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.