Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The gut microbiota–brain axis in behaviour and brain disorders

Abstract

In a striking display of trans-kingdom symbiosis, gut bacteria cooperate with their animal hosts to regulate the development and function of the immune, metabolic and nervous systems through dynamic bidirectional communication along the ‘gut–brain axis’. These processes may affect human health, as certain animal behaviours appear to correlate with the composition of gut bacteria, and disruptions in microbial communities have been implicated in several neurological disorders. Most insights about host–microbiota interactions come from animal models, which represent crucial tools for studying the various pathways linking the gut and the brain. However, there are complexities and manifest limitations inherent in translating complex human disease to reductionist animal models. In this Review, we discuss emerging and exciting evidence of intricate and crucial connections between the gut microbiota and the brain involving multiple biological systems, and possible contributions by the gut microbiota to neurological disorders. Continued advances from this frontier of biomedicine may lead to tangible impacts on human health.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The gut microbiota–brain axis.
Fig. 2: Microbiota and microbial-derived molecules modulate host behaviour and nervous system function.

Similar content being viewed by others

References

  1. Cryan, J. F. et al. The microbiota–gut–brain axis. Physiol. Rev. 99, 1877–2013 (2019).

    CAS  PubMed  Google Scholar 

  2. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). This important study demonstrates that the gut microbiota can modulate microglia immune programming mediated by SCFAs in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Clarke, G. et al. The microbiome–gut–brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666–673 (2013).

    CAS  PubMed  Google Scholar 

  4. Lyte, M. Microbial endocrinology and the microbiota–gut–brain axis. Adv. Exp. Med. Biol. 817, 3–24 (2014).

    CAS  PubMed  Google Scholar 

  5. Sharon, G. et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell 177, 1600–1618.e17 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Martin, C. R., Osadchiy, V., Kalani, A. & Mayer, E. A. The brain–gut–microbiome axis. Cell. Mol. Gastroenterol. Hepatol. 6, 133–148 (2018).

    PubMed  PubMed Central  Google Scholar 

  7. Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30, 492–506 (2020).

    PubMed  PubMed Central  Google Scholar 

  8. Dabke, K., Hendrick, G. & Devkota, S. The gut microbiome and metabolic syndrome. J. Clin. Invest. 129, 4050–4057 (2019).

    PubMed  PubMed Central  Google Scholar 

  9. Collins, J., Borojevic, R., Verdu, E. F., Huizinga, J. D. & Ratcliffe, E. M. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol. Motil. 26, 98–107 (2014).

    CAS  PubMed  Google Scholar 

  10. de la Cuesta-Zuluaga, J. et al. Age- and sex-dependent patterns of gut microbial diversity in human adults. mSystems 4, e00261–e00319 (2019).

    PubMed  PubMed Central  Google Scholar 

  11. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    CAS  PubMed  Google Scholar 

  12. Vich Vila, A. et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 11, 362 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340 (2016).

    CAS  PubMed  Google Scholar 

  14. Tierney, B. T. et al. The landscape of genetic content in the gut and oral human microbiome. Cell Host Microbe 26, 283–295.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Szabo, G. Gut–liver axis in alcoholic liver disease. Gastroenterology 148, 30–36 (2015).

    CAS  PubMed  Google Scholar 

  16. Dalile, B., Van Oudenhove, L., Vervliet, B. & Verbeke, K. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat. Rev. Gastroenterol. Hepatol. 16, 461–478 (2019).

    PubMed  Google Scholar 

  17. Schroeder, F. A., Lin, C. L., Crusio, W. E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol. Psychiatry 62, 55–64 (2007).

    CAS  PubMed  Google Scholar 

  18. Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004). This seminal study shows that GF mice have alterations in the HPA axis relevant to stress and anxiety, and shows the impact of a probiotic on stress responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ghatei, M. A., Ratcliffe, B., Bloom, S. R. & Goodlad, R. A. Fermentable dietary fibre, intestinal microflora and plasma hormones in the rat. Clin. Sci. 93, 109–112 (1997).

    CAS  Google Scholar 

  20. Aresti Sanz, J. & El Aidy, S. Microbiota and gut neuropeptides: a dual action of antimicrobial activity and neuroimmune response. Psychopharmacology 236, 1597–1609 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

    PubMed  PubMed Central  Google Scholar 

  22. Wichmann, A. et al. Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 14, 582–590 (2013).

    CAS  PubMed  Google Scholar 

  23. Buckley, M. M. et al. Glucagon-like peptide-1 secreting L-cells coupled to sensory nerves translate microbial signals to the host rat nervous system. Front. Cell Neurosci. 14, 95 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Strandwitz, P. et al. GABA-modulating bacteria of the human gut microbiota. Nat. Microbiol. 4, 396–403 (2019).

