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Altering gut bacteria pathways may stimulate fat tissue to prevent obesity

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Cleveland Clinic researchers have uncovered a biological link between gut bacteria metabolism and obesity. The team showed that blocking a specific intestinal microbial pathway can prevent obesity and insulin resistance, as well as cause fat tissue to become more metabolically active. The study was recently published in Cell Reports.

The research team, led by J. Mark Brown, Ph.D., of Cleveland Clinic's Lerner Research Institute, studied the metabolic pathway that creates trimethylamine oxide (TMAO), a chemical produced by gut bacteria during digestion of key nutrients – choline, lecithin and carnitine – found abundantly in animal products, such as red meat, processed meats, egg yolks and liver.

Dr. Brown's colleague on the current study – Stanley Hazen, M.D., Ph.D. – previously showed that high levels of TMAO are associated with a higher risk of severe cardiovascular events, such as heart attack and stroke.

Since cardiovascular disease and obesity are so closely linked, the team hypothesized that TMAO may also be involved in metabolic pathways that lead to obesity. They focused on a host enzyme called flavin-containing monooxygenase 3(FMO3), which converts TMAO into its active form. They discovered that mice that had a missing or deactivated FMO3 gene were protected from obesity, even when fed a high-fat, high-calorie diet. Furthermore, the FMO3-negative mice showed higher expression of genes associated with beige or brown fat cells, which are more metabolically active than white fat cells.

The study confirmed in 435 patients that high levels of TMAO are associated with higher incidence of Type 2 diabetes.

"Obesity, diabetes and cardiovascular disease are strongly linked. While the microbiome has been shown to affect cardiovascular disease, there is as yet no concrete evidence of precisely how gut bacteria influence obesity," Brown said. "These findings shed light on a possible way to manipulate the microbiome with therapeutics to combat our obesity and diabetes epidemic."

Brown is a member of the scientific staff in the Lerner Research Institute's Department of Cellular & Molecular Medicine. Rebecca Schugar, PhD, is first author on the publication in Cell Reports.

"Given the numerous strong associations of the gut microbe-driven TMAO pathway with human disease, this work has broad implications for drug discovery efforts targeting gut microbes themselves," said Dr. Hazen, chair of the Department of Cellular & Molecular Medicine for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart & Vascular Institute at Cleveland Clinic. "However, additional work is needed to better understand the entire pathway and the links between TMA, FMO3, TMAO and human health."

TMAO is a byproduct of bacterial digestion of choline, lecithin and carnitine, nutrients that are especially abundant in animal products such as red meat, processed meats and liver. Dr. Hazen, who also holds the Jan Bleeksma Chair in Vascular Cell, has previously linked TMAO to an increased risk of cardiovascular disease and has shown it can be a powerful tool for predicting future heart attacks, stroke and death in multiple patient populations. Dr. Hazen is an inventor of a test for TMAO that was licensed to Cleveland HeartLab, Inc., a Cleveland Clinic spin-off company. Dr. Hazen and Cleveland Clinic would benefit financially from sales of the test.

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This work was supported by multiple grants from the National Institutes of Health and its Office of Dietary Supplements – grants R00 HL096166 (J.M.B.), R01 HL122283, P50 AA024333, R01 HL103866, R01 HL126827, R01 DK106000, R01 HL130819, R01 DK090111, R00 HL12172, P01 HL028481, P01 HL030568-31A1, P01 HL49373 (L.L.R.) – as well as by the Deutsche Forschungsgemeinschaft, the Academy of Finland and the Finnish Cardiovascular Research Foundation, and the American Heart Association.

About the Lerner Research Institute

The 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 ~1,500 articles in peer-reviewed biomedical journals each year. Lerner's total annual research expenditure was $260 million in 2016 (with $140 million in competitive federal funding, placing Lerner in the top five research institutes in the nation in federal grant funding). Approximately 1,500 people (including approximately 200 principal investigators, 240 research fellows, and about 150 graduate students) in 12 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 (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 Lerner is a significant source of commercial property, generating 64 invention disclosures, 15 licenses, 121 patents, and one new spinoff company in 2016. Visit us at http://www.lerner.ccf.org. Follow us on Twitter at http://www.twitter.com/CCLRI.

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 51,000 employees are more than 3,500 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, 10 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 2016, there were 7.1 million outpatient visits, 161,674 hospital admissions and 207,610 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.

Editor's Note: Cleveland Clinic News Service is available to provide broadcast-quality interviews and B-roll upon request.

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Alicia Reale
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