Gut Microbiota–Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms

作者：Tyler W. Benson, Kelsey A. Conrad, Xinmin S. Li, Zeneng Wang, Robert N. Helsley, Rebecca C. Schugar, Taylor Coughlin, Caris Wadding-Lee, Salma Fleifil, Hannah Russell, Timothy Stone, Michael Brooks, Jennifer A. Buffa, Kevin Mani, Martin Björck, Anders Wanhainen, Naseer Sangwan, Sudha B. Biddinger, Rohan Bhandari, Akiirayi Ademoya, Crystal Pascual, W.H. Wilson Tang, Michael Tranter, Scott J. Cameron, J. Mark Brown, Stanley L. Hazen, A. Phillip Owens · 发表于：Circulation · 年份：2023 · DOI：10.1161/circulationaha.122.060573 · 被引用次数：161 · 研究领域：Aortic aneurysm repair treatments、Infectious Aortic and Vascular Conditions、Aortic Disease and Treatment Approaches

Background: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. Methods: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor–deficient ( Ldlr −/− ) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 ( Fmo3 −/− ). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. Results: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, at...