Further evidence that the gut microbiome affects the development of cardiovascular disease, heart failure in particular, has emerged in a new report.
The study directly linked elevated levels of phenylacetylglutamine (PAG), a byproduct created when microbes in the gut break down dietary protein, to increased heart failure risk and severity. It follows previous studies that have also linked increased PAG levels to a higher risk of myocardial infarction (MI), stroke, and death.
“The present study raises the exciting possibility that the gut microbiome may be a participant in, and thus an attractive target for, novel therapeutics for the management of heart failure,” write the authors of the report, which was published online December 16 in Circulation: Heart Failure.
“This study expands our knowledge of how gut microbes contribute to cardiovascular disease,” senior author Stanley Hazen, MD, PhD, chair of the Department of Cardiovascular and Metabolic Sciences at the Cleveland Clinic, Ohio, told theheart.org | Medscape Cardiology.
“What we eat is the single biggest environmental factor that we experience. How we experience it from person to person has to do with the filter of our gut microbiome,” he said. “Our study shows that individuals who have a microbiome that is predisposed towards making PAG are going to be at higher risk of cardiovascular disease, especially heart failure.”
Hazen explained that his group had previously identified PAG as a potential new pathway contributing to the residual risk of cardiovascular disease independently of traditional risk factors.
Earlier studies suggested that higher PAG levels are associated with future risk of MI, stroke, and death, that PAG in preclinical models fosters potential for thrombosis, and that PAG interacts with beta-adrenergic receptors, he noted. “Recognizing that beta-adrenergic receptors play a prominent role in heart failure, we wanted to study PAG in heart failure and in people at risk for heart failure.”
For the current study, the researchers examined associations among plasma levels of PAG and heart failure, left ventricular ejection fraction (LVEF), and N-terminal pro-B type natriuretic peptide (NT-proBNP) in two independent cohorts of patients undergoing coronary angiography at tertiary referral centers. They consisted of an initial discovery US cohort of 3256 patients and a validation European cohort with 829 patients.
In both cohorts, circulating PAG levels were dose-dependently associated with the presence of heart failure and markers of severity ― reduced LVEF and elevated NT-proBNP ― independently of traditional risk factors and renal function.
The group’s studies using cells from mice suggested that both PAG and its murine counterpart, phenylacetylglycine, directly foster heart failure–relevant phenotypes. They include decreased cardiomyocyte sarcomere contraction and B-type natriuretic peptide gene expression in cultured cardiomyoblasts and murine atrial tissue.
“We found that increased PAG levels are a very strong risk factor for the development of heart failure, and for the severity of heart failure. We also report preclinical studies showing that PAG has a negative inotropic effect in that it attenuates the norepinephrine-induced heightened contraction of cardiomyocytes and in explants of human ventricular tissue,” Hazen said.
“PAG shifts the susceptibility to develop heart failure quite significantly. It affects how we perceive sympathetic tone,” he added.
“In the heart failure world, the role of the microbiome has previously been thought for the most part to be involved with bowel wall edema, causing enhanced gut leakiness and thus leading to systemic inflammation and potentially adverse remodeling,” Hazen explained.
“That happens, I’m sure. But this is different ― it is more refined. This is a specific molecule acting at specific receptors, which appears to be directly fostering many of the phenotypes associated with heart failure.”
Noting that another compound produced by the microbiome, trimethylamine-N-oxide (TMAO), has also been linked to increased risk of various cardiovascular conditions, Hazen says it is likely that there are going to be many more substances derived from the gut microbiome that will be found to influence cardiovascular disease.
“The gut membrane is the largest endocrine organ in the body. It produces many different bioactive small-molecule substances. We have receptors that recognize these compounds. Manipulation of the gut microbiome is a new strategy in medicine,” he commented.
The next step in this research will be to identify which microbes and their enzymes make PAG and to develop drugs that block them. Hazen says his research team has already developed drugs that block TMAO generation and that have shown benefit in preclinical models of cardiovascular disease.
“We still have a lot of work to do. We can speculate, but we don’t have any data yet on blocking PAG formation with inhibitors. We need to do studies in which we change levels of these substances in the body,” Hazen noted. “I’m a big believer that the gut microbiome is an eminently pharmacologically targetable site, just like any other enzyme reaction in our body.”
He also proposed that it may be easier to develop drugs that target the microbiome than drugs that have other targets, as they will not have to be systemically absorbed and might thus have better safety profiles.
“A drug targeting the microbiome can stay in the intestine so should have the potential for fewer adverse effects than drugs that are systemically absorbed,” Hazen added. “We don’t want to use antibiotics, as that would kill the microbiome. We just want to inhibit specific reactions.”
Could Dietary Changes Help?
In an accompanying editorial, Ayodeji Awoyemi, MD, PhD, Johannes R. Hov, MD, PhD, and Marius Trøseid, MD, PhD, Oslo University Hospital, Norway, write that PAG seems like a promising biomarker in cardiovascular disease, including heart failure, and this study “nicely shows that PAG could be a potential therapeutic target in heart failure.”
The editorialists, pending development of pharmaceutical strategies for targeting PAG, ask whether patients with heart failure should be advised to avoid foods rich in phenylalanine, a PAG precursor, to avoid high PAG levels.
They note that the artificial sweetener aspartame, a phenylalanine-rich peptide, was recently reported to be associated with increased risk of cardiovascular events. They also point out that food based on animal protein seems to act as precursor for both PAG and TMAO.
“Although promising, we are still in need of more studies exploring the use of PAG as a biomarker in heart failure, but also in other populations, as well as further experimental characterization of the molecule and its effect,” write Awoyemi and associates.
They note that adrenergic receptors are not exclusive to the cardiovascular system, which is highlighted by the fact that PAG has recently been associated with the risk of developing lethal prostate cancer, possibly through the effect of beta-adrenergic signaling on cancer cells.
“The present study provides encouraging evidence that PAG could be more than an innocent bystander in heart failure,” the editorialists state. “To further strengthen the case, there is a need of effective pharmacological agents to block or decrease levels of PAG, in order to examine the effect of such blockade on cardiac remodeling and ultimately prognosis.”
The study was supported by grants from the National Institutes of Health, the Office of Dietary Supplements, and the Foundation Leducq. Hazen is named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics and is a paid consultant formerly for Procter & Gamble and currently with Zehna Therapeutics. He also has received research funds from Procter & Gamble, Zehna Therapeutics‚ and Roche Diagnostics and is 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, Procter & Gamble‚ and Zehna Therapeutics. The editorialists have disclosed no relevant financial relationships.