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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Veröffentlicht in:Cell Jg. 180; H. 5; S. 862
Hauptverfasser: 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, W H Wilson, Fischbach, Michael A, DiDonato, Joseph A, Hazen, Stanley L
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 05.03.2020
Schlagworte:
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
cardiovascular disease
GPCR
thrombosis
gut microbe
metabolomics
adrenergic receptors
ISSN:1097-4172, 1097-4172
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2020.02.016