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Cell. 2020 Mar 5;180(5):862-877.e22. doi: 10.1016/j.cell.2020.02.016.

A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors.

Author information

1
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.
2
West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.
3
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.
4
Department of Mathematics, Cleveland State University, Cleveland, OH 44115, USA.
5
Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.
6
Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
7
Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA.
8
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.
9
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.

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.

KEYWORDS:

GPCR; adrenergic receptors; cardiovascular disease; gut microbe; metabolomics; thrombosis

PMID:
32142679
DOI:
10.1016/j.cell.2020.02.016

Conflict of interest statement

Declaration of Interests S.L.H. reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, being a paid consultant for P&G, having received research funds from P&G and Roche Diagnostics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Quest Diagnostics, and P&G. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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