12/21/2022
Cleveland Clinic researchers identify key enzymes in gut microbiome that produce compound linked to heart disease
Cleveland Clinic research identified two ways microbes in the gut produce the metabolite phenylacetylglutamine (PAG), a byproduct derived from dietary protein in foods like red meat, chicken, liver and fish.
The study, published in Cell Host & Microbe, is the latest research exploring the association between PAG and atherosclerotic cardiovascular disease from a team led by Stanley Hazen, MD, PhD, Chair of the Department of Cardiovascular & Metabolic Sciences. The results highlight two pathways through which the microbes convert dietary protein – the amino acid phenylalanine – into PAG.
Understanding these biological processes is key for developing therapeutics that lower PAG levels, potentially preventing diseases like heart failure. Another recent study from Dr. Hazen's lab showed PAG serves as an indicator of both cardiovascular disease (heart attack) and heart failure risk.
"PAG is an example of another gut microbial pathway that, if targeted correctly, could provide a new approach for treating and preventing cardiovascular disease," says Dr. Hazen, who also serves as section head of Preventive Cardiology. "But to do that, we need to deeply understand all the players in the process and the steps to producing this metabolite."
Researchers identified two microbial pathways using a combination of bioinformatics, microbial genetic engineering, preclinical models and metagenomic data from patients with atherosclerotic cardiovascular disease.
The gut microbial enzymes phenylpyruvate:ferredoxin oxidoreductase (PPFOR) and phenylpyruvate decarboxylase (PPDC) both catalyze a process called decarboxylation, which removes a carbon and releases carbon dioxide in a compound. This is essential for dietary protein-bound phenylalanine to be digested by gut microbes into phenylacetic acid, the immediate precursor to forming PAG.
Researchers also analyzed patient metagenomic data from isolated DNA for the microbial genes connected to PPFOR and PPDC. Results showed markedly higher levels of the gut microbial genes encoding PPFOR and PPDC in patients with atherosclerotic cardiovascular disease.
"It's all about trying to help patients and change clinical practice," Dr. Hazen says. "Looking at these pathways from a genetic perspective, in conjunction with our preclinical model research, presents a stronger case. We hope one day this ultimately translates into new diagnostic tests and therapies."
Funding for this study came from NIH and Office of Dietary Supplements (grants P01HL147823 and R01HL103866), as well as the Foundation Leducq.
Disclosures: Stanley L. Hazen, Zeneng Wang and James T. Anderson report being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and/or therapeutics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, a wholly owned subsidiary of Quest Diagnostics, P&G, and Zehna Therapeutics. Hazen. and Anderson report being paid consultants for 458 Zehna Therapeutics. Hazen also reports having received research funds from P&G, Roche Diagnostics, and Zehna Therapeutics.
