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New Diet-Associated Gut-Microbe Metabolite Linked to CVD

Dr. Hazen found that a metabolic byproduct of phenylalanine, called PAGln, increases risk for adverse cardiac events, and that part of beta blockers’ potent efficacy may be due to blocking the activity of this metabolite.


A Cleveland Clinic-led study has identified a new diet-associated gut microbe linked with cardiovascular disease (CVD) and related events, including myocardial infarction, stroke and death.

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 & Metabolic Sciences and co-section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart, Vascular & Thoracic Institute—found that when phenylalanine is broken down by microbes in the gut, it produces a by-product (metabolite) called phenylacetylglutamine (PAGln), which ultimately shows up in the blood.

Analyzing samples from more than 5,000 patients followed for several years revealed that PAGln levels were elevated among patients who experienced adverse cardiac events like heart attack and stroke, and also in patients with type 2 diabetes (an independent risk factor for CVD). Preclinical and microbe transplantation studies suggest that the gut microbe-produced metabolite may play an important role in driving disease.

“We actually found that PAGln contributes to CVD risk in a couple of different ways,” said Dr. Hazen, who also directs the Cleveland Clinic Center for Microbiome and Human Health.

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

“Interestingly, we also discovered that PAGln interacts with a class of proteins called G-protein coupled receptors (GPCRs)—specifically a type called adrenergic receptors.”

GPCRs are receptor proteins found on the surface of cells. Like how a key fits into only one lock, certain molecules bind specifically with GPCRs. Bound or “turned on” GPCRs jumpstart events inside of cells. The researchers found that PAGln binds with receptors found on platelets and that these activated receptors lead to a cascade of cellular events that contribute to disease.

“Part of the reason we were so interested to have made this discovery is because we found that PAGln binds to the same receptors as beta blockers, which are drugs commonly prescribed to help lower blood pressure and subsequent risk of cardiac events.”

Administering beta blockers to preclinical models with PAGln was shown to reverse cardiovascular endpoints driven by PAGln. Additionally, researchers found that using gene editing technology or drugs to block PAGln-receptor binding significantly reduced thrombotic activity.

“We believe our findings suggest that some of the benefits of beta blockers may be attributed to preventing PAGln-related activity. Beta blockers have been widely studied and are prescribed to many patients, but, to our knowledge, this is the first time that this mechanism has been suggested as an explanation for some of their benefits.”

It is important to note that PAGln’s effect on CVD risk was found to be independent from, but additive to, the effects of TMAO (trimethylamine N-oxide). In 2011, Dr. Hazen’s team made the seminal discovery that TMAO—a metabolite produced when microbes in the gut breakdown the nutrient choline, found abundantly in animal products like meat and egg yolk—enhances platelet activity and increases cardiovascular disease risks. Recently, Dr. Hazen and his team designed a potential new class of drugs that could reduce CVD risk by targeting the pathway that produces TMAO. It is the most potent therapy to date for “drugging” the microbiome to alter disease processes and represents a novel therapeutic strategy for preventing or treating CVD.

Ina Nemet, PhD; Prasenjit Saha, PhD; and Nilaksh Gupta, PhD, are co-first authors of the present study, which was published in Cell and supported by the National Heart, Lung, and Blood Institute (part of the National Institutes of Health) and the Leducq Foundation.

Dr. Hazen is an elected member of the National Academy of Medicine and holds the Jan Bleeksma Chair in Vascular Biology and Atherosclerosis and the Leonard Krieger Chair in Preventive Cardiology.

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