    CAS  PubMed  Google Scholar 

  25. Barrett, E., Ross, R. P., O’Toole, P. W., Fitzgerald, G. F. & Stanton, C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J. Appl. Microbiol. 113, 411–417 (2012).

    CAS  PubMed  Google Scholar 

  26. Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015). This study reveals microbial regulation of 5-HT production from enterochromaffin cells in the gut by specific microbial molecules. Impacts on the brain or behaviour are not yet known.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Poutahidis, T. et al. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS ONE 8, e78898 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Morris, G. et al. The role of the microbial metabolites including tryptophan catabolites and short chain fatty acids in the pathophysiology of immune-inflammatory and neuroimmune disease. Mol. Neurobiol. 54, 4432–4451 (2017).

    CAS  PubMed  Google Scholar 

  29. Muller, P. A. et al. Microbiota modulate sympathetic neurons via a gut–brain circuit. Nature 583, 441–446 (2020). This seminal study uses neuronal tracing techniques to demonstrate modulation of neuronal pathways of the gut–brain axis by the gut microbiota.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yoo, B. B. & Mazmanian, S. K. The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46, 910–926 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. De Vadder, F. et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc. Natl Acad. Sci. USA 115, 6458–6463 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kabouridis, P. S. et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Aktar, R. et al. Human resident gut microbe Bacteroides thetaiotaomicron regulates colonic neuronal innervation and neurogenic function. Gut Microbes 11, 1745–1757 (2020).

    PubMed  PubMed Central  Google Scholar 

  34. Obata, Y. et al. Neuronal programming by microbiota regulates intestinal physiology. Nature 578, 284–289 (2020).

    CAS  PubMed  Google Scholar 

  35. Mao, Y.-K. et al. Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons. Nat. Commun. 4, 1465 (2013).

    PubMed  Google Scholar 

  36. Golubeva, A. V. et al. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine 24, 166–178 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. Fülling, C., Dinan, T. G. & Cryan, J. F. Gut microbe to brain signaling: what happens in vagus. Neuron 101, 998–1002 (2019).

    PubMed  Google Scholar 

  38. Wang, F.-B. & Powley, T. L. Vagal innervation of intestines: afferent pathways mapped with new en bloc horseradish peroxidase adaptation. Cell Tissue Res. 329, 221–230 (2007).

    PubMed  Google Scholar 

  39. Han, W. et al. A neural circuit for gut-induced reward. Cell 175, 887–888 (2018).

    CAS  PubMed  Google Scholar 

  40. Kaelberer, M. M. et al. A gut–brain neural circuit for nutrient sensory transduction. Science 361, eaat5236 (2018).

    PubMed  PubMed Central  Google Scholar 

  41. Tan, H.-E. et al. The gut–brain axis mediates sugar preference. Nature 580, 511–516 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bellono, N. W. et al. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170, 185–198.e16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bonaz, B., Picq, C., Sinniger, V., Mayol, J. F. & Clarençon, D. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol. Motil. 25, 208–221 (2013).

    CAS  PubMed  Google Scholar 

  44. Bravo, J. A. 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. USA 108, 16050–16055 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sgritta, M. et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron 101, 246–259.e6 (2019).

    CAS  PubMed  Google Scholar 

  46. Milby, A. H., Halpern, C. H. & Baltuch, G. H. Vagus nerve stimulation for epilepsy and depression. Neurotherapeutics 5, 75–85 (2008).

    PubMed  PubMed Central  Google Scholar 

  47. Abdel-Haq, R., Schlachetzki, J. C. M., Glass, C. K. & Mazmanian, S. K. Microbiome–microglia connections via the gut–brain axis. J. Exp. Med. 216, 41–59 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Luck, B. et al. Bifidobacteria shape host neural circuits during postnatal development by promoting synapse formation and microglial function. Sci. Rep. 10, 7737 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Thion, M. S. et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172, 500–516.e16 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Bollinger, J. L., Collins, K. E., Patel, R. & Wellman, C. L. Behavioral stress alters corticolimbic microglia in a sex- and brain region-specific manner. PLoS ONE 12, e0187631 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e12 (2016). This study is the first to demonstrate the importance of the gut microbiota for PD-like symptoms in a mouse model. Using a translational approach, transplantation of gut bacteria from individuals with PD into GF mice can replicate some PD-like motor symptoms.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013). This study implicates the gut microbiota in an animal model of ASD. Treatment at weaning with the human gut commensal B. fragilis is able to reverse core behavioural patterns of ASD in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Yuan, N., Chen, Y., Xia, Y., Dai, J. & Liu, C. Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses. Transl. Psychiatry 9, 233 (2019).

