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

肥胖饮食诱导的肠上皮修复反应将生态失调与心血管疾病联系起来

• 批准号: 10345474
• 负责人: Mariana Xavier Byndloss
• 金额: $ 50.55万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345474
• 关键词: Address; Adult; Aerobic; Affect; Anaerobic Bacteria; Atherosclerosis; Automobile Driving; Blood Circulation; Cardiovascular Diseases; Cessation of life; Choline; Chronic; Colon; Complex; Data; Development; Diet; Disease; Enterobacteriaceae; Epithelial Cells; Event; Exposure to; Goals; Health; Heart Diseases; High Fat Diet; Hyperplasia; In Vitro; Inflammatory; Intestinal Diseases; Intestines; Knowledge; Link; Mediating; Metabolism; Modeling; Molecular; Mucous Membrane; Obesity; Pathway interactions; Population; Production; Research Personnel; Respiration; Role; Saturated Fatty Acids; Study models; Taxon; Testing; atherosclerosis risk; base; cardiovascular disorder risk; colonic crypt; diet-induced obesity; dysbiosis; epithelial repair; experimental study; gut dysbiosis; gut inflammation; gut microbiota; host-associated microbial communities; in vivo; innovation; insight; interest; intestinal epithelium; microbial; mitochondrial dysfunction; monocyte; mouse model; novel; obesogenic; recruit; response; shift work; trimethylamine; trimethyloxamine

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.

项目摘要 致肥胖的西式（HF）饮食会导致轻度肠道炎症，肠道微生物群 不平衡和心血管疾病的风险增加。然而，我们对这些途径的了解 产生这些不同的疾病表现中的每一种都是不完整的，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 目标是阐明使肠道微生物群在非传染性疾病期间成为负担的分子机制。 疾病本申请旨在研究HF饮食驱动肠道生态失调的机制， 确定所产生的不平衡是否会增加微生物代谢物的产生， 心血管疾病的风险。我们的中心假设是， 致肥胖HF饮食激活上皮修复反应（例如，隐窝增生），这反过来又驱动了一个 扩大兼性厌氧肠杆菌科，已知产生代谢物，加速 动脉粥样硬化为了验证我们的假设，我们将确定线粒体功能障碍诱导的单核细胞 募集促进结肠上皮修复反应（具体目标1）。我们将确定结肠的作用 上皮修复反应驱动HF饮食诱导的肠杆菌科扩增（具体目标2）。我们将 还阐明了HF饮食诱导的肠杆菌科扩增增加循环的机制， 三甲胺N-氧化物（TMAO）水平并促进心血管疾病（具体目标3）。通过定义 由于这些疾病表现之间存在着复杂的联系，我们希望完成拟议的 实验，以迎来一个决定性的概念进步，以了解HF饮食如何增加心血管疾病 疾病风险。