Intestinal metabolite of the protein linked to CVD – NewsDio

A team from the Cleveland Clinic has identified a by-product generated by intestinal microbiota clinically and mechanically linked to cardiovascular disease (CVD). The metabolite, called phenylacetylglutamine (PAGln, or simply PAG), has been shown to act through adrenergic receptors, causing increased reactivity and platelet aggregation and thrombosis in vivo.

Stanley Hazen

"We have discovered a new connection to the gut microbiome that is causally related to the risk of cardiovascular disease, and the identified metabolite is not only associated with future event risks, but based on animal model data appears to actually contribute to disease. cardiovascular and better platelet reactivity and thrombosis or risk of clotting, "said Stanley Hazen, MD, PhD, of the Cleveland Clinic.

Hazen and colleagues, including first author Ina Nemet, PhD, also from the Cleveland Clinic, published their findings March 5 in Cell. "This compound, generated by gut microbes, appears to regulate or modulate the epinephrine receptor and we believe this is why it is so closely related to many phenotypes and cardiovascular diseases," Hazen said in an interview with theheart.org | Medscape Cardiology. PAG is a by-product of the breakdown of the essential amino acid phenylalanine by gut microbes. Phenylalanine is found in many plant and animal protein sources, including meat, beans, and soy.

According to Hazen, after the protein is digested and broken down into individual amino acids, most of the phenylalanine is absorbed by the small intestine. The unabsorbed phenylalanine that reaches the large intestine can be metabolized by the intestinal microbiota to form phenylpyruvic acid (the initial deamination product generated by the microbiota) and subsequently phenylacetic acid. After passing through the liver, phenylacetic acid is metabolized to produce PAG.

"The determining step in velocity is the bacteria that works on phenylalanine as a fuel source for the bacteria, and the metabolite that is produced eventually becomes PAG," Hazen said. The researchers used an emerging platform called undirected metabolomics to identify plasma metabolites associated with cardiovascular disease. Those subjects with type 2 diabetes mellitus (n = 1162) were chosen as subjects because they are more likely to show metabolic disorders associated with CVD, increasing the possibility of discovering a new pathway.

PAG was shown in an independent cohort of 4,000 subjects associated with CVD and incident cardiovascular events, including myocardial infarction, stroke, and death. Going even further (registering 17 pages without appendices, this paper is the result of many years of study), the researchers found that administering beta-blockers to animal models with elevated PAG reversed the cardiovascular endpoints powered by PAG.

Furthermore, the use of gene or drug editing technology to block PAG receptor signaling significantly reduced coagulation activity.

"Towards the end of the paper, we show that high levels of PAG promote cardiovascular phenotypes, and by giving beta blockers they reversed PAG-induced adverse phenotypes, making it possible for some of the benefits of beta blockers to emerge by reversing the effects of high levels of PAG levels, "said Hazen. "As far as we know, this is the first time this mechanism has been suggested as an explanation of some of its benefits."

"Hazen's team has expanded our understanding of the specific gut microbial pathways involved in diabetes and heart disease, and the potential to direct them to treatment," said Ahmed Hasan, MD, PhD, of the National Heart Institute, Lungs. and Blood, which supported this research, in a press release from the Cleveland Clinic.

"Overall, this study uses novel tools and shows how the foods we eat are linked, through gut microbes, to our health and disease risks. It could help personalize cardiovascular medicine in the future."

This work is supported by grants from the NIH and the Office of Dietary Supplements and the Leducq Foundation.

Hazen reports that he was named co-inventor of pending and issued patents held by the Cleveland Clinic related to cardiovascular diagnosis and therapy; be a paid consultant for P&G; having received research funding from Proctor & Gamble and Roche Diagnostics; and be eligible to receive royalty payments for intentions or discoveries related to cardiovascular diagnoses or therapies from Cleveland HeartLab, Quest Diagnostics and P&G.

Cell. 2020; 180: 862-877. Summary

. (tagsToTranslate) CV (t) cardiovascular (t) microbiome (t) nutrition (t) atherosclerotic heart disease (t) atherosclerotic cardiovascular disease (t) coronary heart disease (t) ischemic heart disease

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