A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors
| Autor: | Nemet, Ina, Saha, Prasenjit Prasad, Gupta, Nilaksh, Zhu, Weifei, Romano, Kymberleigh A, Skye, Sarah M, Cajka, Tomas, Mohan, Maradumane L, Li, Lin, Wu, Yuping, Funabashi, Masanori, Ramer-Tait, Amanda E, Naga Prasad, Sathyamangla Venkata, Fiehn, Oliver, Rey, Federico E, Tang, WH Wilson, Fischbach, Michael A, DiDonato, Joseph A, Hazen, Stanley L |
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| Rok vydání: | 2020 |
| Předmět: |
Blood Platelets
Male Aging alpha Glutamine 1.1 Normal biological development and functioning Myocardial Infarction gut microbe Cardiovascular Medical and Health Sciences Mice GPCR Bacterial Proteins Risk Factors cardiovascular disease Underpinning research Receptors Genetics Animals Humans Metabolomics 2.1 Biological and endogenous factors Aetiology thrombosis Heart Disease - Coronary Heart Disease Arteries Hematology Biological Sciences Platelet Activation Sudden Gastrointestinal Microbiome Death Stroke Heart Disease Good Health and Well Being Cardiovascular Diseases Adrenergic Metabolome beta adrenergic receptors Cardiac Developmental Biology |
| Zdroj: | Cell, vol 180, iss 5 |
| Popis: | 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 toolsreveal 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. |
| Databáze: | OpenAIRE |
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