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: 10599215
• 负责人: Albert Phillip Owens III
• 金额: $ 63.49万
• 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 2025-05-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599215
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Adult; Affect; Age; Aneurysm; Angiotensin II; Animal Model; Antibiotics; Antisense Oligonucleotides; Aorta; Apoptosis; Apoptotic; Atherosclerosis; Attenuated; Autophagocytosis; Binding; Carbon; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Choline; Chronic Kidney Failure; Clinical Trials; Communities; Data; Development; Diameter; 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; Metabolic; Metabolic Pathway; Molecular; Multienzyme Complexes; Mus; Nutrient; Obesity; Operative Surgical Procedures; Oral; Organ; Organism; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacologic Substance; Pharmacological Treatment; 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; male; men; microbial; mouse model; novel; nutrient metabolism; patient population; pharmacologic; 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（项目摘要） 腹主动脉瘤（AAA）的破裂导致15,000至30,000名男性和女性突然死亡 每年在美国，由于老年人口的增加，这一数字都在增长 越来越差的生活方式选择，例如久坐的生活方式和西方饮食，导致心血管 疾病。 AAA的已知危险因素包括烟草使用，高血压，男性和心血管 疾病。但是，这种情况的根本原因仍然鲜为人知。此外，进展几乎没有 被识别出任何可能受益于这些患者离开手术的药理治疗 唯一的治疗选择。最近有证据表明，居住在人类肠中的肠道微生物可以 促进几种心血管疾病。具体而言，高脂食品中存在的营养（磷脂酰胆碱 胆碱和胆碱可以通过肠道微生物酶代谢以产生三甲胺（TMA），这是 由宿主肝酶黄酮单加氧酶3（FMO3）进一步代谢 三甲胺N氧化物（TMAO）。我们的初步数据表明，循环水平是 与人类队列中的AAA直径，生长和严重程度相关。此外，我们提出了广泛的 初步研究表明胆碱喂养的可能通过TMAO增强了动脉瘤的小鼠模型 肠道微生物组的生产。该提案的总体目标是确定肠道微生物组如何 衍生的代谢物TMAO有助于AAA的启动和进展。我们的两个具体目标将（1） 通过研究tmao元基础，检查肠道菌群在启动AAA中的作用 途径； （2）将确定抑制TMAO生产是否会减弱 开发动脉瘤。这项研究的长期目标是提高我们对 肠道微生物组衍生的因素及其对AAA的贡献，以便将这些发现转化为更多 有效的治疗剂可改善患有这种情况的患者的生存和生活质量。我们期待我们的 翻译研究揭示了将肠道微生物衍生因子与动脉瘤联系起来的新分子机制， 最终可能会利用这是有史以来第一个肠道微生物的治疗和药物 干预AAA。