    PubMed  PubMed Central  Google Scholar 

  54. Braniste, V. et al. The gut microbiota influences blood–brain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158 (2014).

    PubMed  PubMed Central  Google Scholar 

  55. Grab, D. J. et al. Borrelia burgdorferi, host-derived proteases, and the blood–brain barrier. Infect. Immun. 73, 1014–1022 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Daneman, R. The blood–brain barrier in health and disease. Ann. Neurol. 72, 648–672 (2012).

    CAS  PubMed  Google Scholar 

  57. Jiang, H. et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav. Immun. 48, 186–194 (2015).

    PubMed  Google Scholar 

  58. Luna, R. A. et al. Distinct microbiome–neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell. Mol. Gastroenterol. Hepatol. 3, 218–230 (2017).

    PubMed  Google Scholar 

  59. Kim, S. et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549, 528–532 (2017).

    PubMed  PubMed Central  Google Scholar 

  60. Choi, J. G. et al. Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice. Sci. Rep. 8, 1275 (2018).

    PubMed  PubMed Central  Google Scholar 

  61. Kelly, J. R. et al. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J. Psychiatr. Res. 82, 109–118 (2016).

    PubMed  Google Scholar 

  62. Cekanaviciute, E. et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc. Natl Acad. Sci. USA 114, 10713–10718 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Walter, J., Armet, A. M., Finlay, B. B. & Shanahan, F. Establishing or exaggerating causality for the gut microbiome: lessons from human microbiota-associated rodents. Cell 180, 221–232 (2020).

    CAS  PubMed  Google Scholar 

  64. Marin, I. A. et al. Microbiota alteration is associated with the development of stress-induced despair behavior. Sci. Rep. 7, 43859 (2017).

    PubMed  PubMed Central  Google Scholar 

  65. Baio, J. et al. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill. Summ. 67, 1–23 (2018).

    PubMed  PubMed Central  Google Scholar 

  66. Lenroot, R. K. & Yeung, P. K. Heterogeneity within autism spectrum disorders: what have we learned from neuroimaging studies? Front. Hum. Neurosci. 7, 733 (2013).

    PubMed  PubMed Central  Google Scholar 

  67. McElhanon, B. O., McCracken, C., Karpen, S. & Sharp, W. G. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 133, 872–883 (2014).

    PubMed  Google Scholar 

  68. Coury, D. L. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics 130, S160–S168 (2012).

    PubMed  Google Scholar 

  69. Buie, T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 125, S1–S18 (2010).

    PubMed  Google Scholar 

  70. Tordjman, S. et al. Gene × environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front. Psychiatry 5, 53 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Kang, D.-W. et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10 (2017).

    PubMed  PubMed Central  Google Scholar 

  72. Strati, F. et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome 5, 24 (2017).

    PubMed  PubMed Central  Google Scholar 

  73. Liu, F. et al. Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review. Transl. Psychiatry 9, 43 (2019).

    PubMed  PubMed Central  Google Scholar 

  74. Son, J. S. et al. Comparison of fecal microbiota in children with autism spectrum disorders and neurotypical siblings in the Simons Simplex Collection. PLoS ONE 10, e0137725 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. Zhang, M., Ma, W., Zhang, J., He, Y. & Wang, J. Analysis of gut microbiota profiles and microbe-disease associations in children with autism spectrum disorders in China. Sci. Rep. 8, 13981 (2018).

    PubMed  PubMed Central  Google Scholar 

  76. Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T. G. & Cryan, J. F. Microbiota is essential for social development in the mouse. Mol. Psychiatry 19, 146–148 (2014).

