The microbes in our gastrointestinal tract, collectively known as the gut microbiome, have a powerful impact on our health and well-being. Researchers are starting to learn more about the effect of specific strains of microbes, the genes they carry, and the molecules they produce and secrete. New work by scientists at the Cleveland Clinic has shown that phenylacetylglutamine (PAG), which is made by gut microbes, is connected to cardiovascular disease development, and heart attacks, strokes, and death it can cause. The findings have been reported in Cell.
Many foods contain an amino acid phenylalanine, including meat, beans, and soy. When microbes encounter phenylalanine in the gut, they break the compound down and in the process, generate a metabolite that ends up in the blood as PAG.
"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 Stanley Hazen, M.D., Ph.D., who holds multiple appointments including chair of the Department of Cardiovascular & Metabolic Sciences at Lerner Research Institute. "We found that blood levels of PAG contribute to cardiovascular disease risk in a couple of different ways."
In this work, the researchers assessed samples that were collected during a three-year period from over 5,000 patients. Elevated levels of PAG were found in patients that experienced strokes or heart attacks, and in type 2 diabetics. Diabetes is considered a risk factor for cardiovascular illness. When PAG was transplanted into animal models, the effects suggested that PAG can drive cardiovascular disease.
In an animal model of arterial injury, PAG was able to encourage the reactivity of platelets and boost clotting. That may be raising the likelihood that blood clots will form and lead to adverse cardiac events.
"Part of the reason we were so interested to have made this discovery is because we found that PAG binds to the same receptors as beta blockers, which are drugs commonly prescribed to help treat cardiac diseases." noted Hazen.
When beta blockers were given to animals that had high levels of PAG, the negative cardiovascular effects were reduced. When gene editing was employed to stop PAG activity, clotting activity was significantly reduced.
"We believe our findings suggest that some of the benefits of beta blockers may be attributed to preventing PAG-related activity," said Hazen. "Beta blockers have been widely studied and are prescribed to many cardiac patients, but, to our knowledge, this is the first time that this mechanism has been suggested as an explanation for some of their benefits."