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A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors.
Cell ( IF 45.5 ) Pub Date : 2020-03-05 , DOI: 10.1016/j.cell.2020.02.016 Ina Nemet 1 , Prasenjit Prasad Saha 1 , Nilaksh Gupta 1 , Weifei Zhu 1 , Kymberleigh A Romano 1 , Sarah M Skye 1 , Tomas Cajka 2 , Maradumane L Mohan 3 , Lin Li 1 , Yuping Wu 4 , Masanori Funabashi 5 , Amanda E Ramer-Tait 6 , Sathyamangla Venkata Naga Prasad 3 , Oliver Fiehn 2 , Federico E Rey 7 , W H Wilson Tang 8 , Michael A Fischbach 5 , Joseph A DiDonato 1 , Stanley L Hazen 8
Cell ( IF 45.5 ) Pub Date : 2020-03-05 , DOI: 10.1016/j.cell.2020.02.016 Ina Nemet 1 , Prasenjit Prasad Saha 1 , Nilaksh Gupta 1 , Weifei Zhu 1 , Kymberleigh A Romano 1 , Sarah M Skye 1 , Tomas Cajka 2 , Maradumane L Mohan 3 , Lin Li 1 , Yuping Wu 4 , Masanori Funabashi 5 , Amanda E Ramer-Tait 6 , Sathyamangla Venkata Naga Prasad 3 , Oliver Fiehn 2 , Federico E Rey 7 , W H Wilson Tang 8 , Michael A Fischbach 5 , Joseph A DiDonato 1 , Stanley L Hazen 8
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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.
中文翻译：
心血管疾病相关的肠道微生物代谢产物通过肾上腺素能受体起作用。
使用非靶向代谢组学（n = 1,162名受试者），发现血浆代谢物（m / z = 265.1188）苯乙酰谷氨酰胺（PAGln），然后在独立队列（n = 4,000名受试者）中显示与心血管疾病（CVD）和事件相关重大不良心血管事件（心肌梗塞，中风或死亡）。肠道菌群衍生的代谢产物PAGln已显示可增强全血，分离的血小板和动脉损伤动物模型中与血小板活化相关的表型和血栓形成潜力。通过对人体的功能和基因工程研究，以及对无菌小鼠的微生物定植，表明微生物porA基因有助于饮食中的苯丙氨酸转化为苯乙酸，与随后的PAGln和苯乙酰基甘氨酸（PAGly）宿主宿主一起培养血小板反应性和血栓形成潜力。使用遗传和药理学工具进行的功能获得和功能丧失研究均显示，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代表了一种新的促进CVD的肠道微生物群依赖性代谢产物，该代谢产物通过肾上腺素能受体发出信号。
更新日期：2020-03-05
中文翻译：
心血管疾病相关的肠道微生物代谢产物通过肾上腺素能受体起作用。
使用非靶向代谢组学（n = 1,162名受试者），发现血浆代谢物（m / z = 265.1188）苯乙酰谷氨酰胺（PAGln），然后在独立队列（n = 4,000名受试者）中显示与心血管疾病（CVD）和事件相关重大不良心血管事件（心肌梗塞，中风或死亡）。肠道菌群衍生的代谢产物PAGln已显示可增强全血，分离的血小板和动脉损伤动物模型中与血小板活化相关的表型和血栓形成潜力。通过对人体的功能和基因工程研究，以及对无菌小鼠的微生物定植，表明微生物porA基因有助于饮食中的苯丙氨酸转化为苯乙酸，与随后的PAGln和苯乙酰基甘氨酸（PAGly）宿主宿主一起培养血小板反应性和血栓形成潜力。使用遗传和药理学工具进行的功能获得和功能丧失研究均显示，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代表了一种新的促进CVD的肠道微生物群依赖性代谢产物，该代谢产物通过肾上腺素能受体发出信号。
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