Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, China (H.X., Y.Y., W.L.).
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, China (H.X., X.C., S.C., Y.Y., W.L.).
Circ Res. 2022 Aug 19;131(5):404-420. doi: 10.1161/CIRCRESAHA.122.321253. Epub 2022 Jul 27.
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.
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.
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.
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.
越来越多的证据表明，肠道微生物群及其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，哪些特定的肠道微生物代谢物有助于动脉粥样硬化的进展，以及它们改变的临床相关性仍不清楚。
我们对 30 名冠心病（CAD）患者和 30 名年龄和性别匹配的健康对照者进行了肠道微生物组-代谢组学综合分析，以确定与 CAD 相关的微生物代谢物，然后在一个独立的 ASCVD 患者和对照者人群（n=256）中进行评估。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。
吲哚-3-丙酸（IPA），一种仅由微生物衍生的色氨酸代谢物，是 CAD 患者中下调最明显的代谢物。在一个独立的人群中，循环 IPA 显示与 ASCVD 的发病风险相关，并与 ASCVD 的严重程度相关。饮食 IPA 补充可减轻 ApoE 小鼠的动脉粥样硬化斑块发展。在鼠源和人源来源的巨噬细胞中，IPA 的给药通过一种未描述的 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向 ApoA-I 的流出。进一步的体内研究表明，IPA 促进了巨噬细胞的胆固醇逆向转运，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，并加速了动脉粥样硬化的进展。此外，CAD 患者的巨噬细胞中 miR-142-5p/ABCA1/逆向胆固醇转运轴失调，与循环 IPA 水平的变化相关。
本研究发现了特定肠道微生物衍生色氨酸代谢物与 ASCVD 之间以前未知的联系。微生物代谢物 IPA/miR-142-5p/ABCA1 通路可能代表 ASCVD 的一个有前途的治疗靶点。
