Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

作者：Jiqing Yang, Zunyue Zhang, Zhenrong Xie, Ling Bai, Pu Xiong, Fengrong Chen, Tailin Zhu, Qingyan Peng, Hongjin Wu, Yong Zhou, Yuru Ma, Yongjin Zhang, Minghui Chen, Jianyuan Gao, Weiwei Tian, Kai Shi, Yan Du, Yong Duan, Huawei Wang, Yu Xu, Yi‐Qun Kuang, Mei Zhu, Juehua Yu, Kunhua Wang · 发表于：Biomedicine & Pharmacotherapy · 年份：2022 · DOI：10.1016/j.biopha.2022.112837 · 被引用次数：47 · 研究领域：Gut microbiota and health、Tryptophan and brain disorders、Metabolomics and Mass Spectrometry Studies

BACKGROUND: Metformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin's participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota. METHODS: In order to define the functional impacts of gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies. RESULTS: First, METH addicts exhibited higher α diversity and distinct microbial structures compared to healthy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and d...