Role of the Gut Microbiota in Abdominal Aortic Aneurysm

肠道微生物群在腹主动脉瘤中的作用

• 批准号: 10176258
• 负责人: Albert Phillip Owens III
• 金额: $ 58.48万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176258
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Adult; Affect; Age; Aneurysm; Angiotensin II; Animal Model; Antibiotics; Antisense Oligonucleotides; Apoptosis; Apoptotic; Atherosclerosis; Attenuated; Autophagocytosis; Binding; Caliber; Carbon; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Choline; Chronic Kidney Failure; Clinical Trials; Communities; Data; Development; Diet; Dilatation - action; Disease; Elderly; Endocrine; Enzymes; Eukaryotic Initiation Factors; FMO3; Fatty acid glycerol esters; Food; Gender; Generations; Goals; Growth; Health; Hepatic; Human; Hypertension; Incidence; Induction of Apoptosis; Inflammatory; Intervention; Intestines; Laboratories; Lecithin; Life Style; Link; Lyase; Mediator of activation protein; Metabolic; Metabolic Pathway; Molecular; Multienzyme Complexes; Mus; Nutrient; Obesity; Operative Surgical Procedures; Oral; Organ; Organism; Oxides; Pathogenesis; Pathway interactions; Patients; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phosphotransferases; Plasma; Population; Prevention; Production; Prognostic Marker; Prokaryotic Initiation Factor-2; Proteins; Public Health; Quality of life; Regulation; Research; Risk Factors; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Severities; Smooth Muscle Myocytes; Source; Sudden Death; Testing; Therapeutic; Time; Tissues; Tobacco use; Translating; Treatment Protocols; United States; Validation; Vascular Diseases; Vascular Smooth Muscle; Woman; abdominal aorta; cohort; feeding; gut microbes; gut microbiome; gut microbiota; host microbiota; human old age (65+); improved; inhibition of autophagy; inhibitor/antagonist; male; men; microbial; mouse model; novel; nutrient metabolism; patient population; renal artery; sedentary lifestyle; targeted treatment; therapeutically effective; transcriptome; transcriptome sequencing; transcriptomics; translational study; trimethylamine; trimethyloxamine; western diet

ABSTRACT (Project Summary) Rupture of abdominal aortic aneurysms (AAA) leads to sudden death in 15,000 to 30,000 men and women each year in the US, and this number is growing due to both an increase in the elderly population and our increasingly poor life-style choices, e.g. sedentary lifestyle and western diet, resulting in cardiovascular disease. Known risk factors for AAA include tobacco use, hypertension, male gender, and cardiovascular disease. However, the underlying cause of this condition is still poorly understood. Further, little progress has been made to identify any pharmacologic treatments which may benefit these patients leaving surgery as the only treatment option. Recent evidence has emerged that gut microbes resident in the human intestine can promote several cardiovascular diseases. Specifically, nutrients present in high fat foods (phosphatidylcholine and choline) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is further metabolized by the host hepatic enzyme Flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine N-oxide (TMAO). Our preliminary data demonstrates that circulating levels of TMAO are associated with AAA diameter, growth, and severity in a human cohort. Further, we present extensive preliminary studies demonstrating choline feeding augments a mouse model of aneurysm potentially via TMAO production by the gut microbiome. The overall goal of this proposal is to determine how the gut microbiome- derived metabolite TMAO contributes to the initiation and progression of AAA. Our two specific aims will (1) examine the role of the gut microbiota in the initiation of AAA by investigating the TMAO meta-organismal pathway; and (2) will determine whether inhibition of TMAO production attenuates the progression of developed aneurysms. The long-term goals of this research are to increase our understanding of the effect of gut microbiome-derived factors and their contribution to AAA in order to translate these findings into more effective therapeutics to improve survival and quality of life for patients with this condition. We anticipate our translational studies to reveal new molecular mechanisms linking gut microbe-derived factors to aneurysm, which may ultimately be leveraged into the first ever gut microbe-targeted therapeutic and pharmaceutical intervention for AAA.

摘要（项目概要） 腹主动脉瘤 (AAA) 破裂导致 15,000 至 30,000 名男性和女性猝死 在美国，每年这个数字都在增长，原因是老年人口的增加和我们的生活 越来越糟糕的生活方式选择，例如久坐的生活方式和西方饮食习惯，导致心血管疾病 疾病。已知的 AAA 危险因素包括吸烟、高血压、男性和心血管疾病 疾病。然而，这种情况的根本原因仍然知之甚少。此外，进展甚微 已确定任何可能使这些患者受益的药物治疗，而将手术作为治疗的方法 唯一的治疗选择。最近的证据表明，居住在人类肠道中的肠道微生物可以 促进多种心血管疾病。具体来说，高脂肪食物中存在的营养素（磷脂酰胆碱） 和胆碱）可以被肠道微生物酶代谢产生三甲胺（TMA）， 进一步被宿主肝酶含黄素单加氧酶 3 (FMO3) 代谢产生 三甲胺 N-氧化物 (TMAO)。我们的初步数据表明，TMAO 的循环水平是 与人类 AAA 直径、生长和严重程度相关。此外，我们还提供广泛的 初步研究表明，胆碱喂养可能通过 TMAO 增强小鼠动脉瘤模型 由肠道微生物组产生。该提案的总体目标是确定肠道微生物组如何 衍生代谢物 TMAO 有助于 AAA 的发生和进展。我们的两个具体目标将 (1) 通过研究 TMAO 元有机体来研究肠道微生物群在 AAA 启动中的作用 途径； (2) 将确定抑制 TMAO 的产生是否会减缓疾病的进展 形成动脉瘤。这项研究的长期目标是加深我们对影响的理解 肠道微生物组衍生因素及其对 AAA 的贡献，以便将这些发现转化为更多 有效的治疗方法可以提高这种疾病患者的生存率和生活质量。我们预计我们的 转化研究揭示肠道微生物衍生因子与动脉瘤之间的新分子机制， 最终可能会被用于第一个针对肠道微生物的治疗和药物 AAA 的干预。