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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.

项目概要人类和小鼠研究已经确定肠道微生物组的变化与疾病进展相关动脉粥样硬化。虽然肠道微生物为宿主提供了许多好处（例如提供代谢能力，但不代表在我们的人类基因组中），它们也可能是有害的。与我们肠道微生物的共存很大程度上是由肠屏障实现——由管腔粘液层、上皮细胞和内部功能细胞组成免疫屏障——限制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。最近的工作来自我们的团队和其他人将肠道微生物组的变化与肠道屏障功能的改变联系起来心脏代谢疾病。然而，肠道屏障功能对动脉粥样硬化发展的作用以及控制这一过程的微生物、饮食和宿主因素在很大程度上仍未得到探索。定义这些将打开疾病预防和治疗的新途径，因为饮食和肠道微生物组都可以改变。我们已经确定了与肠道稳态、炎症和相关的微生物和宿主靶标动脉粥样硬化。简而言之，我们检查了一组超过 100 种不同的遗传多样性的近交系小鼠（称为混合小鼠多样性小组，HMDP）用于动脉粥样硬化易感性和肠道微生物群作品。在此筛选中，我们鉴定了几种与动脉粥样硬化保护相关的细菌分类群，实验验证了一种预测的保护性微生物，肠罗斯布里亚菌，其效果取决于促进其生长和丁酸盐产生的膳食基质（即纤维）的可用性。此外，我们研究表明，肠杆菌的有益作用与改善肠道屏障功能有关，降低血浆脂多糖水平。此外，通过将丁酸盐输送到远端肠道来模拟这些效应。我们的 HMDP 研究还揭示了一种人们知之甚少的蛋白质，主要在肠道树突状细胞中表达，并且巨噬细胞，ADAM 样 Decysin-1 (Adamdec1)，作为一种对微生物组组成敏感的蛋白质，有助于肠道稳态、葡萄糖稳态和全身炎症。在这个应用程序中，我们建议对这些令人兴奋的观察结果进行后续研究，以获得关于如何调节的新机制见解通过饮食产生丁酸的细菌相互作用和 Adamdec1 影响肠道稳态动脉粥样硬化。我们为整体方法提供了强有力的验证，工作将分两步完成技能互补的实验室：Rey 博士（微生物学、无菌小鼠模型）和 Lusis 博士（遗传学、动脉粥样硬化）。调查人员已经合作多年。我们期待发现肠道细菌调节动脉粥样硬化发展的新机制，这应该为针对肠道微生物群的新型心血管疾病治疗方法。