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

肠道共生粪球菌在血管紧张素转换酶抑制剂抵抗性高血压中的作用

• 批准号: 10509954
• 负责人: Tao Yang
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-04 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10509954
• 关键词: Adrenergic alpha-Antagonists; Adult; Affect; African American; African American population; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Attention; Blood Circulation; Blood Pressure; Brain; CD3 Antigens; Calcium; Captopril; Catabolism; Dahl Hypertensive Rats; Data; Development; Diuretics; Dose; Drug usage; Enalapril; Esters; Etiology; FOXP3 gene; Female; Functional disorder; Gastrointestinal tract structure; Helper-Inducer T-Lymphocyte; Hydrolysis; Hypertension; Immune response; In Vitro; Inflammation; Interleukin-10; Interleukin-17; Intervention; Intestines; Kidney; Link; Lisinopril; Liver; Long-Term Effects; Lymphocyte; Measures; Mediating; Metabolism; Metagenomics; Mission; Modeling; National Heart, Lung, and Blood Institute; Oral Administration; Participant; Pathogenicity; Patients; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Phenotype; Population; Proteins; Public Health; Ramipril; Rattus; Regulatory T-Lymphocyte; Renin-Angiotensin System; Reporting; Research; Resistance; Resistant Hypertension; Rodent; Role; Serum; Sex Differences; Sodium Chloride; Spleen; Testing; Therapeutic; United States; United States National Institutes of Health; absorption; base; blood pressure control; blood pressure elevation; blood pressure reduction; blood pressure regulation; caucasian American; clinical phenotype; clinically relevant; comorbidity; cytokine; drinking water; drug metabolism; dysbiosis; experimental study; gut dysbiosis; gut microbiota; gut-brain axis; high risk; high salt diet; hypertension control; hypertensive; improved; in vivo; male; microbial; microbiota; mortality; normotensive; novel; racial and ethnic; response; salt sensitive; systemic inflammatory response; trait; trandolapril; translational barrier; treatment response; working group

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.

项目概要及摘要 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佳的高血压，其中之一 这是利尿剂。尽管有多种抗高血压药物可供使用，但大约 20% 高血压患者属于难治性高血压。肠道微生物群是一个新兴的重要参与者 高血压的发生和进展。最近，肠道微生物群被证明与药物有关 新陈代谢，然后影响其功效。在体外和体内，我们的实验室发现肠道 共生粪球菌能够分解代谢血管紧张素转换酶 (ACE) 抑制剂 喹那普利。根据顽固性高血压的临床表型和我们的初步数据，我们建议 研究 C. 在 ACE 抑制剂代谢以及发展中的功能 高血压。中心假设是 C. come 通过两种途径导致 ACE 抑制剂抵抗性高血压 独立机制：（1）可分解ACE抑制剂，降低其降血压作用； (2)它可以升高宿主血压。本研究的具体目的是调查两个独立的 机制：（1）确定C. come是否可以分解代谢ACE抑制剂； (2) 确定 C. 是否可以 增加宿主血压。为了实现这些目标，我们将进行体外实验来量化 最广泛使用的 ACE 抑制剂的分解代谢。 ACE抑制剂的降血压作用 无论是否存在 C. come，都将利用高血压大鼠模型进行体内研究。实验 将用或不用 C. come 治疗的正常血压和高血压大鼠来说明 C.参与血压调节。该项目的长期目标是发现 C. 导致难治性高血压的新机制。因此，特定的肠道微生物群或 肠道共生 C. 的改变将使高血压人群受益，特别是耐药人群 高血压患者。顽固性高血压背后的机制仍不清楚。因此，常见的 顽固性高血压的血压控制方法只是徒劳地添加或替代 药物。鉴于这些事实，该项目具有重大的科学和临床意义，因为 肠道共生菌 C. 在顽固性高血压病因学中的机制作用将导致潜在的 难治性高血压的管理和治疗策略。国家心肺血液研究所 公布了工作组的几份报告，强调肠道微生物群、性别的研究 差异和翻译障碍。当前的提议是根据这些报告和使命 美国国立卫生研究院的。