Project summary and abstract In the United States, hypertension is a serious public health concern. Resistant hypertension is defined as hypertension with poor responses to the treatment of at least three classes of antihypertensive drugs, one of which is diuretic. Despite the availability of multiple classes of antihypertensive drugs, approximately 20% of hypertensive patients belong to resistant hypertension. Gut microbiota is an emergent and important participant in the initiation and progression of hypertension. Recently, the gut microbiota is shown to be involved in drug metabolism and thereafter impacts their efficacies. In vitro and in vivo, our lab has discovered that the gut commensal Coprococcus comes is capable of catabolizing the angiotensin-converting enzyme (ACE) inhibitor quinapril. Based on clinical phenotypes of resistant hypertension and our preliminary data, we propose to investigate the functions of C. comes in the metabolism of ACE inhibitors as well as in the development of hypertension. The central hypothesis is that C. comes leads to ACE inhibitor resistant hypertension via two independent mechanisms: (1) it can catabolize ACE inhibitors and reduce their blood pressure-lowering effects; and (2) it can raise host blood pressure. The specific aims of this study are to investigate the two independent mechanisms: (1) determine if C. comes can catabolize ACE inhibitors; and (2) determine if C. comes can increase host blood pressure. To execute these aims, we will conduct in vitro experiments to quantify the catabolism of the most widely prescribed ACE inhibiors. The blood pressure-lowering effect of ACE inhibitors will be studied in vivo utilizing hypertensive rat models, whether or not C. comes is present. Experiments on normotensive and hypertensive rats treated with or without C. comes will be conducted to illustrate the involvement of C. comes in blood pressure regulation. The long-term objective of this project is to uncover a novel mechanism by which C. comes contributes to resistant hypertension. Therefore, specific gut microbiota or gut commensal C. comes alterations would benefit the hypertensive population, particularly resistant hypertensive patients. The mechanisms behind resistant hypertension remains unclear. Thus, the common approach to blood pressure control in resistant hypertension is simply the futile addition or substitution of medications. Given these facts, this project is of great scientific and clinical relevances, since the demonstrating the mechanistic role of gut commensal C. comes in the etiology of resistant hypertension will lead to potential strategies for resistant hypertension management and therapy. The National Heart, Lung, and Blood Institute has announced several reports from working groups to emphasize the research on gut microbiota, sex differences, and translational barriers. The current proposal is in accordance with these reports and the mission of the National Institute of Health.