Microbiota regulate social behaviour via stress response neurons in the brain

Wei-Li Wu (), Mark D. Adame, Chia-Wei Liou, Jacob T. Barlow, Tzu-Ting Lai, Gil Sharon, Catherine E. Schretter, Brittany D. Needham, Madelyn I. Wang, Weiyi Tang, James Ousey, Yuan-Yuan Lin, Tzu-Hsuan Yao, Reem Abdel-Haq, Keith Beadle, Viviana Gradinaru, Rustem F. Ismagilov and Sarkis K. Mazmanian
Additional contact information
Wei-Li Wu: California Institute of Technology
Mark D. Adame: California Institute of Technology
Chia-Wei Liou: National Cheng Kung University
Jacob T. Barlow: California Institute of Technology
Tzu-Ting Lai: National Cheng Kung University
Gil Sharon: California Institute of Technology
Catherine E. Schretter: California Institute of Technology
Brittany D. Needham: California Institute of Technology
Madelyn I. Wang: California Institute of Technology
Weiyi Tang: California Institute of Technology
James Ousey: California Institute of Technology
Yuan-Yuan Lin: National Cheng Kung University
Tzu-Hsuan Yao: National Cheng Kung University
Reem Abdel-Haq: California Institute of Technology
Keith Beadle: California Institute of Technology
Viviana Gradinaru: California Institute of Technology
Rustem F. Ismagilov: California Institute of Technology
Sarkis K. Mazmanian: California Institute of Technology

Nature, 2021, vol. 595, issue 7867, 409-414

Abstract: Abstract Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut–brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03669-y

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