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.

The gut microbiome and mental health: advances in research and emerging priorities

Abstract

The gut microbiome exerts a considerable influence on human neurophysiology and mental health. Interactions between intestinal microbiology and host regulatory systems have now been implicated both in the development of psychiatric conditions and in the efficacy of many common therapies. With the growing acceptance of the role played by the gut microbiome in mental health outcomes, the focus of research is now beginning to shift from identifying relationships between intestinal microbiology and pathophysiology, and towards using this newfound insight to improve clinical outcomes. Here, we review recent advances in our understanding of gut microbiome–brain interactions, the mechanistic underpinnings of these relationships, and the ongoing challenge of distinguishing association and causation. We set out an overarching model of the evolution of microbiome–CNS interaction and examine how a growing knowledge of these complex systems can be used to determine disease susceptibility and reduce risk in a targeted manner.

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: The microbiome–gut–brain axis: active communication pathways connecting the microbiome and the central nervous system to affect brain function.
Fig. 2: The known key functional pathways of gut microbes that mediate neurological homeostasis.
Fig. 3: The evolutionary basis of microbiome–host interactions.

References

  1. Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016;21:738–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Wasser CI, Mercieca EC, Kong G, Hannan AJ, McKeown SJ, Glikmann-Johnston Y, et al. Gut dysbiosis in Huntington’s disease: associations among gut microbiota, cognitive performance and clinical outcomes. Brain Commun. 2020;2:fcaa110.

    PubMed  PubMed Central  Google Scholar 

  3. Jangi S, Gandhi R, Cox LM, Li N, von Glehn F, Yan R, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Nguyen TT, Kosciolek T, Daly RE, Vazquez-Baeza Y, Swafford A, Knight R, et al. Gut microbiome in Schizophrenia: altered functional pathways related to immune modulation and atherosclerotic risk. Brain Behav Immun. 2021;91:245–56.

    CAS  PubMed  Google Scholar 

  5. Xu R, Wu B, Liang J, He F, Gu W, Li K, et al. Altered gut microbiota and mucosal immunity in patients with schizophrenia. Brain Behav Immun. 2020;85:120–7.

    CAS  PubMed  Google Scholar 

  6. Zhu F, Ju Y, Wang W, Wang Q, Guo R, Ma Q, et al. Metagenome-wide association of gut microbiome features for schizophrenia. Nat Commun. 2020;11:1612.

    PubMed  PubMed Central  Google Scholar 

  7. Guan F, Ni T, Zhu W, Williams LK, Cui LB, Li M, et al. Integrative omics of schizophrenia: from genetic determinants to clinical classification and risk prediction. Mol Psychiatry. 2021. https://doi.org/10.1038/s41380-021-01201-2.

  8. Yang Z, Li J, Gui X, Shi X, Bao Z, Han H, et al. Updated review of research on the gut microbiota and their relation to depression in animals and human beings. Mol Psychiatry. 2020;25:2759–72.

    PubMed  Google Scholar 

  9. Zhang Q, Yun Y, An H, Zhao W, Ma T, Wang Z, et al. Gut microbiome composition associated with major depressive disorder and sleep quality. Front Psychiatry. 2021;12:645045.

    PubMed  PubMed Central  Google Scholar 

  10. Mason BL, Li Q, Minhajuddin A, Czysz AH, Coughlin LA, Hussain SK, et al. Reduced anti-inflammatory gut microbiota are associated with depression and anhedonia. J Affect Disord. 2020;266:394–401.

    CAS  PubMed  Google Scholar 

  11. Madan A, Thompson D, Fowler JC, Ajami NJ, Salas R, Frueh BC, et al. The gut microbiota is associated with psychiatric symptom severity and treatment outcome among individuals with serious mental illness. J Affect Disord. 2020;264:98–106.

    CAS  PubMed  Google Scholar 

  12. Niesler B, Rappold GA. Emerging evidence for gene mutations driving both brain and gut dysfunction in autism spectrum disorder. Mol Psychiatry. 2021;26:1442–4.

    PubMed  Google Scholar 

  13. Richarte V, Sanchez-Mora C, Corrales M, Fadeuilhe C, Vilar-Ribo L, Arribas L, et al. Gut microbiota signature in treatment-naive attention-deficit/hyperactivity disorder. Transl Psychiatry. 2021;11:382.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. de Bartolomeis A, Sarappa C, Magara S, Iasevoli F. Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur J Pharmacol. 2012;682:1–11.

    PubMed  Google Scholar 

  15. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391:1357–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sjostedt P, Enander J, Isung J. Serotonin reuptake inhibitors and the gut microbiome: significance of the gut microbiome in relation to mechanism of action, treatment response, side effects, and tachyphylaxis. Front Psychiatry. 2021;12:682868.

    PubMed  PubMed Central  Google Scholar 

  17. Morgan AP, Crowley JJ, Nonneman RJ, Quackenbush CR, Miller CN, Ryan AK, et al. The antipsychotic olanzapine interacts with the gut microbiome to cause weight gain in mouse. PLoS One. 2014;9:e115225.