    CAS  PubMed  Google Scholar 

  77. Degroote, S., Hunting, D. J., Baccarelli, A. A. & Takser, L. Maternal gut and fetal brain connection: increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure. Prog. Neuropsychopharmacol. Biol. Psychiatry 71, 76–82 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Leclercq, S. et al. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat. Commun. 8, 15062 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016). Together with reference 45, this study demonstrates that a specific probiotic can improve social deficits in mice via the oxytocin pathway and vagus nerve, providing initial insights into gut–brain pathways that impact complex behaviours.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kang, D.-W. et al. Long-term benefit of microbiota transfer therapy on autism symptoms and gut microbiota. Sci. Rep. 9, 5821 (2019).

    PubMed  PubMed Central  Google Scholar 

  81. Sandler, R. H. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J. Child Neurol. 15, 429–435 (2000).

    CAS  PubMed  Google Scholar 

  82. Rodakis, J. An n = 1 case report of a child with autism improving on antibiotics and a father’s quest to understand what it may mean. Microb. Ecol. Health Dis. 26, 26382 (2015).

    PubMed  Google Scholar 

  83. de Theije, C. G. M. et al. Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav. Immun. 37, 197–206 (2014).

    PubMed  Google Scholar 

  84. Coretti, L. et al. Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder. Sci. Rep. 7, 45356 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Tabouy, L. et al. Dysbiosis of microbiome and probiotic treatment in a genetic model of autism spectrum disorders. Brain Behav. Immun. 73, 310–319 (2018).

    PubMed  Google Scholar 

  86. Needham, B. D. et al. Plasma and fecal metabolite profiles in autism spectrum disorder. Biol. Psychiatry https://doi.org/10.1016/j.biopsych.2020.09.025 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  87. West, P. R. et al. Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children. PLoS ONE 9, e112445 (2014).

    PubMed  PubMed Central  Google Scholar 

  88. Emond, P. et al. GC-MS-based urine metabolic profiling of autism spectrum disorders. Anal. Bioanal. Chem. 405, 5291–5300 (2013).

    CAS  PubMed  Google Scholar 

  89. Ming, X., Stein, T. P., Barnes, V., Rhodes, N. & Guo, L. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J. Proteome Res. 11, 5856–5862 (2012).

    CAS  PubMed  Google Scholar 

  90. Kałużna-Czaplińska, J., Żurawicz, E., Struck, W. & Markuszewski, M. Identification of organic acids as potential biomarkers in the urine of autistic children using gas chromatography/mass spectrometry. J. Chromatogr. B 966, 70–76 (2014).

    Google Scholar 

  91. Chao, O. Y., Yunger, R. & Yang, Y.-M. Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: implications for an animal model of psychiatric comorbidity in autism. Behav. Brain Res. 347, 140–147 (2018).

    PubMed  Google Scholar 

  92. Smith, S. E. P., Li, J., Garbett, K., Mirnics, K. & Patterson, P. H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 27, 10695–10702 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Estes, M. L. & McAllister, A. K. Maternal immune activation: implications for neuropsychiatric disorders. Science 353, 772–777 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008).

    CAS  PubMed  Google Scholar 

  95. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/results?cond=autism&term=microbiota&cntry=&state=&city=&dist (2020).

  96. Santocchi, E. et al. Gut to brain interaction in autism spectrum disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry 16, 183 (2016).

    PubMed  PubMed Central  Google Scholar 

  97. Kong, X.-J. et al. Probiotics and oxytocin nasal spray as neuro-social-behavioral interventions for patients with autism spectrum disorders: a pilot randomized controlled trial protocol. Pilot Feasibility Stud. 6, 20 (2020).

    PubMed  PubMed Central  Google Scholar 

  98. Sichel, J. Improvements in gastrointestinal symptoms among children with autism spectrum disorder receiving the Delpro® probiotic and immunomodulator formulation. J. Prob. Health https://doi.org/10.4172/2329-8901.1000102 (2013).

  99. Tysnes, O.-B. & Storstein, A. Epidemiology of Parkinson’s disease. J. Neural Transm. 124, 901–905 (2017).

    PubMed  Google Scholar 

  100. Blandini, F., Nappi, G., Tassorelli, C. & Martignoni, E. Functional changes of the basal ganglia circuitry in Parkinson’s disease. Prog. Neurobiol. 62, 63–88 (2000).

    CAS  PubMed  Google Scholar 

  101. Chen, H. et al. Meta-analyses on prevalence of selected Parkinson’s nonmotor symptoms before and after diagnosis. Transl. Neurodegener. 4, 1 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. Cersosimo, M. G. & Benarroch, E. E. Pathological correlates of gastrointestinal dysfunction in Parkinson’s disease. Neurobiol. Dis. 46, 559–564 (2012).

