Exogenous microbiota-derived metabolite trimethylamine N-oxide treatment alters social behaviors: Involvement of hippocampal metabolic adaptation

Increasing evidence indicates that gut microbiota and its metabolites can influence the brain function and the related behaviors. Trimethylamine N-oxide (TMAO), an indirect metabolite of gut microbiota, has been linked to aging, cognitive impairment, and many brain disorders. However, the potential effects of TMAO on social behaviors remain elusive. The present study investigated the effects of early life systemic TMAO exposure and intra-hippocampal TMAO infusion during adulthood on social behaviors in mice. We also analyzed the effects of intra-hippocampus infusion of TMAO during adulthood on levels of metabolites. The results showed that both systemic TMAO exposure in the post-weaning period and intra-hippocampal TMAO infusion during adulthood decreased social rank and reduced sexual preference in adult mice. Data from LC-MS metabolomics analysis showed that intra-hippocampal TMAO infusion induced a total 207 differential metabolites, which belongs to several metabolic or signaling pathways, especially FoxO signaling pathway and retrograde endocannabinoid signaling pathway. These data suggest that TMAO may affect social behaviors by regulating metabolites in the hippocampus, which may provide a new insight into the role of gut microbiota in regulating social behaviors.