Role of the Gut Microbiota in Abdominal Aortic Aneurysm

摘要（项目摘要） 腹主动脉瘤（AAA）破裂导致15，000至30，000名男性和女性猝死 每年在美国，这一数字正在增长，由于老年人口的增加和我们的 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，导致心血管疾病 疾病AAA的已知危险因素包括吸烟、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， 已经确定了任何药物治疗，可能有利于这些患者离开手术， 唯一的治疗选择。最近的证据表明，人类肠道中的肠道微生物可以 引发多种心血管疾病。具体来说，高脂肪食物中的营养物质（磷脂酰胆碱 和胆碱）可以被肠道微生物酶代谢以产生三甲胺（TMA）， 进一步由宿主肝酶含黄素单加氧酶3（FMO 3）代谢，产生 N-氧化三甲胺（TMAO）。我们的初步数据表明，TMAO的循环水平是 与人类队列中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可能通过TMAO增强小鼠动脉瘤模型 由肠道微生物组产生。这项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的发生和发展。我们的两个具体目标将（1） 通过研究TMAO微生物，检查肠道微生物群在AAA启动中的作用 途径;和（2）将确定TMAO产生的抑制是否会减弱TMAO的进展。 出现了动脉瘤这项研究的长期目标是增加我们对 肠道微生物组衍生因子及其对AAA的贡献，以便将这些发现转化为更多 有效的治疗方法，以提高生存和生活质量的患者与这种情况。我们期待我们的 转化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， 这可能最终会成为第一个肠道微生物靶向治疗和药物 介入AAA。

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.