    PubMed  Google Scholar 

  103. Braak, H. et al. Pathology associated with sporadic Parkinson’s disease — where does it end? J. Neural Transm. Suppl. 70, 89–97 (2006).

    Google Scholar 

  104. Forsyth, C. B. et al. Increased intestinal permeability correlates with sigmoid mucosa α-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS ONE 6, e28032 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kim, S. et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103, 627–641.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Challis, C. et al. Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat. Neurosci. 23, 327–336 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Chai, X.-Y. et al. Investigation of nerve pathways mediating colorectal dysfunction in Parkinson’s disease model produced by lesion of nigrostriatal dopaminergic neurons. Neurogastroenterol. Motil. 32, e13893 (2020).

    CAS  PubMed  Google Scholar 

  108. Parkinson, J. An essay on the shaking palsy. 1817. J. Neuropsychiatry Clin. Neurosci. 14, 223–236 (2002).

    PubMed  Google Scholar 

  109. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).

    PubMed  Google Scholar 

  110. Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).

    PubMed  Google Scholar 

  111. Barichella, M. et al. Unraveling gut microbiota in Parkinson’s disease and atypical parkinsonism. Mov. Disord. 34, 396–405 (2019).

    PubMed  Google Scholar 

  112. Hasegawa, S. et al. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease. PLoS ONE 10, e0142164 (2015).

    PubMed  PubMed Central  Google Scholar 

  113. Keshavarzian, A. et al. Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 30, 1351–1360 (2015).

    CAS  PubMed  Google Scholar 

  114. Scheperjans, F. et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov. Disord. 30, 350–358 (2015).

    PubMed  Google Scholar 

  115. Weimers, P. et al. Inflammatory bowel disease and Parkinson’s disease: a nationwide Swedish cohort study. Inflamm. Bowel Dis. 25, 111–123 (2019).

    PubMed  Google Scholar 

  116. Matheoud, D. et al. Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1–/– mice. Nature 571, 565–569 (2019).

    CAS  PubMed  Google Scholar 

  117. Bedarf, J. R. et al. Functional implications of microbial and viral gut metagenome changes in early stage l-DOPA-naïve Parkinson’s disease patients. Genome Med. 9, 39 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Unger, M. M. et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat. Disord. 32, 66–72 (2016).

    PubMed  Google Scholar 

  119. Maini Rekdal, V., Bess, E. N., Bisanz, J. E., Turnbaugh, P. J. & Balskus, E. P. Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism. Science 364, eaau6323 (2019).

    PubMed  Google Scholar 

  120. Çamcı, G. & Oğuz, S. Association between Parkinson’s disease and Helicobacter pylori. J. Clin. Neurol. 12, 147–150 (2016).

    PubMed  PubMed Central  Google Scholar 

  121. van Kessel, S. P. et al. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat. Commun. 10, 310 (2019). Together with reference 119, this interesting study links gut microbial enzymatic pathways that alter availability of l-dopa, a first-line drug used for PD.

    PubMed  PubMed Central  Google Scholar 

  122. Dawson, T. M., Golde, T. E. & Lagier-Tourenne, C. Animal models of neurodegenerative diseases. Nat. Neurosci. 21, 1370–1379 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Sampson, T. R. et al. A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice. eLife 9, e53111 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Yang, X., Qian, Y., Xu, S., Song, Y. & Xiao, Q. Longitudinal analysis of fecal microbiome and pathologic processes in a rotenone induced mice model of Parkinson’s disease. Front. Aging Neurosci. 9, 441 (2017).

    PubMed  Google Scholar 

  125. Sun, M.-F. et al. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav. Immun. 70, 48–60 (2018).

    CAS  PubMed  Google Scholar 

  126. Ekstrand, M. I. et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl Acad. Sci. USA 104, 1325–1330 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Hsieh, T.-H. et al. Probiotics alleviate the progressive deterioration of motor functions in a mouse model of Parkinson’s disease. Brain Sci. 10, 206 (2020).

    CAS  PubMed Central  Google Scholar 

  128. Castelli, V. et al. Effects of the probiotic formulation SLAB51 in in vitro and in vivo Parkinson’s disease models. Aging 12, 4641–4659 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. The Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 16, 391–460 (2020).

