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.

项目摘要和摘要 在美国，高血压是一个严重的公共卫生问题。耐药性高血压定义为 高血压对至少三类降压药的治疗反应不佳，这是 是利尿剂。尽管有多种类别的降压药，但约有20％ 高血压患者属于耐药性高血压。肠道微生物群是一个新兴而重要的参与者 在高血压的启动和进展中。最近，肠道菌群被证明与药物有关 新陈代谢及其之后会影响其效率。在体外和体内，我们的实验室发现肠道 共生cocococcus能够分解血管紧张素转换酶（ACE）抑制剂 Quinapril。基于耐药性高血压和我们的初步数据的临床表型，我们建议 研究C的功能是ACE抑制剂的代谢以及 高血压。中心假设是C。来到通过两个 独立机制：（1）它可以分解ACE抑制剂并降低其血压抑制作用； （2）它可以升高宿主血压。这项研究的具体目的是研究两个独立 机制：（1）确定C.是否可以分解ACE抑制剂； （2）确定C.是否来 增加宿主血压。为了执行这些目标，我们将进行体外实验以量化 最广泛规定的ACE抑制剂的分解代谢。 ACE抑制剂的血压降压作用 是否存在高血压大鼠模型的体内研究，无论是否存在C。实验 有或没有C来治疗的正常血统和高血压大鼠将进行以说明 C的参与来自血压调节。该项目的长期目标是发现 C.的新型机制有助于耐药性高血压。因此，特定的肠道菌群或 肠道C. C.的改变将使高血压人群受益，特别是抗药性 高血压患者。耐药性高血压背后的机制尚不清楚。因此，共同 在耐药性高血压中控制血压的方法只是徒劳的或替代 药物。鉴于这些事实，该项目具有很大的科学和临床意义，因为 肠道共生的机械作用C在耐药性高血压的病因中会导致潜力 抵抗高血压管理和治疗的策略。国家心脏，肺和血液研究所 宣布了工作组的几份报告，以强调有关肠道菌群，性别的研究 差异和翻译障碍。当前的提案符合这些报告和任务 国家卫生研究院。