Trimethylamine N-Oxide Alters Socioemotional Behaviors: Involvement of Hippocampal Metabolic Adaptation

Abstract

Background: Gut microbiota and its metabolites can influence brain function and related behaviors. Trimethylamine N-oxide (TMAO), an indirect metabolite of gut microbiota, has been linked to aging, cognitive impairment, and many brain disorders, but its potential effects on socioemotional behaviors remain elusive. Methods: The present study investigated the effects of early life systemic TMAO exposure and intra-hippocampal TMAO infusion during adulthood on socioemotional behaviors in mice. Hippocampal metabolomics analysis was performed to explore its potential mechanisms. Findings: The results showed both systemic TMAO exposure in post-weaning period and intra-hippocampal TMAO infusion during adulthood decreased social rank and reduced sexual preference in adult mice. Metabolomics analysis showed the behavioral effects of TMAO were associated with alterations of particular metabolic and signaling pathways in hippocampus, including AMPA receptor, FOXO, and endogenous cannabinoid retrograde signaling pathway. Interpretation: TMAO may affect socioemotional behaviors by regulating hippocampal metabolism. Funding Statement: This work was supported in part by the National Natural Science Foundation of China (81771462, 81501150), Natural Science Foundation of Hebei Province (H2018206119, SLRC2019047), Foundation from Educational Commission of Hebei Province of China (ZD2019059), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-055), and Special Foundation for Excellent Undergraduate Students from Hebei Medical University (USIP2020016). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: All animal experiments were reviewed and approved by the Local Animal Use Committee of Hebei Medical University, following its guidelines for the use and care of laboratory animals.