Role of the Gut Microbiota in Abdominal Aortic Aneurysm

摘要(项目摘要) 腹主动脉瘤破裂(AAA)导致15,000至30,000名男性和女性猝死 在美国，这个数字每年都在增长，这是因为老年人口的增加和我们的 越来越差的生活方式选择，例如久坐不动的生活方式和西方饮食，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，几乎没有取得什么进展 以确定任何可能使这些离开手术的患者受益的药物治疗 唯一的治疗选择。最近有证据表明，寄居在人体肠道中的肠道微生物可以 推广几种心血管疾病。具体地说，高脂肪食物中存在的营养物质(磷脂酰胆碱 和胆碱)可被肠道微生物酶代谢产生三甲胺(TMA)，这是 进一步由宿主肝酶黄素单加氧酶3(FMO3)代谢产生 三甲胺氮氧化物(TMAO)。我们的初步数据表明，循环中的TMAO水平是 在人类队列中与AAA直径、生长和严重性有关。此外，我们还提出了广泛的 初步研究表明，喂饲胆碱可能通过TMAO增加小鼠动脉瘤模型 由肠道微生物群产生。这项提案的总体目标是确定肠道微生物群如何- 其衍生代谢产物TMAO参与了AAA的发生和发展。我们的两个具体目标将：(1) 通过对TMAO元生物的研究，研究肠道微生物区系在AAA启动中的作用 途径；以及(2)将确定抑制TMAO的产生是否延缓了 出现了动脉瘤。这项研究的长期目标是增加我们对 肠道微生物群衍生因子及其对AAA的贡献，以便将这些发现转化为更多 有效的治疗方法，以改善这种情况下患者的生存和生活质量。我们期待我们的 翻译研究揭示了肠道微生物衍生因子与动脉瘤之间的新分子机制， 最终可能被利用到第一种肠道微生物靶向治疗和药物中 对AAA的干预。

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.