Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA.
West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.
Cell. 2020 Mar 5;180(5):862-877.e22. doi: 10.1016/j.cell.2020.02.016.
Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
使用无靶向代谢组学（n=1162 名受试者），发现了血浆代谢物（m/z=265.1188）苯乙酰谷氨酰胺（PAGln），然后在独立队列（n=4000 名受试者）中表明其与心血管疾病（CVD）和主要不良心血管事件（心肌梗死、中风或死亡）相关。一种源自肠道微生物群的代谢物 PAGln 被证明可增强全血、分离血小板和动脉损伤动物模型中的血小板激活相关表型和血栓形成潜力。与人类共生菌的功能和基因工程研究，以及无菌小鼠的微生物定植表明，微生物 porA 基因有助于膳食苯丙氨酸转化为苯乙酸，随后宿主生成 PAGln 和苯乙酰甘氨酸（PAGly）促进血小板反应性和血栓形成潜力。使用遗传和药理学工具的增益和失能研究表明，PAGln 通过包括α2A、α2B 和β2-肾上腺素能受体在内的 G 蛋白偶联受体介导细胞事件。因此，PAGln 代表了一种新的促进 CVD 的依赖肠道微生物群的代谢物，通过肾上腺素能受体发出信号。
