Gut microbiota-derived short-chain fatty acids ameliorate methamphetamine-induced depression-and anxiety-like behaviors in a Sigmar-1 receptor-dependent manner  

作　　者：Kaikai Zhang Lijian Chen Jianzheng Yang Jiali Liu Jiahao Li Yi Liu Xiuwen Li Long Chen Clare Hsu Jiahao Zeng Xiaoli Xie Qi Wang 

机构地区：[1]Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification,School of Forensic Medicine,Southern Medical University,Guangzhou 510515,China [2]Department of Toxicology,School of Public Health,Southern Medical University(Guangdong Provincial Key Laboratory of Tropical Disease Research),Guangzhou 510515,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4801-4822,共22页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China under Grant No.82171877;the Department of Science and Technology of Guangzhou city under Grant No.202002030043(China);the Guangdong Natural Science Foundation under Grant No.2021A1515012456(China).

摘　　要：Methamphetamine(Meth)abuse can cause serious mental disorders,including anxiety and depression.The gut microbiota is a crucial contributor to maintaining host mental health.Here,we aim to investigate if microbiota participate in Meth-induced mental disorders,and the potential mechanisms involved.Here,15 mg/kg Meth resulted in anxiety-and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor(SIGMAR1)/BDNF/TRKB pathway in the hippocampus.Mean-while,Meth impaired gut homeostasis by arousing the Toll-like receptor 4(TLR4)-related colonic inflammation,disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids(SCFAs).Moreover,fecal microbiota from Meth-administrated mice mediated the colonic inflam-mation and reproduced anxiety-and depression-like behaviors in recipients.Further,SCFAs supple-mentation optimized Meth-induced microbial dysbiosis,ameliorated colonic inflammation,and repressed anxiety-and depression-like behaviors.Finally,Sigmarl knockout(Sigmar1^(-/-))repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure,and elim-inated the anti-anxiety and-depression effects of SCFAs.The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety-and depression-like behaviors.Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis,and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner.This study confirms the crucial role of microbiota in Methrelated mental disorders and provides a potential preemptive therapy.

关 键 词：METHAMPHETAMINE Gut microbiota Short-chain fatty acids Sigma-1 receptor Mental disorders Colonic inflammation Intestinal barrier Gut-brain axis 

分 类 号：R57[医药卫生—消化系统]