Gut microbiota regulate social behavior via a stress response pathway in the brain

Social interaction among animals mediates essential behaviors including mating, nurturing, and defense, and is controlled by internal states and external cues. While the intestinal microbiome contributes to aspects of social activity, gut-brain connections that regulate complex behaviors and their underlying neural basis remain poorly understood. Herein, we reveal that the microbiota modulates specific brain regions in mice related to canonical stress responses during social behavior paradigms. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced via activation of the hypothalamus-pituitary-adrenal (HPA) axis. Accordingly, removal of the adrenal gland, antagonism of the glucocorticoid receptor, and pharmacological inhibition of corticosterone synthesis effectively correct social deficits modulated by gut bacteria. Genetic ablation of the glucocorticoid receptor in specific brain regions and chemogenetic inactivation of neuronal populations in the paraventricular nucleus of the hypothalamus (PVN) dramatically rescue social impairments caused by microbiome depletion. Conversely, specific activation of corticotrophin-releasing hormone (CRH)-expressing neurons in the PVN of mice is sufficient to induce social deficits. Finally, we identify a specific bacterial species that promotes social activity in mice. These discoveries demonstrate that the gut microbiome can modulate social interactions via specific neuronal circuits that control stress responses in the brain.