A small molecule left over after gut microbes finish digesting your meal may one day provide a new angle for managing cardiovascular disease.
Certain gut microbes break down the amino acid histidine, one of the building blocks of proteins, into a small molecule called imidazole propionate, or ImP. In a new study published July 16 in Nature, researchers found an association between higher blood levels of ImP and early cardiovascular disease. And in mice, the international team demonstrated how ImP contributes to the disease, opening up a potential therapeutic target.
The primary driver of cardiovascular disease is atherosclerosis, the buildup of fatty plaques in the arterial walls. “When you think about atherosclerosis, usually people think cholesterol, and indeed cholesterol plays an extremely important role,” says Ina Nemet, whose work at the Cleveland Clinic Lerner Research Institute focuses on the gut microbiome and how it affects health and disease. Cholesterol is one of the key components of those plaques, which, as they get larger, narrow a vessel’s opening and decrease blood flow, leading to symptoms such as chest pain and shortness of breath. Statin medications, which lower cholesterol, are a mainstay for the prevention and treatment of cardiovascular disease.
But high cholesterol and other known cardiovascular risk factors don’t explain all cases of the disease. So researchers have been looking for other contributors, and “ImP could be one of those,” says Nemet, who was not involved in the new study. ImP has previously been associated with diabetes and advanced cardiovascular disease. The Nature study not only ties ImP to early disease in people, Nemet says, but also maps out in mice how ImP affects plaque formation and a way to block that impact.
The researchers assessed images of people’s blood vessels to look for those with early cardiovascular disease. Plaque buildup progresses silently for some time and is often discovered only after symptoms develop or a person has a heart attack. Compared with about 600 people who did not have early disease, and controlling for factors such as age and family history, the roughly 1,600 with early disease had higher ImP levels.
The research team found that, in mice, ImP contributed to plaque formation by calling in immune cells, which provoke inflammation and become part of plaques. But ImP did not impact levels of cholesterol in the mice. The small molecule’s activity “is all cholesterol independent,” Nemet says. The researchers also identified a cellular protein, or receptor, that ImP binds to and showed that blocking this interaction could halt the progression of plaques in mice.
“Once you know the receptor and the mechanism,” Nemet says, “that really opens new venues for treatment.”
Before ImP, other research had identified the chemical trimethylamine N-oxide, or TMAO, as a breakdown byproduct of gut microbes that affects human health. TMAO occurs after a person eats meat or consumes energy drinks, and is also linked to a higher risk of cardiovascular disease.