Cleveland Clinic discovers new gut microbe metabolite linked to cardiovascular disease

Cleveland Clinic researchers have identified a gut microbe generated byproduct, phenylacetylglutamine (PAG), that is linked to the development of cardiovascular disease, including heart attack, stroke, and death, according to new research published in the journal Cell.

Phenylalanine is an amino acid found in many foods, including plant- and animal-based protein sources like meat, beans and soy. The researchers, led by Stanley Hazen, MD, PhD, chair of the Department of Cardiovascular and Metabolic Sciences in the Lerner Research Institute and co-section head of Preventive Cardiology and Rehabilitation in the Miller Family Heart, Vascular, and Thoracic Institute, found that when phenylalanine is broken down by microbes in the gut, it produces the byproduct or metabolite PAG, which ultimately shows up in blood and contributes to heart disease.

For the study, the researchers analyzed blood samples from more than 5,000 patients over three years. They found patients with elevated PAG levels went on to experience adverse cardiac events, like heart attack and stroke, as well as type 2 diabetes, an independent risk factor for cardiovascular disease.

Animal model and microbe transplantation studies previously suggested PAG can play an important role in driving cardiovascular disease, according to Hazen.

The researchers also analyzed whole blood, platelet-rich plasma, and isolated platelets from patient samples to understand how PAG affects cell processes. They then analyzed animal models of arterial injury to see how PAG induced cellular changes manifest into disease. Hazen and his team found that PAG enhanced platelet reactivity and clotting potential, which increases the likelihood of blood clots, a major cause of adverse cardiac events like heart attack and stroke.

"Over the past decade there has been an increasing amount of data to suggest that gut microbes play a role in health, especially as it relates to heart disease," said Hazen, who also directs the Cleveland Clinic Center for Microbiome and Human Health. "We found that blood levels of PAG contribute to cardiovascular disease risk in a couple of different ways.”