Gut Metabolite From Protein Linked to CVD

Debra L Beck

March 16, 2020

A team from the Cleveland Clinic have identified a gut-microbiota-generated byproduct linked clinically and mechanistically to cardiovascular disease (CVD).

The metabolite, called phenylacetylglutamine (PAGln, or just PAG), has been shown to act via adrenergic receptors, causing enhanced platelet reactivity and aggregation and in vivo thrombosis.

Stanley Hazen

"We've discovered a new gut microbiome connection that is causally linked to cardiovascular disease risk, and the metabolite identified is not only associated with future risks of events, but also, based on the animal model data, seems to actually contribute to cardiovascular disease and enhanced platelet reactivity and thrombosis or clotting risk," said Stanley Hazen, MD, PhD, from 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 think it's because of this that it's so tightly linked to many cardiovascular phenotypes and diseases," said Hazen in an interview with theheart.org | Medscape Cardiology.

PAG is a byproduct of the breakdown of the essential amino acid phenylalanine by gut microbes. Phenylalanine is found in many plant- and animal-based protein sources, including meat, beans, and soy.

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

"The rate-determining step is the bacteria working on phenylalanine as a fuel source for the bacteria, and the metabolite that gets made ultimately gets turned into PAG," said Hazen.

The researchers used an emerging platform called untargeted metabolomics to identify the plasma metabolites associated with cardiovascular disease. They picked as their subjects those with type 2 diabetes mellitus (n = 1162) because they are more likely to show metabolic derangements associated with CVD, enhancing the possibility of uncovering a novel pathway.

PAG was then shown in an independent cohort of 4000 subjects to be associated with CVD and incident cardiovascular events, including myocardial infarction, stroke, and death.

Going even further (clocking in at 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 driven by PAG.

Also, using gene-editing technology or drugs to block PAG-receptor signaling significantly reduced clotting activity.

"Toward the end of the paper, we show that high PAG levels promote cardiovascular phenotypes, and giving beta blockers reversed the PAG-induced adverse phenotypes, making it possible that some of the benefits from beta blockers may arise from reversing the effects of high PAG levels," said Hazen. "To our knowledge, this is the first time that this mechanism has been suggested as an explanation for some of their benefits."

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

"Overall, this study uses novel tools and shows how the food we eat is linked, via 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 Office of Dietary Supplements and the Foundation Leducq.

Hazen reports being named as a coinventor on pending and issued patents held by the Cleveland Clinic related to cardiovascular diagnostic and therapeutics; being a paid consultant for P&G; having received research funds from Proctor & Gamble and Roche Diagnostics; and being eligible to receive royalty payments for intentions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Quest Diagnostics, and P&G.

Cell. 2020;180:862-877. Abstract

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