Potential new class of drugs may reduce cardiovascular risk by targeting gut microbes

Credit: Cleveland Clinic

EMBARGOED UNTIL 11:00 a.m. ET, August 6, 2018, CLEVELAND: Cleveland Clinic researchers have designed a potential new class of drugs that may reduce cardiovascular risk by targeting a specific microbial pathway in the gut.

Unlike antibiotics, which non-specifically kill gut bacteria and can lead to adverse side effects and resistance, the new class of compounds prevents microbes from making a harmful molecule linked to heart disease without killing the microbes, which are part of the gut flora and may be beneficial to overall health.

In the study, which took place in mice, the new drugs reversed two major risk factors for cardiovascular disease – increased platelet responsiveness and excessive clot formation – by lowering levels of TMAO (trimethylamine N-oxide), a gut bacteria byproduct that forms during digestion.

The research was published in the September issue of Nature Medicine and was led by Stanley Hazen, M.D., Ph.D.

High levels of TMAO in the blood have been shown to be a powerful tool for predicting future heart attack, stroke and death risks, according to previous research initially spearheaded by Dr. Hazen and his team, and subsequently replicated around the world. TMAO testing is now in clinical use as a result.

In several landmark studies in the last five years, Dr. Hazen's team was the first to demonstrate that the metabolite TMAO is produced when gut bacteria digest choline, lechithin and carnitine, nutrients that are abundant in animal products such as red meat and liver. Choline is also abundant in egg yolk and high-fat dairy products. Dr. Hazen's group went on to show that TMAO affects platelet reactivity and thrombosis (clotting) potential, which lead to a higher risk of myocardial infarction (heart attack) and stroke.

In this new study, Dr. Hazen's group demonstrated that a new series of inhibitors, called mechanism-based inhibitors, potently interrupt the gut microbial pathway that produces TMAO. Because the compounds are structurally similar to choline (called analogues), the bacterial cells are "tricked" into taking them up as nutrients. Once transported into the microbe, the inhibitors then block the production of TMAO by inactivating a specific gut microbe enzyme called cutC (choline utilization protein C).

"To our knowledge, this is the most potent therapy to date for 'drugging' the microbiome to alter a disease process. In addition, gut bacteria are altered but not killed by this drug, and there were no observable toxic side effects," said Dr. Hazen. "The approach developed could potentially be used to target other gut microbial pathways. We look forward to advancing this novel therapeutic strategy into humans."

The group found that a single oral dose of one of the potent inhibitors in animal models significantly reduced TMAO levels in the blood for up to three days and reversed both enhanced platelet responsiveness and heightened thrombus (clot) formation following arterial injury. Once taken, the drugs were minimally absorbed into the body, and instead stayed in the gut where they targeted just the microbial pathway. The drugs also reduced "hyperresponsive" platelet function to normal, inhibiting excessive blood clot formation but with very little risk for increased bleeding, which is a common side effect of other anti-platelet therapies.

In addition, the drugs were designed to not kill the bacterial cells and, therefore, likely do not contribute to antibiotic resistance.

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Dr. Hazen directs the Cleveland Clinic Center for Microbiome and Human Health. He also chairs the Department of Cellular and Molecular Medicine in Cleveland Clinic's Lerner Research Institute and is co-section head of Preventive Cardiology & Cardiac Rehabilitation in the Miller Heart &Vascular Institute. Co-first authors on the paper were Adam Roberts, Ph.D., Jennifer Buffa, MS and Xiaodong Gu, Ph.D., all of the Department of Cellular and Molecular Medicine in Cleveland Clinic's Lerner Research Institute. Investigators from Procter & Gamble participated in some of the studies reported. Dr. Hazen is named as co-inventor on pending and issued patents held by Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, and having the right to receive royalty payment for inventions or discoveries related to cardiovascular diagnostics or therapeutics. Dr. Hazen also reports having been paid as a consultant for P&G, and receiving research funds from P&G.

Heart disease is the leading cause of death for both men and women in the United States. Every year, about 610,000 people die of heart disease in this country, accounting for one in every four deaths.

This research was supported by grants from the National Institutes of Health and the Office of Dietary Supplements.

About Cleveland Clinic

Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. Among Cleveland Clinic's 52,000 employees are more than 3,600 full-time salaried physicians and researchers and 14,000 nurses, representing 140 medical specialties and subspecialties. Cleveland Clinic's health system includes a 165-acre main campus near downtown Cleveland, 11 regional hospitals, more than 150 northern Ohio outpatient locations – including 18 full-service family health centers and three health and wellness centers – and locations in Weston, Fla.; Las Vegas, Nev.; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2017, there were 7.6 million outpatient visits, 229,000 hospital admissions and 207,000 surgical cases throughout Cleveland Clinic's health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.

About the Lerner Research Institute

Lerner Research Institute 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. Lerner researchers publish more than 1,000 articles in peer-reviewed biomedical journals each year. Lerner's total annual research expenditure was $272 million in 2017 (with $118 million in competitive federal funding). Approximately 1,500 people (including approximately 175 principal investigators, 250 research fellows, and about 200 graduate students) in 11 departments work in research programs focusing on heart and vascular, cancer, brain, eye, metabolic, musculoskeletal, inflammatory and fibrotic diseases. The Lerner has more than 700,000 square feet of lab, office and scientific core services space. Lerner faculty oversee the curriculum and teach students enrolled in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University – training the next generation of physician-scientists. Lerner faculty also participate in multiple doctoral programs, including the Molecular Medicine PhD Program, which integrates traditional graduate training with an emphasis on human diseases. Lerner is a significant source of new technologies that can be commercialized, generating 53 invention disclosures, 20 licenses, 98 patents, and one new spinoff company in 2017. Visit us at http://www.lerner.ccf.org. Follow us on Twitter at http://www.twitter.com/CCLRI.

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       http://dx.doi.org/10.1038/s41591-018-0128-1 
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