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

Yixiao Luo; Penghui Zhao; Mengxiao Dou; Jiawen Mao; Ge Zhang; Yujiao Su; Qingqun Wang; Qian Wang; Yurun Wang; Ruoxuan Sun; Tingxuan Liu; Miao Gong; Yuan Gao; Xi Yin; Li Song; Haishui Shi

doi:10.1016/j.neuropharm.2021.108563

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

Neuropharmacology. 2021 Jun 15:191:108563. doi: 10.1016/j.neuropharm.2021.108563. Epub 2021 Apr 20.

Authors

Yixiao Luo¹, Penghui Zhao², Mengxiao Dou², Jiawen Mao², Ge Zhang², Yujiao Su², Qingqun Wang², Qian Wang², Yurun Wang², Ruoxuan Sun², Tingxuan Liu², Miao Gong³, Yuan Gao⁴, Xi Yin⁵, Li Song⁶, Haishui Shi⁷

Affiliations

¹ Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China; Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China.
² Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China.
³ Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medicinal University, 050017, China.
⁴ Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang, 050017, China.
⁵ Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China; Department of Functional Region of Diagnosis, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China. Electronic address: yinxixi2002@163.com.
⁶ Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang, 050017, China. Electronic address: biosongli@hebmu.edu.cn.
⁷ Neuroscience Research Center, Institute of Medical and Health Science of HeBMU, Hebei Medical University, Shijiazhuang, 050017, China; Hebei Key Laboratory of Neurophysiology, Hebei Medicinal University, 050017, China; Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medicinal University, Shijiazhuang, 050017, China; Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology. Chinese Academy of Medical Sciences, Shijiazhuang, 050017, China. Electronic address: shihs@hebmu.edu.cn.

PMID: 33887311
DOI: 10.1016/j.neuropharm.2021.108563

Abstract

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.

Keywords: Hippocampus; Metabolomics analysis; Microbiota; Sexual preference; Social dominance; Trimethylamine N-Oxide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Gastrointestinal Microbiome*
Hippocampus / drug effects*
Hippocampus / metabolism*
Male
Methylamines / pharmacology*
Mice
Mice, Inbred ICR
Social Behavior*

Substances

Methylamines
trimethyloxamine