A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors
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 (my...
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| Vydáno v: | Cell Ročník 180; číslo 5; s. 862 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
05.03.2020
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| ISSN: | 1097-4172, 1097-4172 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
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| Abstract | 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. |
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| AbstractList | 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. 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.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. |
| Author | Nemet, Ina Saha, Prasenjit Prasad Gupta, Nilaksh Tang, W H Wilson Li, Lin DiDonato, Joseph A Romano, Kymberleigh A Fiehn, Oliver Naga Prasad, Sathyamangla Venkata Fischbach, Michael A Hazen, Stanley L Funabashi, Masanori Rey, Federico E Cajka, Tomas Mohan, Maradumane L Ramer-Tait, Amanda E Skye, Sarah M Wu, Yuping Zhu, Weifei |
| Author_xml | – sequence: 1 givenname: Ina surname: Nemet fullname: Nemet, Ina organization: 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 – sequence: 2 givenname: Prasenjit Prasad surname: Saha fullname: Saha, Prasenjit Prasad organization: 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 – sequence: 3 givenname: Nilaksh surname: Gupta fullname: Gupta, Nilaksh organization: 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 – sequence: 4 givenname: Weifei surname: Zhu fullname: Zhu, Weifei organization: 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 – sequence: 5 givenname: Kymberleigh A surname: Romano fullname: Romano, Kymberleigh A organization: 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 – sequence: 6 givenname: Sarah M surname: Skye fullname: Skye, Sarah M organization: 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 – sequence: 7 givenname: Tomas surname: Cajka fullname: Cajka, Tomas organization: West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA – sequence: 8 givenname: Maradumane L surname: Mohan fullname: Mohan, Maradumane L organization: Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA – sequence: 9 givenname: Lin surname: Li fullname: Li, Lin organization: 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 – sequence: 10 givenname: Yuping surname: Wu fullname: Wu, Yuping organization: Department of Mathematics, Cleveland State University, Cleveland, OH 44115, USA – sequence: 11 givenname: Masanori surname: Funabashi fullname: Funabashi, Masanori organization: Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA – sequence: 12 givenname: Amanda E surname: Ramer-Tait fullname: Ramer-Tait, Amanda E organization: Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA – sequence: 13 givenname: Sathyamangla Venkata surname: Naga Prasad fullname: Naga Prasad, Sathyamangla Venkata organization: Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA – sequence: 14 givenname: Oliver surname: Fiehn fullname: Fiehn, Oliver organization: West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA – sequence: 15 givenname: Federico E surname: Rey fullname: Rey, Federico E organization: Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA – sequence: 16 givenname: W H Wilson surname: Tang fullname: Tang, W H Wilson organization: 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; Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44106, USA – sequence: 17 givenname: Michael A surname: Fischbach fullname: Fischbach, Michael A organization: Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA – sequence: 18 givenname: Joseph A surname: DiDonato fullname: DiDonato, Joseph A organization: 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 – sequence: 19 givenname: Stanley L surname: Hazen fullname: Hazen, Stanley L email: hazens@ccf.org organization: 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; Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44106, USA. Electronic address: hazens@ccf.org |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32142679$$D View this record in MEDLINE/PubMed |
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| Keywords | cardiovascular disease GPCR thrombosis gut microbe metabolomics adrenergic receptors |
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| References | 32210404 - Nat Rev Cardiol. 2020 May;17(5):265 32348162 - Platelets. 2020 Jul 3;31(5):618-620 |
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| Snippet | Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an... Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an... |
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| SubjectTerms | Animals Arteries - injuries Arteries - metabolism Arteries - microbiology Bacterial Proteins - genetics Bacterial Proteins - metabolism Blood Platelets - metabolism Blood Platelets - microbiology Cardiovascular Diseases - blood Cardiovascular Diseases - genetics Cardiovascular Diseases - microbiology Cardiovascular Diseases - pathology Death, Sudden, Cardiac - pathology Gastrointestinal Microbiome - genetics Glutamine - analogs & derivatives Glutamine - blood Glutamine - genetics Humans Male Metabolome - genetics Metabolomics - methods Mice Myocardial Infarction - blood Myocardial Infarction - microbiology Platelet Activation - genetics Receptors, Adrenergic, alpha - blood Receptors, Adrenergic, alpha - genetics Receptors, Adrenergic, beta - blood Receptors, Adrenergic, beta - genetics Risk Factors Stroke - blood Stroke - microbiology Stroke - pathology Thrombosis - genetics Thrombosis - metabolism Thrombosis - microbiology Thrombosis - pathology |
| Title | A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors |
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