Indole derivatives ameliorated the methamphetamine-induced depression and anxiety via aryl hydrocarbon receptor along “microbiota-brain” axis

作者：Xi Wang, Miaoyang Hu, Weilan Wu, Xinyu Lou, Rong Gao, Tengfei Ma, S. Thameem Dheen, Jie Cheng, Jianping Xiong, Xufeng Chen, Jun Wang · 发表于：Gut Microbes · 年份：2025 · DOI：10.1080/19490976.2025.2470386 · 被引用次数：51 · 研究领域：Gut microbiota and health、Tryptophan and brain disorders、Neuroinflammation and Neurodegeneration Mechanisms

In addition to the high neurotoxicity, depression, and anxiety are the most prominent characteristics of methamphetamine (Meth) withdrawal. Studies to date on the issue of Meth-associated depression and anxiety are focused on the brain, however, whether peripheral homeostasis, especially the “microbiota-gut” axis participates in these adverse outcomes, remains poorly understood. In the current study, with the fecal microbiota transplantation (FMT) assay, the mice received microbiota from Meth withdrawal mice displayed marked depression and anxiety behaviors. The 16S rRNA sequencing results showed that Meth withdrawal contributed to a striking reduction of Akkermansia, Bacteroides, Faecalibaculum, Desulfovibrio, and Anaerostipes, which are known to be associated with tryptophan (TRP) metabolism. Noteworthily, the substantial decreases of the indole derivatives from the TRP metabolic pathway, including IAA, IPA, ILA, IET, IArA, IAld, and TRM were observed in the serum of both Meth abusing humans and mice during Meth withdrawal with the UHPLC-MS/MS analysis. Combining the high and low TRP diet mouse model, the mice with high TRP diet obviously impeded Meth-associated depression and anxiety behaviors, and these results were further strengthened by the evidence that administration of IPA, IAA, and indole dramatically ameliorated the Meth induced aberrant behaviors. Importantly, these protective effects were remarkably counteracted in aryl hydrocarbon receptor knockout (AhR KO) mic...