Sleep interacts reciprocally with the gut microbiota. However, mechanisms of the gut microbe-brain metabolic axis that are responsible for sleep behavior have remained largely unknown. Here, we showed that the absence of the gut microbiota can alter sleep behavior. Sleep deprivation reduced butyrate levels in fecal content and the hypothalamus in specific pathogen-free mice but not in germ-free mice. The microbial metabolite butyrate can promote sleep by modulating orexin neuronal activity in the lateral hypothalamic area in mice. Insomnia patients had lower serum butyrate levels and a deficiency in butyrate-producing species within the gut microbiota. Transplantation of the gut microbiota from insomnia patients to germ-free mice conferred insomnia-like behaviors, accompanied by a decrease in serum butyrate levels. The oral administration of butyrate rescued sleep disturbances in recipient mice. Overall, these findings reveal the causal role of microbial metabolic pathways in modulating insomnia-like behaviors, suggesting potential therapeutic strategies for treating sleep disorders.
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.