    Google Scholar 

  130. Cattaneo, A. et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 49, 60–68 (2017).

    CAS  PubMed  Google Scholar 

  131. Vogt, N. M. et al. Gut microbiome alterations in Alzheimer’s disease. Sci. Rep. 7, 13537 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. Wang, X. et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 29, 787–803 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Minter, M. R. et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci. Rep. 6, 30028 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Dodiya, H. B. et al. Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1-21 Alzheimer’s transgenic mice. Sci. Rep. 10, 8183 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Mezö, C. et al. Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 8, 119 (2020).

    PubMed  PubMed Central  Google Scholar 

  136. Mangalam, A. et al. Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep. 20, 1269–1277 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108, 4615–4622 (2011).

    CAS  PubMed  Google Scholar 

  138. Berer, K. et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc. Natl Acad. Sci. USA 114, 10719–10724 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. McEwen, B. S. & Wingfield, J. C. The concept of allostasis in biology and biomedicine. Horm. Behav. 43, 2–15 (2003).

    PubMed  Google Scholar 

  140. Silverman, M. N. & Sternberg, E. M. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann. NY Acad. Sci. 1261, 55–63 (2012).

    CAS  PubMed  Google Scholar 

  141. Gareau, M. G., Jury, J., MacQueen, G., Sherman, P. M. & Perdue, M. H. Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut 56, 1522–1528 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Savignac, H. M., Kiely, B., Dinan, T. G. & Cryan, J. F. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol. Motil. 26, 1615–1627 (2014).

    CAS  PubMed  Google Scholar 

  143. Bercik, P. et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut–brain communication. Neurogastroenterol. Motil. 23, 1132–1139 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Bailey, M. T. & Coe, C. L. Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev. Psychobiol. 35, 146–155 (1999).

    CAS  PubMed  Google Scholar 

  145. García-Ródenas, C. L. et al. Nutritional approach to restore impaired intestinal barrier function and growth after neonatal stress in rats. J. Pediatr. Gastroenterol. Nutr. 43, 16–24 (2006).

    PubMed  Google Scholar 

  146. O’Mahony, S. M. et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol. Psychiatry 65, 263–267 (2009).

    PubMed  Google Scholar 

  147. Jašarević, E. et al. The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus. Nat. Neurosci. 21, 1061–1071 (2018).

    PubMed  Google Scholar 

  148. World Health Organization. Depression and other common mental disorders: global health estimates (WHO, 2017).

  149. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Publishing, 2013).

  150. Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010).

    CAS  PubMed  Google Scholar 

  151. Zheng, P. et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol. Psychiatry 21, 786–796 (2016).

    CAS  PubMed  Google Scholar 

  152. Valles-Colomer, M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat. Microbiol. 4, 623–632 (2019).

    CAS  PubMed  Google Scholar 

  153. De Palma, G. et al. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat. Commun. 6, 7735 (2015).

    PubMed  Google Scholar 

  154. Li, N. et al. Oral probiotics ameliorate the behavioral deficits induced by chronic mild stress in mice via the gut microbiota–inflammation axis. Front. Behav. Neurosci. 12, 266 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. Pinto-Sanchez, M. I. et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology 153, 448–459.e8 (2017). This pilot human study demonstrates that probiotic administration of B. longum NCC3001 improves depression in a cohort of individuals with irritable bowel syndrome and modulates activity of areas of the brain that process emotions.

    PubMed  Google Scholar 

  156. Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005).

    PubMed  PubMed Central  Google Scholar 

  157. Lyte, M., Varcoe, J. J. & Bailey, M. T. Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiol. Behav. 65, 63–68 (1998).

    CAS  PubMed  Google Scholar 

  158. Goehler, L. E., Park, S. M., Opitz, N., Lyte, M. & Gaykema, R. P. A. Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav. Immun. 22, 354–366 (2008).

    CAS  PubMed  Google Scholar 

  159. Bruch, J. D. Intestinal infection associated with future onset of an anxiety disorder: results of a nationally representative study. Brain Behav. Immun. 57, 222–226 (2016).

    PubMed  Google Scholar 

  160. Neufeld, K. M., Kang, N., Bienenstock, J. & Foster, J. A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–64, e119 (2011).

    CAS  PubMed  Google Scholar 

  161. Diaz Heijtz, R. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011). Together with references 44 and 143, this study is among the first in mice to demonstrate the effects of probiotics on anxiety-like behaviour, which may be dependent on the vagus nerve.

    PubMed  Google Scholar 

  162. Davis, D. J., Bryda, E. C., Gillespie, C. H. & Ericsson, A. C. Microbial modulation of behavior and stress responses in zebrafish larvae. Behav. Brain Res. 311, 219–227 (2016).