    PubMed  PubMed Central  Google Scholar 

  18. Cussotto S, Strain CR, Fouhy F, Strain RG, Peterson VL, Clarke G, et al. Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function. Psychopharmacol (Berlin). 2019;236:1671–85.

    CAS  Google Scholar 

  19. Lukic I, Getselter D, Ziv O, Oron O, Reuveni E, Koren O, et al. Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior. Transl Psychiatry. 2019;9:133.

    PubMed  PubMed Central  Google Scholar 

  20. Lyte M, Daniels KM, Schmitz-Esser S. Fluoxetine-induced alteration of murine gut microbial community structure: evidence for a microbial endocrinology-based mechanism of action responsible for fluoxetine-induced side effects. PeerJ. 2019;7:e6199.

    PubMed  PubMed Central  Google Scholar 

  21. Ramsteijn AS, Jasarevic E, Houwing DJ, Bale TL, Olivier JD. Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression. Gut Microbes. 2020;11:735–53.

    PubMed  PubMed Central  Google Scholar 

  22. Fung TC, Vuong HE, Luna CDG, Pronovost GN, Aleksandrova AA, Riley NG, et al. Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut. Nat Microbiol. 2019;4:2064–73.

    PubMed  PubMed Central  Google Scholar 

  23. McGovern AS, Hamlin AS, Winter G. A review of the antimicrobial side of antidepressants and its putative implications on the gut microbiome. Aust N Z J Psychiatry. 2019;53:1151–66.

    PubMed  Google Scholar 

  24. Duan J, Huang Y, Tan X, Chai T, Wu J, Zhang H, et al. Characterization of gut microbiome in mice model of depression with divergent response to escitalopram treatment. Transl Psychiatry. 2021;11:303.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Shen Y, Yang X, Li G, Gao J, Liang Y. The change of gut microbiota in MDD patients under SSRIs treatment. Sci Rep. 2021;11:14918.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Nehme H, Saulnier P, Ramadan AA, Cassisa V, Guillet C, Eveillard M, et al. Antibacterial activity of antipsychotic agents, their association with lipid nanocapsules and its impact on the properties of the nanocarriers and on antibacterial activity. PLoS One. 2018;13:e0189950.

    PubMed  PubMed Central  Google Scholar 

  27. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Vich Vila A, Collij V, Sanna S, Sinha T, Imhann F, Bourgonje AR, et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat Commun. 2020;11:362.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Macedo D, Filho A, Soares de Sousa CN, Quevedo J, Barichello T, Junior HVN, et al. Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness. J Affect Disord. 2017;208:22–32.

    CAS  PubMed  Google Scholar 

  30. Yuan X, Wang Y, Li X, Jiang J, Kang Y, Pang L, et al. Gut microbial biomarkers for the treatment response in first-episode, drug-naive schizophrenia: a 24-week follow-up study. Transl Psychiatry. 2021;11:422.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Targum SD. Identification and treatment of antidepressant tachyphylaxis. Innov Clin Neurosci. 2014;11:24–8.

    PubMed  PubMed Central  Google Scholar 

  32. Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 2017;179:204–22.

    CAS  PubMed  Google Scholar 

  33. Xie Y, Hu F, Xiang D, Lu H, Li W, Zhao A, et al. The metabolic effect of gut microbiota on drugs. Drug Metab Rev. 2020;52:139–56.

    CAS  PubMed  Google Scholar 

  34. Seeman MV. The gut microbiome and antipsychotic treatment response. Behav Brain Res. 2021;396:112886.

    PubMed  Google Scholar 

  35. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011;23:255–64.e119.

    CAS  PubMed  Google Scholar 

  36. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA. 2011;108:3047–52.

    PubMed  Google Scholar 

  37. Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141:599–609.e1-3.

    CAS  PubMed  Google Scholar 

  38. Wang S, Ishima T, Zhang J, Qu Y, Chang L, Pu Y, et al. Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve. J Neuroinflammation. 2020;17:241.

    PubMed  PubMed Central  Google Scholar 

  39. Ericsson AC, Hart ML, Kwan J, Lanoue L, Bower LR, Araiza R, et al. Supplier-origin mouse microbiomes significantly influence locomotor and anxiety-related behavior, body morphology, and metabolism. Commun Biol. 2021;4:716.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Data & Statistics on Austism Spectrum Disorder: Centers for Disease Control and Prevention. 2020. https://www.cdc.gov/ncbddd/autism/data.html.

  41. Li Y, Luo ZY, Hu YY, Bi YW, Yang JM, Zou WJ, et al. The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice. Microbiome. 2020;8:120.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sharon G, Cruz NJ, Kang DW, Gandal MJ, Wang B, Kim YM, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell. 2019;177:1600–18.e17.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167:1469–80.e12.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, et al. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-alpha signaling pathway. Brain Behav Immun. 2018;70:48–60.

    CAS  PubMed  Google Scholar 

  45. Kim MS, Kim Y, Choi H, Kim W, Park S, Lee D, et al. Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model. Gut. 2020;69:283–94.

    CAS  PubMed  Google Scholar 

  46. Du G, Dong W, Yang Q, Yu X, Ma J, Gu W, et al. Altered gut microbiota related to inflammatory responses in patients with Huntington’s disease. Front Immunol. 2020;11:603594.

