This novel approach centers around the research team's previous discovery that TMAO - trimethylamine N-oxide, a byproduct formed in the gut during digestion of animal fats - is linked to atherosclerosis and heart disease. Now, the team has identified a naturally occurring inhibitor called DMB - 3,3-dimethyl-1-butanol, found in some cold-pressed extra virgin olive oils and grape seed oils - that reduced levels of TMAO and reduced atherosclerosis in mice.
This discovery may represent a potential new therapeutic approach for the prevention of heart disease, the No. 1 killer in the United States, as well as other metabolic diseases linked to gut microbes, such as diabetes.
The current research will be published both online and in the Dec. 17 print edition of Cell.
The link between TMAO, gut microbes and heart disease was first discovered four years ago by the same investigative team, led by Stanley Hazen, M.D., Ph.D., Chair of the Department of Cellular & Molecular Medicine in the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart & Vascular Institute at Cleveland Clinic. Zeneng Wang, Ph.D., first author on the manuscript, is also a member in the Department of Cellular & Molecular Medicine in the Lerner Research Institute.
"Many chronic diseases like atherosclerosis, obesity and diabetes are linked to gut microbes," said Dr. Hazen. "These studies demonstrate the exciting possibility that we can prevent or retard the progression of diet-induced heart diseases starting in the gut. This opens the door in the future for new types of therapies for atherosclerosis, as well as other metabolic diseases."
TMAO is a gut metabolite formed during the digestion of the nutrients choline, phosphatidylcholine (lecithin) and carnitine, which are abundant in animal products. Blood TMAO levels are associated with heightened risk of heart attacks, stroke and death in clinical studies. Carnitine is abundant in red meat and liver, while choline and lecithin are abundant in beef, lamb, liver, egg yolk and high-fat dairy products.
The present study suggests that targeted inhibition of the first step in TMAO generation, commensal microbial trimethylamine (TMA) production, can help to prevent diet-induced atherosclerosis. The research team inhibited TMA production using 3,3-dimethyl-1-butanol (DMB) in mice fed a high choline or carnitine diet. The mice treated with the inhibitor had less TMAO and developed less atherosclerosis. DMB is not an antibiotic. This important fact suggests that a treatment could target a specific microbial pathway while protecting the gut flora and avoiding antibiotic overuse and resistance, which is a worldwide health crisis.
"We were able to show that 'drugging the microbiome' is an effective way to block this type of diet-induced heart disease. The inhibitor prevents formation of a waste product produced by gut microbes, leading to lowering of TMAO levels and prevention of diet-dependent atherosclerosis." said Dr. Hazen. "This is much like how we use statins to inhibit cholesterol synthesis in human cells."
According to the Centers for Disease Control and Prevention, heart disease kills about 610,000 in the United States annually, accounting for one in every four deaths. It's the leading cause of the death in the U.S. for both men and women.
This research was supported by grants from the National Institutes of Health, the Office of Dietary Supplements and the American Heart Association.
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About the Lerner Research Institute
The Lerner Research Institute (LRI) is home to Cleveland Clinic's laboratory, translational and clinical research. Its mission is to promote human health by investigating in the laboratory and the clinic the causes of disease and discovering novel approaches to prevention and treatments; to train the next generation of biomedical researchers; and to foster productive collaborations with those providing clinical care. In 2014, LRI researchers published nearly 600 articles in high-impact biomedical journals (top 10% of all biomedical journals). LRI's total annual research expenditure was $255 million in 2014 (with $98 million in competitive federal funding). More than 2,000 people (including approximately 175 principal investigators, 200 postdoctoral fellows, and about 170 graduate students) in 13 departments work in research programs focusing on cardiovascular, cancer, neurologic, musculoskeletal, allergic and immunologic, eye, metabolic, and infectious diseases. The LRI has more than 700,000 square feet of lab, office, and scientific core services space. LRI faculty oversee the curriculum and teach students enrolled in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University - training the next generation of physician-scientists. Institute faculty also participate in multiple doctoral programs, including the Molecular Medicine PhD Program, which integrates traditional graduate training with an emphasis on human diseases. The LRI is a significant source of commercial property, generating 66 invention disclosures, 4 licenses, and 50 patents in 2014.
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