    PubMed  PubMed Central  Google Scholar 

  163. Crumeyrolle-Arias, M. et al. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology 42, 207–217 (2014).

    CAS  PubMed  Google Scholar 

  164. Hoban, A. E. et al. The microbiome regulates amygdala-dependent fear recall. Mol. Psychiatry 23, 1134–1144 (2018).

    CAS  PubMed  Google Scholar 

  165. Chu, C. et al. The microbiota regulate neuronal function and fear extinction learning. Nature 574, 543–548 (2019). This study discovers that gut bacteria are involved in fear extinction in mice, potentially through microbial metabolites.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609 (2011).

    CAS  PubMed  Google Scholar 

  167. Messaoudi, M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br. J. Nutr. 105, 755–764 (2011).

    CAS  PubMed  Google Scholar 

  168. Cowan, C. S. M., Callaghan, B. L. & Richardson, R. The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats. Transl. Psychiatry 6, e823 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Bermudez-Martin, P. et al. The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota. Preprint at BioRxiv https://doi.org/10.1101/2020.05.18.101147 (2020).

    Article  Google Scholar 

  170. Kang, D.-W. et al. Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe 49, 121–131 (2018).

    CAS  PubMed  Google Scholar 

  171. Wang, Y. et al. Probiotics and fructo-oligosaccharide intervention modulate the microbiota–gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder. Pharmacol. Res. 157, 104784 (2020).

    CAS  PubMed  Google Scholar 

  172. Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019).

    CAS  PubMed  Google Scholar 

  173. Cirstea, M. S. et al. Microbiota composition and metabolism are associated with gut function in Parkinson’s disease. Mov. Disord. 35, 1208–1217 (2020).

    CAS  PubMed  Google Scholar 

  174. Liu, B. et al. Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology 88, 1996–2002 (2017).

    PubMed  PubMed Central  Google Scholar 

  175. Perez-Pardo, P. et al. Role of TLR4 in the gut–brain axis in Parkinson’s disease: a translational study from men to mice. Gut 68, 829–843 (2019).

    CAS  PubMed  Google Scholar 

  176. Peter, I. et al. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 75, 939–946 (2018).

    PubMed  PubMed Central  Google Scholar 

  177. Chen, S. G. et al. Exposure to the functional bacterial amyloid protein curli enhances α-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci. Rep. 6, 34477 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. van de Wouw, M. et al. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations. J. Physiol. 596, 4923–4944 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. Allen, A. P. et al. Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers. Transl. Psychiatry 6, e939 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Dalile, B., Vervliet, B., Bergonzelli, G., Verbeke, K. & Van Oudenhove, L. Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: a randomized, placebo-controlled trial. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-0732-x (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  181. O’Leary, O. F. et al. GABAB(1) receptor subunit isoforms differentially regulate stress resilience. Proc. Natl Acad. Sci. USA 111, 15232–15237 (2014).

    PubMed  PubMed Central  Google Scholar 

  182. Desbonnet, L. et al. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179–1188 (2010).

    CAS  PubMed  Google Scholar 

  183. Kelly, J. R. et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain Behav. Immun. 61, 50–59 (2017).

    CAS  PubMed  Google Scholar 

  184. Ogbonnaya, E. S. et al. Adult hippocampal neurogenesis is regulated by the microbiome. Biol. Psychiatry 78, e7–e9 (2015).

    PubMed  Google Scholar 

  185. Lu, J. et al. Effects of intestinal microbiota on brain development in humanized gnotobiotic mice. Sci. Rep. 8, 5443 (2018).

    PubMed  PubMed Central  Google Scholar 

  186. Hoban, A. E. et al. Regulation of prefrontal cortex myelination by the microbiota. Transl. Psychiatry 6, e774 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Gacias, M. et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. eLife 5, e13442 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Codagnone, M. G. et al. Programming bugs: microbiota and the developmental origins of brain health and disease. Biol. Psychiatry 85, 150–163 (2019).

