Lifelong Innovation: The TMAO Story

Lifelong Innovation: The TMAO Story

A member of Cleveland Clinic’s staff since 1997, Stanley Hazen, MD, PhD, is both a practicing physician and researcher with many leadership roles. Dr. Hazen is chair, Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Director, Center for Microbiome & Human Health, and co-Section Head, Preventative Cardiology & Rehabilitation, in the Robert and Suzanne Tomsich Department, Cardiovascular Medicine, Cleveland Clinic. He has received numerous awards and recognitions for his pioneering research, including being an elected member of the National Academy of Medicine, and an elected fellow of the American Association for the Advancement of Science. He has published over 400 peer-reviewed manuscripts and is counted amongst some of the most highly cited investigators in the country – attesting to the high impact his studies have made. But his thirst for research has yet to be quenched.

Dr. Hazen’s latest influential work stems from a 2011 publication heralding the discovery that gut microbes participate in cardiovascular disease (CVD) development. The level of a compound found in blood called trimethylamine-N-oxide (TMAO) was discovered to be strikingly associated with future development of CVD and risk for major adverse cardiovascular events (MACE = heart attack, stroke and death). The discovery, and significance of, the TMAO compound would shape Hazen’s work from there on. Says Hazen, “The whole discovery began without us knowing what we were looking for – we just knew the approach should lead us to something new. We didn’t realize exactly where the science would take us.” But Dr. Hazen and team soon learned the importance of TMAO. Through “reverse engineering” the pathway, the team discovered that the compound is ultimately made by gut microbes during the digestion of foods abundant in a Western diet. TMAO is produced by the liver during oxidation of its precursor, trimethylamine (TMA) – a waste product when one eats nutrients like lecithin (phosphatidylcholine), choline and carnitine. Lecithin, choline, and carnitine are nutrients found at high levels in animal products like red meat.

From his preliminary work, Dr. Hazen knew TMAO and CVD were closely related, but set out to figure exactly how. Teasing out the discovery, subsequent animal model studies would directly show increased TMAO levels to accelerate the heart disease development. With continued work, he noticed a direct connection between TMAO and the reactivity of blood platelets themselves, making them sticky and more likely to clot. Studies spanning from different animal models, to healthy volunteers with diet and nutrient changes, all led to evidence that TMAO has direct effects on the components of blood (platelets) and vessel walls (endothelial cells) that contribute to the occurrence of MACE in patients with high levels.

Honing in on TMAO creation in the body, Dr. Hazen and his team are now focused on both developing inhibitors of the pathway, and detailing how elevated TMAO levels occur by diet and altered kidney handling with change in diet. A research area to be expanded upon, he and his team look to prevent production of TMAO through intervention at the level of the gut microbes. As section head of Preventive Cardiology, Dr. Hazen emphasizes the importance of diet, exercise and other healthy lifestyle habits. But he also sees the need to look beyond dietary efforts, “There will always be people who present with chest pain, a recent heart attack, or some other event with established cardiovascular disease, and these subjects remain at heightened risks for experiencing a heart attack, stroke or death – even with adherence to a strict diet and healthy lifestyle. One day, our medicine cabinets will have drugs that target gut microbial pathways, much like how statins inhibit cholesterol synthesis by our liver, to treat and prevent progression of heart disease.” 

From his research, Dr. Hazen has made many things clear to the medical and scientific communities, and opened numerous doors for future studies. His work is recognized as helping to usher in our improved understanding of how important the gut microbiome is to our health, and susceptibility to disease.  Some of his latest advancements? Showing one can transplant specific TMAO microbes, into recipient mice and transmit an enhanced risk for clotting in an animal model of stroke – findings published in Circulation Research (November 2018). Or uncovering more precisely the connections between TMAO and red meat. In a chronic diet intervention study in subjects that included isotope tracers, and mass spectrometry analyses of blood, and urine, his work further teased out changes in both the gut microbiome, and kidney function, from a chronic diet rich in red meat – findings published in European Heart Journal (December 2018). Dr. Hazen leads a team that recently reported development of a new class of drugs that target the TMAO pathway, and showed these new drugs prevented clotting risk in a stroke model in studies – findings published in Nature Medicine (September 2018). Developing new approaches for treating microbiome-related disorders, there is increasing opportunity for commercialization of a successful therapeutic through CCI. Dr. Hazen has worked closely with Innovations for years, and has numerous issued and pending patents to protect his research. As he continues to evaluate the role of gut microbes in influencing our health and susceptibility for diseases, Dr. Hazen is always looking for opportunities to INVENT®.
 

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