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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要肥胖的西方风格（HF）饮食会引起低度肠炎，肠道菌群不平衡，心血管疾病的风险增加。但是，我们对路径的了解产生这些不同的疾病表现是不完整的，因此很难看到联系。本应用程序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成为非传染性责任的分子机制疾病。该应用旨在研究HF饮食驱动肠道营养不良和的机制确定所产生的不平衡是否会升级的微生物代谢产物的产生心血管疾病的风险。我们的中心假设是，线粒体功能障碍肥胖的HF饮食激活上皮修复反应（例如，隐窝增生），这又驱动了扩展兼性厌氧肠杆菌科，该分类单元已知会产生加速的代谢产物动脉粥样硬化。为了检验我们的假设，我们将确定线粒体功能障碍诱导的单核细胞是否招募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的扩张中的上皮修复反应（特定目标2）。我们将还阐明了HF饮食诱导的肠杆菌科扩展的机制增加了循环三甲胺N氧化物（TMAO）水平并促进心血管疾病（特定目标3）。通过定义将这些疾病表现联系起来的复杂事件顺序，我们预计该提议的完成实验以引入决定性的概念进步，以了解HF饮食如何增加心血管疾病风险。