    CAS  PubMed  Google Scholar 

  47. Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med. 2008;205:1869–77.

    PubMed  PubMed Central  Google Scholar 

  48. Fulling C, Dinan TG, Cryan JF. Gut microbe to brain signaling: what happens in vagus. Neuron. 2019;101:998–1002.

    CAS  PubMed  Google Scholar 

  49. Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, et al. A gut-brain neural circuit for nutrient sensory transduction. Science. 2018;361:eaat5236.

  50. Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, et al. A neural circuit for gut-induced reward. Cell. 2018;175:665–78.e23.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang FB, Powley TL. Vagal innervation of intestines: afferent pathways mapped with new en bloc horseradish peroxidase adaptation. Cell Tissue Res. 2007;329:221–30.

    PubMed  Google Scholar 

  52. Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci. 2018;12:49.

    PubMed  PubMed Central  Google Scholar 

  53. Raybould HE. Gut chemosensing: interactions between gut endocrine cells and visceral afferents. Auton Neurosci. 2010;153:41–6.

    CAS  PubMed  Google Scholar 

  54. Buckley MM, O’Brien R, Brosnan E, Ross RP, Stanton C, Buckley JM, 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. 2020;14:95.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Ye L, Bae M, Cassilly CD, Jabba SV, Thorpe DW, Martin AM, et al. Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways. Cell Host Microbe. 2021;29:179–96.e9.

    CAS  PubMed  Google Scholar 

  56. Goehler LE, Gaykema RP, Opitz N, Reddaway R, Badr N, Lyte M. Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun. 2005;19:334–44.

    PubMed  Google Scholar 

  57. Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron. 2019;101:246–59.e6.

    CAS  PubMed  Google Scholar 

  58. Zhang J, Ma L, Chang L, Pu Y, Qu Y, Hashimoto K. A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration. Transl Psychiatry. 2020;10:186.

    PubMed  PubMed Central  Google Scholar 

  59. Lee KE, Kim JK, Han SK, Lee DY, Lee HJ, Yim SV, et al. The extracellular vesicle of gut microbial Paenalcaligenes hominis is a risk factor for vagus nerve-mediated cognitive impairment. Microbiome. 2020;8:107.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Buffington SA, Dooling SW, Sgritta M, Noecker C, Murillo OD, Felice DF, et al. Dissecting the contribution of host genetics and the microbiome in complex behaviors. Cell. 2021;184:1740–56 e16.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Liu Y, Forsythe P. Vagotomy and insights into the microbiota-gut-brain axis. Neurosci Res. 2021;168:20–7.

    CAS  PubMed  Google Scholar 

  62. Liu Y, Sanderson D, Mian MF, McVey Neufeld KA, Forsythe P. Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response. Neuropharmacology. 2021;195:108682.

    CAS  PubMed  Google Scholar 

  63. Marx W, McGuinness AJ, Rocks T, Ruusunen A, Cleminson J, Walker AJ, et al. The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies. Mol Psychiatry. 2021;26:4158–78.

  64. Lai WT, Zhao J, Xu SX, Deng WF, Xu D, Wang MB, et al. Shotgun metagenomics reveals both taxonomic and tryptophan pathway differences of gut microbiota in bipolar disorder with current major depressive episode patients. J Affect Disord. 2021;278:311–9.

    CAS  PubMed  Google Scholar 

  65. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Brummelte S, Galea LA. Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats. Neuroscience. 2010;168:680–90.

    CAS  PubMed  Google Scholar 

  67. Levone BR, Codagnone MG, Moloney GM, Nolan YM, Cryan JF, O‘Leary OF. Adult-born neurons from the dorsal, intermediate, and ventral regions of the longitudinal axis of the hippocampus exhibit differential sensitivity to glucocorticoids. Mol Psychiatry. 2021;26:3240–52.

  68. Luo Y, Zeng B, Zeng L, Du X, Li B, Huo R, et al. Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus. Transl Psychiatry. 2018;8:187.

    PubMed  PubMed Central  Google Scholar 

  69. Sun JH, Cai GJ, Xiang ZH. Expression of P2X purinoceptors in PC12 phaeochromocytoma cells. Clin Exp Pharm Physiol. 2007;34:1282–6.

    CAS  Google Scholar 

  70. Jepma M, Deinum J, Asplund CL, Rombouts SA, Tamsma JT, Tjeerdema N, et al. Neurocognitive function in dopamine-beta-hydroxylase deficiency. Neuropsychopharmacology. 2011;36:1608–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Miecz D, Januszewicz E, Czeredys M, Hinton BT, Berezowski V, Cecchelli R, et al. Localization of organic cation/carnitine transporter (OCTN2) in cells forming the blood-brain barrier. J Neurochem. 2008;104:113–23.

    CAS  PubMed  Google Scholar 

  72. Wu WL, Adame MD, Liou CW, Barlow JT, Lai TT, Sharon G, et al. Microbiota regulate social behaviour via stress response neurons in the brain. Nature. 2021;595:409–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Correa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MA. Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunol. 2016;5:e73.

    Google Scholar 

  74. 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. 2019;16:461–78.

