Obesogenic diet-induced intestinal epithelium repair responses link dysbiosis and cardiovascular disease

项目总结 肥胖的西式(HF)饮食会导致低度肠道炎症，肠道微生物区系 不平衡，心血管疾病的风险增加。然而，我们对这些路径的了解 产生这些不同的疾病表现是不完整的，因此很难看出它们之间的联系。 本申请中提出的实验旨在解决知识中的这一关键差距。我们的远程 目的是阐明在非传染性疾病期间肠道微生物区系易受影响的分子机制。 疾病。这项应用旨在研究HF饮食推动肠道生物失调和 确定由此产生的失衡是否会加剧微生物代谢物的生产，从而增加 患心血管疾病的风险。我们的中心假设是，由一种 肥胖性HF饮食激活上皮修复反应(例如，隐窝增生)，这反过来又推动 兼性厌氧肠杆菌科的扩张，这是一种已知能产生加速代谢产物的分类群 动脉硬化。为了验证我们的假设，我们将确定线粒体功能障碍是否会导致单核细胞 募集促进结肠上皮修复反应(特定目标1)。我们将确定结肠的作用 驱动HF饮食诱导的肠杆菌科扩张的上皮修复反应(特定目标2)。我们会 还阐明了HF饮食诱导肠杆菌科细菌扩张增加循环的机制 三甲胺氮氧化物(TMAO)水平和促进心血管疾病(具体目标3)。通过定义 复杂的事件顺序将这些疾病表现联系在一起，我们预计将完成拟议的 为了解HF饮食如何增加心血管疾病带来决定性概念进展的实验 疾病风险。

PROJECT SUMMARY An obesogenic Western-style (HF) diet causes low-grade intestinal inflammation, intestinal microbiota imbalance, and an increased risk of cardiovascular disease. However, our knowledge about the pathways producing each of these different disease manifestations is incomplete, making it difficult to see connections. Experiments proposed in this application are aimed at addressing this critical gap in knowledge. Our long-range goal is to elucidate molecular mechanisms that make the gut microbiota a liability during non-communicable diseases. This application aims to study the mechanisms through which HF diet drives gut dysbiosis and determine whether the resulting imbalance escalates the production of microbial metabolites that increase the risk for cardiovascular disease. Our central hypothesis is that mitochondrial dysfunction induced by an obesogenic HF diet activates epithelial repair responses (e.g., crypt hyperplasia), which in turn drives an expansion of facultative anaerobic Enterobacteriaceae, a taxon known to produce metabolites that accelerate atherosclerosis. To test our hypothesis, we will determine whether mitochondrial dysfunction-induced monocyte recruitment promotes colonic epithelium repair responses (specific aim 1). We will identify the role of colonic epithelium repair responses in driving HF diet-induced Enterobacteriaceae expansion (specific aim 2). We will also elucidate the mechanism by which HF diet-induced Enterobacteriaceae expansion increases circulating trimethylamine N-oxide (TMAO) levels and promotes cardiovascular disease (specific aim 3). By defining the complex order of events that links these disease manifestations, we expect the completion of the proposed experiments to usher in a decisive conceptual advance to understand how HF diet increases cardiovascular disease risk.