Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice

Social impairment is a major symptom of neuropsychiatric conditions, such as autism spectrum disorder (ASD), schizophrenia, anxiety and depression. While the microbiome has been linked to social interaction in animals, gut-brain connections that regulate this complex behavior remain entirely undescribed. Herein, we demonstrate that depletion of microbiota in mice not only impairs social behavior, but also activates specific brain regions related to canonical stress responses. 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 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. Genetic ablation of the glucocorticoid receptor in specific brain regions and chemogenetic inactivation of hypothalamic neurons dramatically increase social behavior. Further, we identify specific bacterial metabolites that suppress activation of the HPA axis and improve social impairment. These findings reveal that the gut microbiome regulates social behavior by co-opting neuronal circuits that control stress responses in mice.