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.

Long-lasting effects of postweaning sodium butyrate exposure on social behaviors in adult mice.

BACKGROUND: The function of gut microbiota as its role in normal physiology and involvement in brain function has gained a great deal of attention. The potential long-lasting effects of postweaning sodium butyrate (SB) exposure on social behaviors are still unknown; however it acts as one of the metabolites of gut microbiota. METHODS: Male mice (24-day old) were exposed to SB through drinking water for 21 continuous days. A series of behavioral tests, mainly including bedding preference test (BP), sexual preference test (SP), social interaction test (SI), tube dominance test (SDT), forced swimming test (FST), open field test (OFT), novel object recognition task (NOR) were conducted at different time after 21-d SB exposure. Serum Trimethylamine oxide (TMAO) levels were investigated to gain insight into a potential mechanism. RESULTS: Behavioral results indicated that postweaning SB exposure significantly decreased the social dominance status of low-ranked mice and decreased the sexual preference without affecting social interaction. SB exposure also exerted transient anxiolytic-like effects, while having induced a long-lasting depression-like effect without effects on memory formation. Postweaning SB exposure increased serum TMAO levels in mice, especially in lower-ranked mice, but decreased in higher-ranked mice. LIMITATIONS: Lack of understanding of the underlying mechanism. CONCLUSIONS: These findings provide direct evidence, for the first time, that postweaning SB exposure produces long-term effects on social behaviors in adult mice, mainly referring to sexual orientation, social dominance, and depression-like behaviors, which may be related to the serum TMAO levels, highlighting the long-lasting potential effects of gut-brain interaction on social behaviors.