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Not Just Cholesterol: Cleveland Clinic, Tufts Red Meat Study Elaborates on Gut Bacteria’s Role in Forecasting Heart Disease

Building on more than a decade of research from Dr. Stanley Hazen’s lab, researchers explored how elevated levels of trimethylamine N-Oxide (TMAO) could serve as a warning sign for heart disease


A new study from Cleveland Clinic’s Lerner Research Institute and Tufts University adds to a growing list of evidence that eating more animal-sourced foods and red meat could lead to a higher risk of heart disease.

The findings also clarified how elevated levels of a metabolite produced in the gut called trimethylamine N-Oxide (TMAO) contribute to that risk. Published in Arteriosclerosis, Thrombosis, and Vascular Biology, the study is the first to investigate the association between animal-sourced foods and atherosclerotic heart disease and how TMAO-associated metabolites fit into that link.

Though animal-sourced foods, especially red meat, are widely studied and often discussed as contributors to heart disease risk, the association is still “controversial” and traditional indicators, like cholesterol, might not tell the whole story, authors wrote.

Data from nearly 4,000 adults over age 65 showed eating unprocessed red meat, total meat and animal-sourced foods in general are all associated with higher risk of heart disease. Unprocessed red meat specifically showed a 15% risk associated with each 1.1 daily serving. Higher levels of poultry, eggs and fish consumption did not show the same connection.

Between 8 and 11% of that risk was mediated by TMAO and its intermediate metabolites, γ-butyrobetaine, and crotonobetaine. Gut bacteria produce TMAO through metabolizing L- carnitine, a compound plentiful in red meat and found in some other products like energy drinks or supplements.

“This is yet another large independent verification of the importance of this pathway and its contribution to cardiovascular disease,” says senior co-author Stanley Hazen, MD, PhD, Chair of the Lerner Research Institute’s Cardiovascular and Metabolic Sciences Department. “Luckily, we now have tools to monitor it and determine who is at risk based on elevated levels.”

Potential for early diagnosis and prevention

These findings build on more than a decade of research from Dr. Hazen’s team about the link between the gut microbiome and atherosclerotic heart disease. Previous research associated TMAO with more severe outcomes from strokes and an increased chance of blood clots, among other outcomes.

Exploring biological processes like TMAO production can open up options for forecasting and preventing heart disease, says co-lead author Zeneng Wang, PhD, a staff scientist at the Cardiovascular Metabolic Sciences Department. High blood pressure and high cholesterol do not manifest in some patients, and TMAO serves as a potential alternative indicator, Dr. Wang says.

Studying TMAO also shows potential for developing therapeutics, he said, if researchers can target TMAO production. Dr. Hazen’s lab also previously located a gene cluster critical to converting carnitine to TMAO which could serve as a potential therapeutic target.

The study also showed that blood glucose and insulin, as well as systematic inflammation, partly mediated the association between meat and higher risk of cardiovascular disease – but not blood pressure or cholesterol levels. Previous studies showed higher levels of TMAO associated with diabetes, a known risk factor for heart disease.

Looking beyond what we know about diet and atherosclerotic heart disease means building out understanding of how our diet and gut microbiome contribute to one of the leading causes of death in the country,” Dr. Hazen says. ““Each step we make brings valuable information to doctors and patients working together for the best outcome through preventive care.”

The study also holds significant implications for patients over the age of 65, who might turn to meat for necessary protein. The American Heart Association currently generally recommends limiting meat portion sizes to 3 ounces – around the size of a deck of cards – and favoring plant-based protein sources or lean meats like poultry or fish.

About the study

This research is a collaboration between the Cleveland Clinic's Lerner Research Institute and Tufts University’s Friedman School of Nutrition Science and Policy, using National Institutes of Health data from a long-term study on cardiovascular health. Dietary habits were self-reported. Researchers reviewed atherosclerotic cardiovascular disease incidence over a median 12.5-year follow-up.

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