A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors.
Animals
Arteries
/ injuries
Bacterial Proteins
/ genetics
Blood Platelets
/ metabolism
Cardiovascular Diseases
/ blood
Death, Sudden, Cardiac
/ pathology
Gastrointestinal Microbiome
/ genetics
Glutamine
/ analogs & derivatives
Humans
Male
Metabolome
/ genetics
Metabolomics
/ methods
Mice
Myocardial Infarction
/ blood
Platelet Activation
/ genetics
Receptors, Adrenergic, alpha
/ blood
Receptors, Adrenergic, beta
/ blood
Risk Factors
Stroke
/ blood
Thrombosis
/ genetics
GPCR
adrenergic receptors
cardiovascular disease
gut microbe
metabolomics
thrombosis
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
05 03 2020
05 03 2020
Historique:
received:
08
08
2019
revised:
16
12
2019
accepted:
07
02
2020
entrez:
7
3
2020
pubmed:
7
3
2020
medline:
18
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32142679
pii: S0092-8674(20)30160-4
doi: 10.1016/j.cell.2020.02.016
pmc: PMC7402401
mid: NIHMS1568846
pii:
doi:
Substances chimiques
Bacterial Proteins
0
Receptors, Adrenergic, alpha
0
Receptors, Adrenergic, beta
0
Glutamine
0RH81L854J
phenylacetylglutamine
92358I79RG
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
862-877.e22Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL147823
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL103866
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL126827
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL134622
Pays : United States
Organisme : NIH HHS
ID : S10 OD016346
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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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