Role of gut commensal Coprococcus comes in angiotensin-converting enzyme inhibitor resistant hypertension

项目总结和摘要 在美国，高血压是一个严重的公共卫生问题。顽固性高血压定义为 对至少三类抗高血压药物治疗反应不良的高血压，其中一种 是利尿剂尽管有多种类型的抗高血压药物，但约20%的 高血压患者属于顽固性高血压。肠道微生物群是一个新兴的和重要的参与者 高血压的发生和发展最近，肠道微生物群被证明与药物有关 从而影响其功效。在体外和体内，我们的实验室发现， 大肠杆菌能分解代谢血管紧张素转换酶（ACE）抑制剂 喹那普利。基于顽固性高血压的临床表型和我们的初步数据，我们建议 探讨C.在血管紧张素转换酶抑制剂的代谢中， 高血压中心假设是C.通过两种途径导致ACE抑制剂抵抗性高血压 独立作用机制：（1）分解代谢ACE抑制剂，降低其降压作用; （2）可升高宿主血压。本研究的具体目的是调查两个独立的 机制：（1）确定C. comes能分解代谢ACE抑制剂;（2）测定C.来可以 增加宿主血压。为了实现这些目标，我们将进行体外实验， 最广泛使用的ACE抑制剂。ACE抑制剂的降血压作用 将利用高血压大鼠模型进行体内研究，无论是否使用C.来是存在的。实验 正常血压和高血压大鼠用或不用C.来将进行说明， C的参与。是血压调节。该项目的长期目标是发现一个 C. comes有助于顽固性高血压。因此，特定的肠道微生物群或 肠囊藻C.这些改变将使高血压人群受益，特别是抵抗性高血压人群。 高血压患者。顽固性高血压背后的机制仍不清楚。因此， 顽固性高血压的血压控制方法只是徒劳的添加或替代 药物治疗鉴于这些事实，该项目具有重大的科学和临床意义，因为证明 肠上皮细胞C.在顽固性高血压的病因中， 难治性高血压管理和治疗策略。国家心脏、肺和血液研究所 宣布了几份工作组的报告，强调对肠道微生物群，性别， 差异和翻译障碍。目前的提议是根据这些报告和使命提出的。 国家卫生研究所的

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.