美国克利夫兰诊所•勒纳研究所Stanley L. Hazen课题组宣布他们发现与心血管疾病相关的肠道菌群代谢产物通过肾上腺素受体发挥功能。2020年3月5日，国际学术期刊《细胞》发表了这一成果。
对1162名受试者使用非靶向代谢组学，研究人员发现血浆代谢物（m / z = 265.1188）苯乙酰谷氨酰胺（PAGln），并在独立队列（n = 4,000名受试者）中发现其与心血管疾病（CVD）和重大不良心血管事件（心肌梗塞，中风或死亡）相关。在全血、分离的血小板和动脉损伤动物模型中，肠道菌群衍生代谢物PAGln可增强血小板活化相关的表型和促进血栓形成。对人类共生菌的功能和基因研究以及对无菌小鼠进行微生物定植的研究都表明微生物porA基因有利于食物中的苯丙氨酸转化为苯乙酸，随后宿主产生PAGln和苯乙酰基甘氨酸（PAGly）可促进培养血小板的反应性和血栓形成。使用遗传和药理学方法进行的功能获得和功能丧失研究均表明，PAGln通过G蛋白偶联受体（包括α2A，α2B和β2-肾上腺素受体）介导细胞事件。
因此，PAGln是一种促进CVD新的肠道菌群依赖性代谢产物，该代谢产物通过肾上腺素受体传递信号。
附：英文原文
Title: A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors
Author: Ina Nemet, Prasenjit Prasad Saha, Nilaksh Gupta, Weifei Zhu, Kymberleigh A. Romano, Sarah M. Skye, Tomas Cajka, Maradumane L. Mohan, Lin Li, Yuping Wu, Masanori Funabashi, Amanda E. Ramer-Tait, Sathyamangla Venkata Naga Prasad, Oliver Fiehn, Federico E. Rey, W.H. Wilson Tang, Michael A. Fischbach, Joseph A. DiDonato, Stanley L. Hazen
Issue&Volume: 2020/03/05
Abstract: Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independentcohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) andincident major adverse cardiovascular events (myocardial infarction, stroke, or death).A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-relatedphenotypes and thrombosis potential in whole blood, isolated platelets, and animalmodels 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 subsequenthost generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsivenessand thrombosis potential. Both gain- and loss-of-function studies employing geneticand pharmacological tools reveal PAGln mediates cellular events through G-proteincoupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus representsa new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
DOI: 10.1016/j.cell.2020.02.016
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30160-4