20051–56 [Google Scholar]
  79. Sin YW, Buesching CD, Burke T, Macdonald DW. 2012. Molecular characterization of the microbial communities in the subcaudal gland secretion of the European badger (Meles meles). FEMS Microbiol. Ecol. 81:648–59 [Google Scholar]
  80. Smith CJ, Emge JR, Berzins K, Lung L, Khamishon R. et al. 2014. Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 307:G793–802 [Google Scholar]
  81. Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. 2015. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav. Immun. 48:258–64 [Google Scholar]
  82. Steiger S, Schmitt T, Schaefer HM. 2011. The origin and dynamic evolution of chemical information transfer. Proc. R. Soc. B 278:970–79 [Google Scholar]
  83. Stilling RM, Ryan FJ, Hoban AE, Shanahan F, Clarke G. et al. 2015. Microbes & neurodevelopment – absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav. Immun. 50:209–20 [Google Scholar]
  84. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N. et al. 2004. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 558:263–75 [Google Scholar]
  85. Theis KR, Venkataraman A, Dycus JA, Koonter KD, Schmitt-Matzen EN. et al. 2013. Symbiotic bacteria appear to mediate hyena social odors. PNAS 110:19832–37 [Google Scholar]
  86. Theodorou V, Belgnaoui AA, Agostini S, Eutamene H. 2014. Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome. Gut Microbes 5:430–629 [Google Scholar]
  87. Tung J, Barreiro LB, Burns MB, Grenier JC, Lynch J. et al. 2015. Social networks predict gut microbiome composition in wild baboons. eLife 4:e05224 [Google Scholar]
  88. Rao AV, Bested AC, Beaulne TM, Katzman MA, Iorio C. et al. 2009. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog 1:6 [Google Scholar]
  89. Venu I, Durisko Z, Xu J, Dukas R. 2014. Social attraction mediated by fruit flies' microbiome. J. Exp. Biol. 217:1346–52 [Google Scholar]
  90. Verdu EF, Bercik P, Verma-Gandhu M, Huang XX, Blennerhassett P. et al. 2006. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 55:182–90 [Google Scholar]
  91. Verhulst NO, Qiu YT, Beijleveld H, Maliepaard C, Knights D. et al. 2011. Composition of human skin microbiota affects attractiveness to malaria mosquitoes. PLOS ONE 6:e28991 [Google Scholar]
  92. Vuong HE, Hsiao EY. 2016. Emerging roles for the gut microbiome in autism spectrum disorder. Biol. Psychiatry 81:411–23 [Google Scholar]
  93. Wada-Katsumata A, Zurek L, Nalyanya G, Roelofs WL, Zhang A, Schal C. 2015. Gut bacteria mediate aggregation in the German cockroach. PNAS 112:15678–83 [Google Scholar]
  94. Wang T, Hu X, Liang S, Li W, Wu X. et al. 2015. Lactobacillus fermentum NS9 restores the antibiotic induced physiological and psychological abnormalities in rats. Benef. Microbes 6:707–17 [Google Scholar]
  95. Zheng P, Zeng B, Zhou C, Liu M, Fang Z. et al. 2016. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol. Psychiatry 21:786–96 [Google Scholar]
  96. Zijlmans MA, Korpela K, Riksen-Walraven JM, de Vos WM, de Weerth C. 2015. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology 53:233–45 [Google Scholar]
  97. Zomer S, Dixon SJ, Xu Y, Jensen SP, Wang H. et al. 2009. Consensus multivariate methods in gas chromatography mass spectrometry and denaturing gradient gel electrophoresis: MHC-congenic and other strains of mice can be classified according to the profiles of volatiles and microflora in their scent-marks. Analyst 134:114–23 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error