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 (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. [Display omitted] [Display omitted] •Gut microbe formed phenylacetyl glutamine (PAGln) contributes to cardiac disease•Microbial porA and fldH impact host PAGln levels, platelet function, and thrombosis•PAGln transmits cellular responses via the α2A, α2B, and β2 adrenergic receptors•β blocker therapy attenuates PAGln-induced heightened thrombosis risk A microbially generated metabolite, PAGIn, is associated with cardiovascular disease and death in humans. Studies in animal models provide insights into PAGIn metabolism as well as its effects in driving platelet responsiveness and thrombosis through adrenergic receptors.