Phenylacetylglutamine (PAGln), a metabolite derived from gut microbiota, may contribute to cardiovascular disease (CVD) and thrombosis, according to a study published in Cell.
Researchers from the Cleveland Clinic utilized untargeted metabolomics to study CVD-associated plasma metabolites in 1162 participants with type 2 diabetes. In 2 independent cohorts, PAGln was shown to be associated with CVD as well as incident major adverse cardiovascular events (MACE) including myocardial infarction, stroke, or death.
Researchers found that the PAGln metabolite acted via adrenergic receptor signaling. This caused enhanced platelet aggregation, invasiveness, and reactivity. Adrenergic receptor signaling also contributed to in vivo thrombosis. Animal models with elevated PAG that were administered beta blockers displayed a reversal of PAG-driven cardiovascular endpoints.
PAGIn was also suggested to be associated with increased clotting risk. The researchers found that the use of gene-editing technology and therapies blocking PAGln receptor signaling resulted in noticeable reductions in clotting activity. Additionally, the researchers found that cellular responses were transmitted by PAGln via the α2A, α2B, and β2 adrenergic receptors.
The researchers also note that PAGln may regulate or modulate the epinephrine receptor. They suggest that this may be explained by its close association to several cardiovascular diseases and phenotypes.
The investigators concluded by theorizing that PAGln has the potential to modulate multiple adverse drug reactions (ADRs), “and accordingly may potentially affect multiple ADRs—linked physiological processes in vivo.”
Nemet I, Saha PP, Gupta N, et al. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020;180(5):862-877.e22.