Background:Accumulating evidence has shown that disorders in the gut microbiota and derived metabolites affect the development of atherosclerotic cardiovascular disease (ASCVD). However, which and how specific gut microbial metabolites contribute to the progression of atherosclerosis and the clinical relevance of their alterations remain unclear.Methods:We performed integrated microbiome–metabolome analysis of 30 patients with coronary artery disease (CAD) and 30 age- and sex-matched healthy controls to identify CAD-associated microbial metabolites, which were then assessed in an independent population of patients with ASCVD and controls (n=256). We further investigate the effect of CAD-associated microbial metabolites on atherosclerosis and the mechanisms of the action.Results:Indole-3-propionic acid (IPA), a solely microbially derived tryptophan metabolite, was the most downregulated metabolite in patients with CAD. Circulating IPA was then shown in an independent population to be associated with risk of prevalent ASCVD and correlated with the ASCVD severity. Dietary IPA supplementation alleviates atherosclerotic plaque development in ApoE^−/− mice. In murine- and human-derived macrophages, administration of IPA promoted cholesterol efflux from macrophages to ApoA-I through an undescribed miR-142-5p/ABCA1 (ATP-binding cassette transporter A1) signaling pathway. Further in vivo studies demonstrated that IPA facilitates macrophage reverse cholesterol transport, correlating with the regulation of miR-142-5p/ABCA1 pathway, whereas reduced IPA production contributed to the aberrant overexpression of miR-142-5p in macrophages and accelerated the progression of atherosclerosis. Moreover, the miR-142-5p/ABCA1/reverse cholesterol transport axis in macrophages were dysregulated in patients with CAD, and correlated with the changes in circulating IPA levels.Conclusions:Our study identify a previously unknown link between specific gut microbiota-derived tryptophan metabolite and ASCVD. The microbial metabolite IPA/miR-142-5p/ABCA1 pathway may represent a promising therapeutic target for ASCVD.

中文翻译：

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肠道微生物产生的吲哚-3-丙酸通过促进胆固醇逆向转运来抑制动脉粥样硬化，其缺乏与动脉粥样硬化性心血管疾病有因果关系

背景：越来越多的证据表明，肠道微生物群和衍生代谢物的紊乱会影响动脉粥样硬化性心血管疾病 (ASCVD) 的发展。然而，具体的肠道微生物代谢物中哪些以及如何促进动脉粥样硬化的进展及其改变的临床相关性仍不清楚。方法：我们对 30 名冠状动脉疾病 (CAD) 患者和 30 名年龄和性别-匹配健康对照以确定与 CAD 相关的微生物代谢物，然后在独立的 ASCVD 患者和对照人群中进行评估（n=256）。我们进一步研究了 CAD 相关微生物代谢物对动脉粥样硬化的影响及其作用机制。结果：吲哚-3-丙酸 (IPA)、一种完全来自微生物的色氨酸代谢物，是 CAD 患者中下调最多的代谢物。然后在独立人群中显示循环 IPA 与流行的 ASCVD 风险相关，并与 ASCVD 严重程度相关。膳食 IPA 补充剂可减轻 ApoE 中动脉粥样硬化斑块的形成^-/-老鼠。在小鼠和人源性巨噬细胞中，施用 IPA 通过未描述的 miR-142-5p/ABCA1（ATP 结合盒转运蛋白 A1）信号通路促进胆固醇从巨噬细胞流出至 ApoA-I。进一步的体内研究表明，IPA 促进巨噬细胞反向胆固醇转运，与 miR-142-5p/ABCA1 通路的调节相关，而 IPA 产生减少导致巨噬细胞中 miR-142-5p 的异常过表达并加速动脉粥样硬化的进展. 此外，巨噬细胞中的 miR-142-5p/ABCA1/反向胆固醇转运轴在 CAD 患者中失调，并与循环 IPA 水平的变化相关。代谢物和 ASCVD。