Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice.
Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice.
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DOI：
10.1016/j.biopha.2022.112837
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发表时间：
2022-03
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通讯作者：
Jiqing Yang;Zunyue Zhang;Zhenrong Xie;Ling Bai;Pu Xiong;Fengrong Chen;Tailin Zhu;Q. 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;M. Zhu;Juehua Yu;Kunhua Wang
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作者：
Jiqing Yang;Zunyue Zhang;Zhenrong Xie;Ling Bai;Pu Xiong;Fengrong Chen;Tailin Zhu;Q. 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;M. Zhu;Juehua Yu;Kunhua Wang
背景二甲双胍对甲基苯丙胺（methamphetamine，METH）所致大鼠行为障碍具有治疗作用。新兴的研究表明肠道菌群可能影响精神症状，但没有直接证据支持二甲双胍通过调节肠道菌群参与戒断症状的病理生理学。方法为了确定肠道菌群和二甲双胍对METH戒断期间行为缺陷的功能影响，我们利用粪便菌群移植（FMT），高通量测序，结果首先，METH成瘾者表现出更高的α多样性和不同的微生物结构相比，健康对照组。特别是，Rikenellaceae的相对丰度与焦虑和抑郁的严重程度呈正相关。其次，人对小鼠和小鼠对小鼠的FMT都证实了MET改变的微生物群移植足以促进受体无菌小鼠的焦虑和抑郁样行为，并且这些行为障碍可以通过二甲双胍改善。深入分析显示，METH显著改变了细菌的组成和结构以及几种细菌分类群和代谢物的相对丰度，分别包括Rikenellaceae和肌苷，而添加二甲双胍可以重塑这些改变。最后，肌苷互补成功地恢复了METH诱导的焦虑和抑郁样behaviors.ConclusionThis研究表明，METH撤药诱导的焦虑和抑郁样行为是可逆的，并通过肠道微生物群在小鼠模型中传输。二甲双胍对精神症状的治疗作用与微生物群衍生的代谢产物有关，突出了肠道微生物群在物质使用障碍和戒断症状的病理生理学中的作用。
BackgroundMetformin 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.MethodsIn 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.ResultsFirst, METH addicts exhibited higher α diversity and distinct microbial structures compared to healthy controls. In particular, the relative abundance ofRikenellaceaewas 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, includingRikenellaceaeand inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice.ConclusionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are reversible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.