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Published July 15, 2021 | Accepted Version + Supplemental Material
Journal Article Open

Microbiota regulate social behaviour via stress response neurons in the brain


Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence. The gut microbiota contribute to social activity in mice, but the gut–brain connections that regulate this complex behaviour and its underlying neural basis are unclear. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus–pituitary–adrenal (HPA) axis. Adrenalectomy, antagonism of glucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.

Additional Information

© The Author(s), under exclusive licence to Springer Nature Limited 2021. Received 05 January 2019; Accepted 25 May 2021; Published 30 June 2021. We thank H.-N. Huang for support and planning in the initial staged of this study; H. Chu, J. Boktor, members of the Mazmanian laboratory and B. E. Deverman for critically reviewing the manuscript; Y. Garcia-Flores for administrative assistance; T. M. Thron, OLAR at Caltech, and LAC at NCKU for animal husbandry; D. J. Anderson and L. C. Hsieh-Wilson for stereotaxic instruments; L.-C. Lo and H. Huang for technical assistance; and J.-W. Chen for biological materials. M. Costa-Mattioli, M. Sgritta and K. Imanbayev provided advice on vagotomy. The BIF at Caltech provided use of confocal microscopes. The CLOVER Center at Caltech provided viral vectors. This work was supported by funds from the Ministry of Science and Technology in Taiwan (MOST 107-2320-B-006-072-MY3; 108-2321-B-006-025-MY2; 109-2314-B-006-046), the Higher Education Sprout Project, Ministry of Education to the Headquarters of University Advancement (NCKU) to W.-L.W.; an NIH Biotechnology Leadership Pre-doctoral Training Program (BLP) Fellowship (T32GM112592) to J.T.B.; the National Science Foundation Graduate Research Fellowship Program (NSF GRFP No. DGE-1745301) to J.O.; a grant from the Jacobs Institute for Molecular Engineering for Medicine (Caltech), the Kenneth Rainin Foundation Innovator Award (2018-1207) to R.F.I.; and Lynda and Blaine Fetter, Charlie Trimble, the Heritage Medical Research Institute, and the NIH (MH100556) to S.K.M. Data availability: All data generated and analysed during this study are included in this published article and its Supplementary Information files. Raw data for 16S rRNA gene sequencing and data analysis have been deposited in the ENA database under BioProject PRJNA632893. Source data are provided with this paper. Author Contributions: W.-L.W., M.D.A., C.-W.L., J.T.B., T.-T.L., G.S., C.E.S., M.I.W., W.T., J.O., Y.-Y.L., T.-H.Y. and R.A.-H. performed the experiments and/or analysed data. J.T.B., G.S., B.D.N. and R.F.I. provided consultations regarding microbiome analysis. K.B. and V.G. provided novel viral vectors. W.-L.W. and S.K.M. designed the research. S.K.M. supervised the research. W.-L.W. and S.K.M. integrated the data, interpreted the results, and wrote the manuscript. All authors discussed the results and commented on the manuscript. Competing interests: W-L.W., M.D.A., B.D.N., and S.K.M. have filed a provisional patent on this work. All other authors declare no competing interests. Peer review information: Nature thanks Ioana Carcea and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Attached Files

Accepted Version - nihms-1723165.pdf

Supplemental Material - 41586_2021_3669_Fig10_ESM.webp

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Additional details

August 22, 2023
December 22, 2023