    PubMed  Google Scholar 

  75. Rodrigues HG, Takeo Sato F, Curi R, Vinolo MAR. Fatty acids as modulators of neutrophil recruitment, function and survival. Eur J Pharmacol. 2016;785:50–8.

    CAS  PubMed  Google Scholar 

  76. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013;145:396–406.e1–10.

    CAS  PubMed  Google Scholar 

  77. Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18:965–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Yang G, Chen S, Deng B, Tan C, Deng J, Zhu G, et al. Implication of G protein-coupled receptor 43 in intestinal inflammation: a mini-review. Front Immunol. 2018;9:1434.

    PubMed  PubMed Central  Google Scholar 

  79. Arentsen T, Qian Y, Gkotzis S, Femenia T, Wang T, Udekwu K, et al. The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior. Mol Psychiatry. 2017;22:257–66.

    CAS  PubMed  Google Scholar 

  80. Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA. 1998;95:10896–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Finneran DJ, Nash KR. Neuroinflammation and fractalkine signaling in Alzheimer’s disease. J Neuroinflammation. 2019;16:30.

    PubMed  PubMed Central  Google Scholar 

  82. Cao P, Chen C, Liu A, Shan Q, Zhu X, Jia C, et al. Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines. Neuron. 2021;109:2573–89.e9.

  83. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Howes OD, McCutcheon R. Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization. Transl Psychiatry. 2017;7:e1024.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature. 2017;549:528–32.

    PubMed  PubMed Central  Google Scholar 

  86. Alves de Lima K, Rustenhoven J, Da Mesquita S, Wall M, Salvador AF, Smirnov I, et al. Meningeal gammadelta T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol. 2020;21:1421–9.

    CAS  PubMed  Google Scholar 

  87. Regen T, Isaac S, Amorim A, Nunez NG, Hauptmann J, Shanmugavadivu A, et al. IL-17 controls central nervous system autoimmunity through the intestinal microbiome. Sci Immunol. 2021;6:eaaz6563.

  88. Fitzpatrick Z, Frazer G, Ferro A, Clare S, Bouladoux N, Ferdinand J, et al. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature. 2020;587:472–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019;4:623–32.

    CAS  PubMed  Google Scholar 

  90. Soto M, Herzog C, Pacheco JA, Fujisaka S, Bullock K, Clish CB, et al. Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. Mol Psychiatry. 2018;23:2287–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Riederer P, Korczyn AD, Ali SS, Bajenaru O, Choi MS, Chopp M, et al. The diabetic brain and cognition. J Neural Transm (Vienna). 2017;124:1431–54.

    PubMed  Google Scholar 

  92. Bertrand PP, Bertrand RL. Serotonin release and uptake in the gastrointestinal tract. Auton Neurosci. 2010;153:47–57.

    CAS  PubMed  Google Scholar 

  93. Bohorquez DV, Chandra R, Samsa LA, Vigna SR, Liddle RA. Characterization of basal pseudopod-like processes in ileal and colonic PYY cells. J Mol Histol. 2011;42:3–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Bellono NW, Bayrer JR, Leitch DB, Castro J, Zhang C, O’Donnell TA, et al. Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell. 2017;170:185–98.e16.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Sternini C, Anselmi L, Rozengurt E. Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing. Curr Opin Endocrinol Diabetes Obes. 2008;15:73–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yu Y, Yang W, Li Y, Cong Y. Enteroendocrine cells: sensing gut microbiota and regulating inflammatory bowel diseases. Inflamm Bowel Dis. 2020;26:11–20.

    PubMed  Google Scholar 

  97. Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, depression, and the microbiome: a role for gut peptides. Neurotherapeutics. 2018;15:36–59.

    CAS  PubMed  Google Scholar 

  98. Erspamer V. Pharmacology of indole-alkylamines. Pharm Rev. 1954;6:425–87.

    CAS  PubMed  Google Scholar 

  99. Martin AM, Yabut JM, Choo JM, Page AJ, Sun EW, Jessup CF, et al. The gut microbiome regulates host glucose homeostasis via peripheral serotonin. Proc Natl Acad Sci USA. 2019;116:19802–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161:264–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Reigstad CS, Salmonson CE, Rainey JF 3rd, Szurszewski JH, Linden DR, Sonnenburg JL, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 2015;29:1395–403.

    CAS  PubMed  Google Scholar 

  102. Colosimo DA, Kohn JA, Luo PM, Piscotta FJ, Han SM, Pickard AJ, et al. Mapping interactions of microbial metabolites with human G-protein-coupled receptors. Cell Host Microbe. 2019;26:273–82.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Lund ML, Egerod KL, Engelstoft MS, Dmytriyeva O, Theodorsson E, Patel BA, et al. Enterochromaffin 5-HT cells – a major target for GLP-1 and gut microbial metabolites. Mol Metab. 2018;11:70–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang H, Kwon YH, Dewan V, Vahedi F, Syed S, Fontes ME, et al. TLR2 plays a pivotal role in mediating mucosal serotonin production in the gut. J Immunol. 2019;202:3041–52.

