PDF(Pubmed)
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.
摘要：
甲基苯丙胺（Meth）滥用会导致严重的精神障碍，包括焦虑和抑郁.肠道微生物群是维持宿主心理健康的关键因素。这里,我们的目的是调查微生物群是否参与Meth引起的精神障碍，以及所涉及的潜在机制。这里,15mg/kgMeth成功导致小鼠焦虑和抑郁样行为，并抑制海马中的Sigma-1受体（SIGMAR1）/BDNF/TRKB通路。同时,Meth通过引起Toll样受体4（TLR4）相关的结肠炎症而损害肠道稳态，扰乱肠道微生物组，减少微生物群衍生的短链脂肪酸（SCFA）。此外，Meth给药小鼠的粪便微生物群介导了结肠炎症，并在接受者中再现了焦虑和抑郁样行为。Further,SCFAs补充优化了Meth诱导的微生物菌群失调，改善结肠炎症，压抑焦虑和抑郁的行为。最后,Sigmar1敲除（Sigmar1-/-）抑制了BDNF/TRKB途径，并产生了与Meth暴露相似的行为表型，消除了SCFA的抗焦虑和抑郁作用。氟伏沙明激活SIGMAR1可减弱Meth诱导的焦虑和抑郁样行为。我们的发现表明，肠道微生物群来源的SCFA可以优化肠道稳态，并以SIGMAR1依赖的方式改善Meth引起的精神障碍。这项研究证实了微生物群在与Meth相关的精神障碍中的关键作用，并提供了一种潜在的先发制人的治疗方法。
