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.

项目概要致胖的西式 (HF) 饮食会导致轻度肠道炎症、肠道微生物群不平衡，增加患心血管疾病的风险。然而，我们对路径的了解产生这些不同疾病表现的每一种都是不完整的，因此很难看出其中的联系。本申请中提出的实验旨在解决这一知识上的关键差距。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。该应用旨在研究高频饮食驱动肠道菌群失调的机制以及确定由此产生的不平衡是否会增加微生物代谢物的产生，从而增加心血管疾病的风险。我们的中心假设是线粒体功能障碍是由致肥胖的高频饮食会激活上皮修复反应（例如隐窝增生），进而驱动兼性厌氧肠杆菌科细菌的扩张，这是一种已知能产生加速代谢产物的分类群动脉粥样硬化。为了检验我们的假设，我们将确定线粒体功能障碍是否会诱导单核细胞招募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细菌扩张（具体目标 2）。我们将还阐明了 HF 饮食诱导的肠杆菌扩张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）。通过定义联系这些疾病表现的复杂事件顺序，我们期望完成拟议的实验在理解高频饮食如何增加心血管方面取得了决定性的概念进展疾病风险。