Stanley Hazen, MD, PhD, is 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. He holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis. Dr. Hazen obtained a Bachelor degree and dual MD /PhD degree in Biophysical Chemistry and Molecular Biology, with subsequent clinical training in Internal Medicine in the subspecialty of Diabetes, Endocrinology and Metabolism at Washington University School of Medicine, St Louis. He has made seminal discoveries linking gut microbial pathways to cardiovascular disease and metabolic diseases, including atherosclerosis, thrombosis, heart failure and chronic kidney disease. Dr. Hazen has received numerous awards, including election to the American Federation for Medical Research, the American Society for Clinical Investigation, the Association of American Physicians, and the National Academy of Medicine. He is a Fellow of the American Association for the Advancement of Science. In 2017, he was named as a Distinguished Scientist by the American Heart Association.
Tuesday 02 June 10:00
Taming the gut microbiota
The gut microbiota act collectively as an integrated organ, regulating multiple biological functions that can modulate cardiovascular risk factors and the pathogenic mechanisms of this process. These activities are mediated by various metabolites that can act locally in the gut, as well as travel systemically to affect host physiology. Changes in the composition of the gut microbiota are identified as contributing factors in the development of atherosclerosis and cardiometabolic disease. In particular, three main classes of gut microorganism-dependent metabolites have been linked to cardiovascular health – trimethylamine N-oxide (TMAO), short chain fatty acids and secondary bile acids. If these pathways are dysregulated, there is the potential for exacerbation of risk for cardiovascular disease.
Perhaps the most compelling evidence for the role of the gut bacterial metabolites in cardiometabolic diseases is provided by TMAO. At the molecular level, TMAO has been shown to activate inflammatory gene expression, increase uptake of modified low-density lipoprotein by macrophages, and predispose to increased aggregation and thrombosis. In population-based and intervention studies, increased plasma levels of TMAO were associated with risk of type 2 diabetes mellitus, cardiovascular disease and incident thrombosis.
Short chain fatty acids produced by the gut microbiota are critical in multiple regulatory roles in energy homeostasis, insulin sensitivity, and glucose and lipid metabolism. Studies consistently show that these metabolites are associated with a reduced risk of cardiovascular and metabolic diseases. The secondary bile acids, deoxycholic acid and lithocholic acid, are the main ligands for TGR5, a G protein-coupled receptor, implicated in weight maintenance and glucose metabolism.
Further understanding of the gut microbe pathways involved in the biosynthesis of cardiovascular-related metabolites, in particular characterisation of their cellular receptors and signalling pathways, may offer potential therapeutic application for managing cardiac health and preventing cardiovascular disease.
Li XS, Obeid S, Wang Z, Hazen BJ, Li L, Wu Y, Hurd AG, Gu X, Pratt A, Levison BS, Chung YM, Nissen SE, Tang WHW, Mach F, Räber L, Nanchen D, Matter CM, Lüscher TF, Hazen SL. Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes. Eur Heart J 2019;40:2700-9.
Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73:2089-105.
McMillan A, Hazen SL. Gut microbiota involvement in ventricular remodeling post-myocardial infarction. Circulation 2019;139:660-2.
Koeth RA, Lam-Galvez BR, Kirsop J, Wang Z, Levison BS, Gu X, Copeland MF, Bartlett D, Cody DB, Dai HJ, Culley MK, Li XS, Fu X, Wu Y, Li L, DiDonato JA, Tang WHW, Garcia-Garcia JC, Hazen SL. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest 2019;129:373-87.