    CAS  PubMed  Google Scholar 

  105. Martin AM, Lumsden AL, Young RL, Jessup CF, Spencer NJ, Keating DJ. The nutrient-sensing repertoires of mouse enterochromaffin cells differ between duodenum and colon. Neurogastroenterol Motil. 2017;29.e13046.

  106. De Silva A, Salem V, Long CJ, Makwana A, Newbould RD, Rabiner EA, et al. The gut hormones PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain activity in appetite centers in humans. Cell Metab. 2011;14:700–6.

    PubMed  PubMed Central  Google Scholar 

  107. Detka J, Glombik K. Insights into a possible role of glucagon-like peptide-1 receptor agonists in the treatment of depression. Pharm Rep. 2021;73:1020–32.

    CAS  Google Scholar 

  108. Martchenko SE, Martchenko A, Cox BJ, Naismith K, Waller A, Gurges P, et al. Circadian GLP-1 secretion in mice is dependent on the intestinal microbiome for maintenance of diurnal metabolic homeostasis. Diabetes. 2020;69:2589–602.

    CAS  PubMed  Google Scholar 

  109. Kaczmarek JL, Musaad SM, Holscher HD. Time of day and eating behaviors are associated with the composition and function of the human gastrointestinal microbiota. Am J Clin Nutr. 2017;106:1220–31.

    CAS  PubMed  Google Scholar 

  110. Zarrinpar A, Chaix A, Yooseph S, Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 2014;20:1006–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell. 2014;159:514–29.

    CAS  PubMed  Google Scholar 

  112. Chandra R, Hiniker A, Kuo YM, Nussbaum RL, Liddle RA. alpha-Synuclein in gut endocrine cells and its implications for Parkinson’s disease. JCI Insight. 2017;2:e92295.

  113. Braak H, Rub U, Gai WP, Del, Tredici K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna). 2003;110:517–36.

    CAS  PubMed  Google Scholar 

  114. Li H, Wang P, Huang L, Li P, Zhang D. Effects of regulating gut microbiota on the serotonin metabolism in the chronic unpredictable mild stress rat model. Neurogastroenterol Motil. 2019;31:e13677.

    PubMed  PubMed Central  Google Scholar 

  115. Kaur H, Bose C, Mande SS. Tryptophan metabolism by gut microbiome and gut-brain-axis: an in silico analysis. Front Neurosci. 2019;13:1365.

    PubMed  PubMed Central  Google Scholar 

  116. Kwon YH, Wang H, Denou E, Ghia JE, Rossi L, Fontes ME, et al. Modulation of gut microbiota composition by serotonin signaling influences intestinal immune response and susceptibility to colitis. Cell Mol Gastroenterol Hepatol. 2019;7:709–28.

    PubMed  PubMed Central  Google Scholar 

  117. Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol. 2015;16:461–72.

    CAS  PubMed  Google Scholar 

  118. Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol. 2018;19:579–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Marks PA, Richon VM, Miller T, Kelly WK. Histone deacetylase inhibitors. Adv Cancer Res. 2004;91:137–68.

    CAS  PubMed  Google Scholar 

  120. Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2004;101:18030–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Shi CS, Kehrl JH. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J Biol Chem. 2008;283:33175–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Xu Y, Jagannath C, Liu XD, Sharafkhaneh A, Kolodziejska KE, Eissa NT. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007;27:135–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Silva MC, Nandi GA, Tentarelli S, Gurrell IK, Jamier T, Lucente D, et al. Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons. Nat Commun. 2020;11:3258.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Xu Y, Propson NE, Du S, Xiong W, Zheng H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc Natl Acad Sci USA. 2021;118:e2023418118.

  125. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19:983–97.

    CAS  PubMed  Google Scholar 

  126. Fujikake N, Shin M, Shimizu S. Association between autophagy and neurodegenerative diseases. Front Neurosci. 2018;12:255.

    PubMed  PubMed Central  Google Scholar 

  127. Cani PD, Plovier H, Van Hul M, Geurts L, Delzenne NM, Druart C, et al. Endocannabinoids-at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol. 2016;12:133–43.

    CAS  PubMed  Google Scholar 

  128. Sharkey KA, Wiley JW. The role of the endocannabinoid system in the brain-gut axis. Gastroenterology. 2016;151:252–66.

    CAS  PubMed  Google Scholar 

  129. Minichino A, Jackson MA, Francesconi M, Steves CJ, Menni C, Burnet PWJ, et al. Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort. Mol Psychiatry. 2021;26:6269–76.

  130. Minichino A, Senior M, Brondino N, Zhang SH, Godwlewska BR, Burnet PWJ, et al. Measuring disturbance of the endocannabinoid system in psychosis: a systematic review and meta-analysis. JAMA Psychiatry. 2019;76:914–23.

    PubMed  PubMed Central  Google Scholar 

  131. Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014;346:89–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22:586–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372–85.

    CAS  PubMed  Google Scholar 

  134. Schroeder JC, Dinatale BC, Murray IA, Flaveny CA, Liu Q, Laurenzana EM, et al. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry. 2010;49:393–400.

    CAS  PubMed  Google Scholar 

  135. Rao J, Qiao Y, Xie R, Lin L, Jiang J, Wang C, et al. Fecal microbiota transplantation ameliorates stress-induced depression-like behaviors associated with the inhibition of glial and NLRP3 inflammasome in rat brain. J Psychiatr Res. 2021;137:147–57.

    PubMed  Google Scholar 

  136. Zhang Y, Huang R, Cheng M, Wang L, Chao J, Li J, et al. Gut microbiota from NLRP3-deficient mice ameliorates depressive-like behaviors by regulating astrocyte dysfunction via circHIPK2. Microbiome. 2019;7:116.

    PubMed  PubMed Central  Google Scholar 

  137. Shukla PK, Delotterie DF, Xiao J, Pierre JF, Rao R, McDonald MP, et al. Alterations in the gut-microbial-inflammasome-brain axis in a mouse model of Alzheimer’s disease. Cells. 2021;10:779.

  138. Fang P, Kazmi SA, Jameson KG, Hsiao EY. The microbiome as a modifier of neurodegenerative disease risk. Cell Host Microbe. 2020;28:201–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhu S, Jiang Y, Xu K, Cui M, Ye W, Zhao G, et al. The progress of gut microbiome research related to brain disorders. J Neuroinflammation. 2020;17:25.

    PubMed  PubMed Central  Google Scholar 

  140. Simpson CA, Diaz-Arteche C, Eliby D, Schwartz OS, Simmons JG, Cowan CSM. The gut microbiota in anxiety and depression – a systematic review. Clin Psychol Rev. 2021;83:101943.

    PubMed  Google Scholar 

  141. Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. The central nervous system and the gut microbiome. Cell. 2016;167:915–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99:1877–2013.

    CAS  PubMed  Google Scholar 

  143. Firth J, Gangwisch JE, Borisini A, Wootton RE, Mayer EA. Food and mood: how do diet and nutrition affect mental wellbeing? BMJ. 2020;369:m2382.

    PubMed  PubMed Central  Google Scholar 

  144. Asnicar F, Berry SE, Valdes AM, Nguyen LH, Piccinno G, Drew DA, et al. Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals. Nat Med. 2021;27:321–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Mobegi FM, Leong LE, Thompson F, Taylor SM, Harriss LR, Choo JM, et al. Intestinal microbiology shapes population health impacts of diet and lifestyle risk exposures in Torres Strait Islander communities. Elife. 2020;9:e58407.

  146. Larroya A, Pantoja J, Codoner-Franch P, Cenit MC. Towards tailored gut microbiome-based and dietary interventions for promoting the development and maintenance of a healthy brain. Front Pediatr. 2021;9:705859.

    PubMed  PubMed Central  Google Scholar 

  147. Marx W, Lane M, Hockey M, Aslam H, Berk M, Walder K, et al. Diet and depression: exploring the biological mechanisms of action. Mol Psychiatry. 2021;26:134–50.

    PubMed  Google Scholar 

  148. Firth J, Veronese N, Cotter J, Shivappa N, Hebert JR, Ee C, et al. What is the role of dietary inflammation in severe mental illness? A review of observational and experimental findings. Front Psychiatry. 2019;10:350.

    PubMed  PubMed Central  Google Scholar 

  149. Melo HM, Santos LE, Ferreira ST. Diet-derived fatty acids, brain inflammation, and mental health. Front Neurosci. 2019;13:265.

    PubMed  PubMed Central  Google Scholar 

  150. Guo Y, Zhu X, Zeng M, Qi L, Tang X, Wang D, et al. A diet high in sugar and fat influences neurotransmitter metabolism and then affects brain function by altering the gut microbiota. Transl Psychiatry. 2021;11:328.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Kaptan Z, Akgun-Dar K, Kapucu A, Dedeakayogullari H, Batu S, Uzum G. Long term consequences on spatial learning-memory of low-calorie diet during adolescence in female rats; hippocampal and prefrontal cortex BDNF level, expression of NeuN and cell proliferation in dentate gyrus. Brain Res. 2015;1618:194–204.

    CAS  PubMed  Google Scholar 

  152. 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;96:557–67.

    CAS  PubMed  Google Scholar 

  153. Bruce-Keller AJ, Salbaum JM, Luo M, Blanchard ET, Taylor CM, Welsh DA, et al. Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol Psychiatry. 2015;77:607–15.

    PubMed  Google Scholar 

  154. Khambadkone SG, Cordner ZA, Dickerson F, Severance EG, Prandovszky E, Pletnikov M, et al. Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats. Mol Psychiatry. 2020;25:560–71.

    PubMed  Google Scholar 

  155. Matt SM, Allen JM, Lawson MA, Mailing LJ, Woods JA, Johnson RW. Butyrate and dietary soluble fiber improve neuroinflammation associated with aging in mice. Front Immunol. 2018;9:1832.

    PubMed  PubMed Central  Google Scholar 

  156. Kimura-Todani T, Hata T, Miyata N, Takakura S, Yoshihara K, Zhang XT, et al. Dietary delivery of acetate to the colon using acylated starches as a carrier exerts anxiolytic effects in mice. Physiol Behav. 2020;223:113004.

    CAS  PubMed  Google Scholar 

  157. Medawar E, Huhn S, Villringer A, Veronica Witte A. The effects of plant-based diets on the body and the brain: a systematic review. Transl Psychiatry. 2019;9:226.

    PubMed  PubMed Central  Google Scholar 

  158. Ghosh TS, Rampelli S, Jeffery IB, Santoro A, Neto M, Capri M, et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut. 2020;69:1218–28.

    CAS  PubMed  Google Scholar 

  159. Gomez-Donoso C, Sanchez-Villegas A, Martinez-Gonzalez MA, Gea A, Mendonca RD, Lahortiga-Ramos F, et al. Ultra-processed food consumption and the incidence of depression in a Mediterranean cohort: the SUN Project. Eur J Nutr. 2020;59:1093–103.

    PubMed  Google Scholar 

  160. Di Gesu CM, Matz LM, Buffington SA. Diet-induced dysbiosis of the maternal gut microbiome in early life programming of neurodevelopmental disorders. Neurosci Res. 2021;168:3–19.

    PubMed  Google Scholar 

  161. Bodden C, Hannan AJ, Reichelt AC. Of ‘junk food’ and ‘brain food’: how parental diet influences offspring neurobiology and behaviour. Trends Endocrinol Metab. 2021;32:566–78.

    CAS  PubMed  Google Scholar 

  162. Bordeleau M, Fernandez de Cossio L, Chakravarty MM, Tremblay ME. From maternal diet to neurodevelopmental disorders: a story of neuroinflammation. Front Cell Neurosci. 2020;14:612705.

    CAS  PubMed  Google Scholar 

  163. Carbia C, Lannoy S, Maurage P, Lopez-Caneda E, O’Riordan KJ, Dinan TG, et al. A biological framework for emotional dysregulation in alcohol misuse: from gut to brain. Mol Psychiatry. 2021;26:1098–118.

    PubMed  Google Scholar 

  164. Qamar N, Castano D, Patt C, Chu T, Cottrell J, Chang SL. Meta-analysis of alcohol induced gut dysbiosis and the resulting behavioral impact. Behav Brain Res. 2019;376:112196.

    PubMed  Google Scholar 

  165. de Timary P, Starkel P, Delzenne NM, Leclercq S. A role for the peripheral immune system in the development of alcohol use disorders? Neuropharmacology. 2017;122:148–60.

    PubMed  Google Scholar 

  166. Hillemacher T, Bachmann O, Kahl KG, Frieling H. Alcohol, microbiome, and their effect on psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2018;85:105–15.

    CAS  PubMed  Google Scholar 

  167. Ma X, Xiao W, Li H, Pang P, Xue F, Wan L, et al. Metformin restores hippocampal neurogenesis and learning and memory via regulating gut microbiota in the obese mouse model. Brain Behav Immun. 2021;95:68–83.

    CAS  PubMed  Google Scholar 

  168. Wang Z, Chen WH, Li SX, He ZM, Zhu WL, Ji YB, et al. Gut microbiota modulates the inflammatory response and cognitive impairment induced by sleep deprivation. Mol Psychiatry. 2021;26:6277–92.

  169. Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology. 2016;17:7–19.

    CAS  PubMed  Google Scholar 

  170. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69:S4–9.

    PubMed  Google Scholar 

  171. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14:576–90.

    CAS  PubMed  Google Scholar 

  172. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396:413–46.

    PubMed  PubMed Central  Google Scholar 

  173. Lopes PC, Block P, Konig B. Infection-induced behavioural changes reduce connectivity and the potential for disease spread in wild mice contact networks. Sci Rep. 2016;6:31790.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Wallner B, Machatschke IH. Influence of nutrition on aggression. CAB Rev. 2010;4:1–10.

    Google Scholar 

  175. Haagensen AM, Sorensen DB, Sandoe P, Matthews LR, Birck MM, Fels JJ, et al. High fat, low carbohydrate diet limit fear and aggression in Gottingen minipigs. PLoS One. 2014;9:e93821.

    PubMed  PubMed Central  Google Scholar 

  176. Hanstock TL, Clayton EH, Li KM, Mallet PE. Anxiety and aggression associated with the fermentation of carbohydrates in the hindgut of rats. Physiol Behav. 2004;82:357–68.

    CAS  PubMed  Google Scholar 

  177. Breithaupt L, Kohler-Forsberg O, Larsen JT, Benros ME, Thornton LM, Bulik CM, et al. Association of exposure to infections in childhood with risk of eating disorders in adolescent girls. JAMA Psychiatry. 2019;76:800–9.

    PubMed  PubMed Central  Google Scholar 

  178. Lassale C, Batty GD, Baghdadli A, Jacka F, Sanchez-Villegas A, Kivimaki M, et al. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Mol Psychiatry. 2019;24:965–86.

    PubMed  Google Scholar 

  179. Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25:1822–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Shukla AK, Johnson K, Giniger E. Common features of aging fail to occur in Drosophila raised without a bacterial microbiome. iScience. 2021;24:102703.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Lynn MA, Eden G, Ryan FJ, Bensalem J, Wang X, Blake SJ, et al. The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life. Cell Rep. 2021;36:109564.

    CAS  PubMed  Google Scholar 

  182. Morkl S, Butler MI, Holl A, Cryan JF, Dinan TG. Probiotics and the microbiota-gut-brain axis: focus on psychiatry. Curr Nutr Rep. 2020;9:171–82.

    PubMed  PubMed Central  Google Scholar 

  183. Desai V, Kozyrskyj AL, Lau S, Sanni O, Dennett L, Walter J, et al. Effectiveness of probiotic, prebiotic, and synbiotic supplementation to improve perinatal mental health in mothers: a systematic review and meta-analysis. Front Psychiatry. 2021;12:622181.

    PubMed  PubMed Central  Google Scholar 

  184. Ng QX, Soh AYS, Venkatanarayanan N, Ho CYX, Lim DY, Yeo WS. A systematic review of the effect of probiotic supplementation on schizophrenia symptoms. Neuropsychobiology. 2019;78:1–6.

    PubMed  Google Scholar 

  185. Johnson D, Thurairajasingam S, Letchumanan V, Chan KG, Lee LH. Exploring the role and potential of probiotics in the field of mental health: major depressive disorder. Nutrients. 2021;13:1728.

  186. Barbosa RSD, Vieira-Coelho MA. Probiotics and prebiotics: focus on psychiatric disorders – a systematic review. Nutr Rev. 2020;78:437–50.

    PubMed  Google Scholar 

  187. Liu RT, Walsh RFL, Sheehan AE. Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials. Neurosci Biobehav Rev. 2019;102:13–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Minichino A, Brondino N, Solmi M, Del Giovane C, Fusar-Poli P, Burnet P, et al. The gut-microbiome as a target for the treatment of schizophrenia: a systematic review and meta-analysis of randomised controlled trials of add-on strategies. Schizophr Res. 2021;234:1–13.

    PubMed  Google Scholar 

  189. Marx W, Scholey A, Firth J, D’Cunha NM, Lane M, Hockey M, et al. Prebiotics, probiotics, fermented foods and cognitive outcomes: a meta-analysis of randomized controlled trials. Neurosci Biobehav Rev. 2020;118:472–84.

    CAS  PubMed  Google Scholar 

  190. Martins LB, Braga Tibaes JR, Sanches M, Jacka F, Berk M, Teixeira AL. Nutrition-based interventions for mood disorders. Expert Rev Neurother. 2021;21:303–15.

    CAS  PubMed  Google Scholar 

  191. Alegria M, NeMoyer A, Falgas Bague I, Wang Y, Alvarez K. Social determinants of mental health: where we are and where we need to go. Curr Psychiatry Rep. 2018;20:95.

    PubMed  PubMed Central  Google Scholar 

  192. Adan RAH, van der Beek EM, Buitelaar JK, Cryan JF, Hebebrand J, Higgs S, et al. Nutritional psychiatry: towards improving mental health by what you eat. Eur Neuropsychopharmacol. 2019;29:1321–32.

    CAS  PubMed  Google Scholar 

  193. Jing Y, Yu Y, Bai F, Wang L, Yang D, Zhang C, et al. Effect of fecal microbiota transplantation on neurological restoration in a spinal cord injury mouse model: involvement of brain-gut axis. Microbiome. 2021;9:59.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Settanni CR, Ianiro G, Bibbo S, Cammarota G, Gasbarrini A. Gut microbiota alteration and modulation in psychiatric disorders: current evidence on fecal microbiota transplantation. Prog Neuropsychopharmacol Biol Psychiatry. 2021;109:110258.

    CAS  PubMed  Google Scholar 

  195. Flint HJ, Duncan SH, Scott KP, Louis P. Links between diet, gut microbiota composition and gut metabolism. Proc Nutr Soc. 2015;74:13–22.

    CAS  PubMed  Google Scholar 

  196. Reichardt N, Duncan SH, Young P, Belenguer A, McWilliam Leitch C, Scott KP, et al. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J. 2014;8:1323–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Kessell AK, McCullough HC, Auchtung JM, Bernstein HC, Song H-S. Predictive interactome modeling for precision microbiome engineering. Curr Opin Chem Eng. 2020;30:77–85.

    Google Scholar 

  198. Choo JM, Rogers GB. Establishment of murine gut microbiota in gnotobiotic mice. iScience. 2021;24:102049.

    PubMed  PubMed Central  Google Scholar 

  199. Choo JM, Rogers GB. Gut microbiota transplantation for colonization of germ-free mice. STAR Protoc. 2021;2:100610.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

GBR conceptualised the idea for the manuscript. APS, JMC, AMM, DJK and GBR reviewed the literature and edited the manuscript. APS, JMC and GBR drafted the manuscript. APS, JMC, AMM, DJK, M-LW, JL and GBR revised, edited and approved the final version of the manuscript.

Corresponding author

Correspondence to Geraint B. Rogers.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shoubridge, A.P., Choo, J.M., Martin, A.M. et al. The gut microbiome and mental health: advances in research and emerging priorities. Mol Psychiatry 27, 1908–1919 (2022). https://doi.org/10.1038/s41380-022-01479-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01479-w

Further reading

Search

Quick links