    CAS  PubMed  Google Scholar 

  189. Rao, M. & Gershon, M. D. Enteric nervous system development: what could possibly go wrong? Nat. Rev. Neurosci. 19, 552–565 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Kaiser, T. & Feng, G. Modeling psychiatric disorders for developing effective treatments. Nat. Med. 21, 979–988 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

S.K.M. is the Luis & Nelly Soux Professor of Microbiology at the California Institute of Technology (Caltech). His laboratory explores biological mechanisms by which the gut microbiota impacts immunological and neurological diseases, including research into mouse models of inflammatory bowel disease, autism spectrum disorder and Parkinson disease. The laboratory is supported by funding from the National Institutes of Health, the Department of Defense, the Heritage Medical Research Institute, the Michael J. Fox Foundation, Autism Speaks, Aligning Science Across Parkinson’s and other charitable organizations and individuals. L.H.M. is a postdoctoral scholar at Caltech and recipient of am American Parkinson’s Disease Association postdoctoral fellowship. H.L.S.IV is a postdoctoral scholar at Caltech and recipient of a Della Martin fellowship. The authors thank R. Abdel-Haq, J. Ousey and G. Sharon for constructive comments and N.J. Cruz and G. Tofani for assistance with the figures.

Author information

Authors and Affiliations

Authors

Contributions

L.H.M. wrote the initial draft of the manuscript with editorial input from H.L.S.IV and S.K.M. All authors contributed substantially to all aspects of the article and revised versions.

Corresponding authors

Correspondence to Livia H. Morais or Sarkis K. Mazmanian.

Ethics declarations

Competing interest

S.K.M. has financial interests in Axial Biotherapeutics, although not directly related to the contents of this article. All other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Microbiology thanks M. Costa-Mattioli, J. Raes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Microglia

The primary resident immune cells in the central nervous system, responsible for pathogen surveillance, immune protection and synaptic pruning. Microglia have been implicated in psychiatric and neurodegenerative disorders, largely in animal models.

Astrocytes

A subtype of glial cells in the central nervous system that play an essential role in blood–brain barrier formation and function, among other activates such as interfacing with microglia and neurons.

Oligodendrocytes

Brain cells that regulate development of neurons and insulate neuronal axons through the formation of the protective myelin sheath.

Homeostasis

The process of maintaining physiological functions necessary for survival of an organism.

Neuroplasticity

The ability of the nervous system to change activity by reorganizing its structure and function.

Epigenetic

DNA modifications that do not alter the sequence but can impact gene expression and biological outcomes.

Brain-derived neurotrophic factor

(BDNF). A protein that has an important role in neuronal survival, growth and synaptic plasticity. Alterations in expression are associated with mood disorders.

γ-Aminobutyric acid

(GABA). The main inhibitory neurotransmitter in the adult brain; crucial for synaptic plasticity and learning.

Serotonin

(5-Hydroxytryptamine (5-HT)). A neurotransmitter involved in controlling mood, social behaviour, gut motility and the sleep cycle.

Blood–brain barrier

(BBB). A physical gatekeeper to separate the brain microenvironment from the rest of the body, formed by mural and microvascular endothelial cells connected by tight-junction proteins.

Internal validity

A measure of the reliability of cause-and-effect relationships determined in a research setting. Internal validity can be improved with an experimental design including blind testing, unbiased analysis and appropriate statistical power.

External validity

A measure of how translatable findings from one experimental setting can be to other experimental settings and to the rest of the world. External validity fails when confounding factors are not considered or controlled in research.

Stress

A physiological and neurological response to demands for change in response to real or perceived threats.

Developmental windows

Crucial periods (for example, prenatal, early life and adolescence) in which dynamic changes in development and maturation of multiple physiological systems are susceptible to environmental factors, such as those of the microbiota.

Synapses

Highly specialized contacts between nerve cells that are the connections underlying dynamic and complex neuronal systems networks.

Oxytocin system

A key neuropeptide system that modulates social behaviour, bonding, mating and stress in animals. Known to be associated with symptoms of autism spectrum disorder.

Face and construct validity

Face validity is achieved when a wide range of features present in human disorders, such as behaviour and circuit abnormalities, are reproduced in an animal model. Construct validity refers to mimicking a disease aetiology in animals, such as environmental or genetic risks for human disease.

Vagotomy

A surgical procedure that severs the vagus nerve in one of several locations, disrupting signalling from various peripheral organs to the brain.

Allostasis

The active process of the body to maintain homeostasis in the face of stress.

Anhedonia

A reduced capacity to experience pleasure.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morais, L.H., Schreiber, H.L. & Mazmanian, S.K. The gut microbiota–brain axis in behaviour and brain disorders. Nat Rev Microbiol 19, 241–255 (2021). https://doi.org/10.1038/s41579-020-00460-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41579-020-00460-0

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing