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

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

doi:10.1016/j.apsb.2023.09.010

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

Acta Pharm Sin B. 2023 Dec;13(12):4801-4822. doi: 10.1016/j.apsb.2023.09.010. Epub 2023 Sep 21.

Authors

Kaikai Zhang¹, Lijian Chen¹, Jianzheng Yang¹, Jiali Liu¹, Jiahao Li¹, Yi Liu¹, Xiuwen Li¹, Long Chen¹, Clare Hsu¹, Jiahao Zeng¹, Xiaoli Xie², Qi Wang¹

Affiliations

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.

Abstract

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. Meanwhile, 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 inflammation and reproduced anxiety- and depression-like behaviors in recipients. Further, SCFAs supplementation optimized Meth-induced microbial dysbiosis, ameliorated colonic inflammation, and repressed anxiety- and depression-like behaviors. Finally, Sigmar1 knockout (Sigmar1^-/-) repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure, and eliminated 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 Meth-related mental disorders and provides a potential preemptive therapy.

Keywords: Colonic inflammation; Gut microbiota; Gut–brain axis; Intestinal barrier; Mental disorders; Methamphetamine; Short-chain fatty acids; Sigma-1 receptor.