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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.

项目总结