Establishing mechanistic links between the gut microbiome and atherosclerosis

建立肠道微生物组和动脉粥样硬化之间的机制联系

基本信息

批准号：
10600832
负责人：
Aldons Jake Lusis
金额：
$ 66.56万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600832
关键词：
Ablation Affect Animal Model Animals Apolipoprotein E Arterial Fatty Streak Atherosclerosis Bacteria Binding Butyrates Cardiometabolic Disease Cardiovascular Diseases Choline Chronic Disease Clinical Research Collection Complex Dendritic Cells Deterioration Development Diet Dietary Factors Dietary Fiber Disease Disease model Distal Environment Environmental Risk Factor Epithelial Cells Exhibits Fiber Genetic Germ-Free Gnotobiotic Goals Growth Health Human Human Genome Human Microbiome Hybrids Immunologics Impairment Inbred Strains Mice Inflammation Inflammatory Integration Host Factors Intervention Intestines Laboratories Lesion Link Lipopolysaccharides Macrophage Mediating Metabolic Metabolic Diseases Metabolism Microbe Microbial Physiology Microbiology Modeling Mouse Strains Mucous body substance Mus Nucleotides Peptidoglycan Phenotype Plasma Positioning Attribute Predisposition Process Production Proteins Research Personnel Resistance Resources Role Signal Pathway System Testing Toll-like receptors Toxin Validation Variant Work blood glucose regulation cardiometabolism cardiovascular disorder therapy cardiovascular risk factor cytokine design dietary disorder prevention dysbiosis follow-up genetic approach gut bacteria gut microbes gut microbiome gut microbiota improved insight interleukin-22 interleukin-23 intestinal barrier intestinal homeostasis microbial microbiome microbiome composition microbiome research microbiota mouse model novel overexpression prevent receptor skills systemic inflammatory response targeted treatment trait translational applications trimethylamine trimethyloxamine vector

项目摘要

Project Summary Human and mouse studies have identified changes in the gut microbiome associated with progression of atherosclerosis. While gut microbes provide many benefits to the host (e.g. provide metabolic capabilities not represented in our human genome), they also can be detrimental. Coexistence with our gut microbes is largely enabled by the intestinal barrier—composed of a luminal mucus layer, epithelial cells and an inner functional immunological barrier— which limits the entry of toxins and microbial pro-inflammatory molecules. Previous studies have shown that diet and microbial metabolism modulate intestinal barrier function. Recent work from our team and others has linked changes in the gut microbiome with alterations in intestinal barrier function and cardiometabolic disease. However, the role of intestinal barrier function on atherosclerosis development and the microbial, dietary and host factors that control this process remain largely unexplored. Defining these will open new avenues for disease prevention and treatment, as both diet and the gut microbiome can be modified. We have identified both microbial and host targets associated with intestinal homeostasis, inflammation, and atherosclerosis. Briefly, we examined a panel of over 100 different genetically diverse inbred strains of mice (known as the Hybrid Mouse Diversity Panel, HMDP) for both atherosclerosis susceptibility and gut microbiota composition. In this screen, we identified several bacterial taxa associated with atherosclerosis protection and experimentally validated one predicted protective microbe, Roseburia intestinalis, whose effect depends on the availability of dietary substrates (i.e., fiber) that promote its growth and butyrate production. Moreover, we showed that the beneficial effects of R. intestinalis are associated with improved intestinal barrier function and lower plasma levels of LPS. Furthermore, these effects are mimicked by delivering butyrate to the distal gut. Our HMDP studies also revealed a poorly understood protein expressed primarily in intestinal dendritic cells and macrophages, ADAM-like Decysin-1 (Adamdec1), as a protein responsive to microbiome composition and contributing to intestinal homeostasis, glucose homeostasis and systemic inflammation. In this application, we propose to follow-up on these exciting observations to gain novel mechanistic insights into how modulation of intestinal homeostasis via diet-butyrate-producing bacteria interactions and Adamdec1 affect progression of atherosclerosis. We provide a strong validation for the overall approach, and the work will be done in two laboratories with complementary skills: Dr. Rey (microbiology, gnotobiotic mouse models) and Dr. Lusis (genetics, atherosclerosis). The investigators have worked together for several years. We anticipate discovery of novel mechanisms by which gut bacteria modulate development of atherosclerosis, which should pave the way for novel cardiovascular disease therapies that target the gut microbiome.

项目摘要人类和小鼠研究已经确定了与肠道微生物组的变化动脉粥样硬化。虽然肠道微生物为宿主带来许多好处（例如，提供代谢能力而不是提供代谢能力它们在我们的人类基因组中）也可以确定。与我们的肠道微生物共存由肠屏障启用 - 由腔粘液层，上皮细胞和内部功能组成免疫障碍 - 限制了毒素和微生物促炎分子的进入。以前的研究表明，饮食和微生物代谢调节肠道屏障功能。最近的工作我们的团队和其他团队在肠道微生物组中已将变化与肠道屏障功能的改变和心脏代谢疾病。但是，肠道屏障功能在动脉粥样硬化发展和控制这一过程的微生物，饮食和宿主因素在很大程度上仍然是出乎意料的。定义这些将打开可以修改饮食和肠道微生物组，用于预防疾病和治疗的新途径。我们已经确定了与肠内稳态，创新和相关的微生物和宿主靶标动脉粥样硬化。简而言之，我们检查了一个超过100多种不同的近交菌株的小组。（称为混合小鼠多样性面板，HMDP），用于动脉粥样硬化易感性和肠道菌群作品。在此屏幕中，我们确定了与动脉粥样硬化保护和实验验证了一个预测的受保护的微生物Roseburia Intestinalis，其作用取决于饮食底物的可用性（即纤维）促进其生长和丁酸盐的生产。而且，我们表明肠道河的有益作用与改善肠道屏障功能和 LPS较低的血浆水平。此外，通过将丁酸酯传递到远端的肠道上可以模仿这些效果。我们的HMDP研究还显示，在肠道树突状细胞和巨噬细胞，类似亚当样的deysin-1（adamdec1），作为对微生物组组成的蛋白质和有助于肠道稳态，葡萄糖稳态和全身注射。在此应用程序中，我们提出跟进这些令人兴奋的观察结果的提议，以获取新的机理见解肠稳态通过饮食丁酸丁酸的细菌相互作用和ADAMDEC1影响动脉粥样硬化。我们为整体方法提供了强有力的验证，这项工作将在两次具有完整技能的实验室：Rey博士（微生物学，Gnotobiotic Mouse模型）和Lusis博士（遗传学，动脉粥样硬化）。调查人员合作了几年。我们期待发现肠道细菌调节动脉粥样硬化的发展的新型机制，应铺平针对肠道微生物组的新型心血管疾病疗法的方法。