Gut-Flora-Dependent Metabolite Trimethylamine-N-Oxide Promotes Atherosclerosis-Associated Inflammation Responses by Indirect ROS Stimulation and Signaling Involving AMPK and SIRT1.
Gut-Flora-Dependent Metabolite Trimethylamine-N-Oxide Promotes Atherosclerosis-Associated Inflammation Responses by Indirect ROS Stimulation and Signaling Involving AMPK and SIRT1.
复制标题
肠道菌群依赖性代谢物三甲胺-N-氧化物通过间接 ROS 刺激和涉及 AMPK 和 SIRT1 的信号传导促进动脉粥样硬化相关的炎症反应
作者：
氧化三甲胺（Trimethylamine-N-oxide，TMAO）是摄入胆碱后肠道微生物群依赖性代谢产物，通过诱导血管炎症而成为动脉粥样硬化的新危险因子。然而，对潜在的分子机制知之甚少。使用体外血管细胞模型，我们发现TMAO诱导的炎症反应与VSMC和HUVEC中ROS水平的升高和SIRT 1表达的下调相关。SIRT 1的过表达可以抑制ROS的刺激和炎症反应。进一步的研究表明，AMPK也被TMAO抑制，并且是SIRT 1上游的介导物。AICAR激活AMPK可减少TMAO诱导的ROS和炎症反应。此外，GSH前体NAC可以减轻TMAO诱导的炎症。小鼠模型的体内研究还表明，胆碱诱导的TMAO产生和导致动脉粥样硬化的相关糖脂代谢变化可以被NAC和益生菌LP 8198缓解。总的来说，本研究揭示了TMAO和动脉粥样硬化风险之间未被认识到的机制联系，益生菌通过影响肠道微生物群来改善TMAO诱导的动脉粥样硬化。与先前的研究一致，我们的数据证实TMAO可以通过调节细胞ROS水平来刺激炎症。然而，这不是由于直接的细胞毒性，而是通过涉及AMPK和SIRT 1的复杂信号通路。
Trimethylamine-N-oxide (TMAO), a gut-microbiota-dependent metabolite after ingesting dietary choline, has been identified as a novel risk factor for atherosclerosis through inducing vascular inflammation. However, the underlying molecular mechanism is poorly understood. Using an in vitro vascular cellular model, we found that the TMAO-induced inflammation responses were correlated with an elevation of ROS levels and downregulation of SIRT1 expression in VSMCs and HUVECs. The overexpression of SIRT1 could abrogate both the stimulation of ROS and inflammation. Further studies revealed that AMPK was also suppressed by TMAO and was a mediator upstream of SIRT1. Activation of AMPK by AICAR could reduce TMAO-induced ROS and inflammation. Moreover, the GSH precursor NAC could attenuate TMAO-induced inflammation. In vivo studies with mice models also showed that choline-induced production of TMAO and the associated glycolipid metabolic changes leading to atherosclerosis could be relieved by NAC and a probiotic LP8198. Collectively, the present study revealed an unrecognized mechanistic link between TMAO and atherosclerosis risk, and probiotics ameliorated TMAO-induced atherosclerosis through affecting the gut microbiota. Consistent with previous studies, our data confirmed that TMAO could stimulate inflammation by modulating cellular ROS levels. However, this was not due to direct cytotoxicity but through complex signaling pathways involving AMPK and SIRT1.