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:9981230
- 负责人:
- 金额:$ 65.97万
- 依托单位:
- 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 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectAnimal ModelAnimalsApolipoprotein EArterial Fatty StreakAtherosclerosisBacteriaBindingButyratesCardiovascular DiseasesCholineChronic DiseaseClinical ResearchCollectionComplexDendritic CellsDeteriorationDevelopmentDietDietary FactorsDietary FiberDiseaseDisease modelDistalEnvironmentEnvironmental Risk FactorEpithelial CellsExhibitsFiberGeneticGenetic VariationGerm-FreeGnotobioticGoalsGrowthHealthHumanHuman GenomeHuman MicrobiomeHybridsImmunologicsImpairmentInbred Strains MiceInflammationInflammatoryIntegration Host FactorsInterventionIntestinesLaboratoriesLesionLinkLipopolysaccharidesMediatingMetabolicMetabolic DiseasesMetabolismMicrobeMicrobial PhysiologyMicrobiologyModelingMouse StrainsMucous body substanceMusNucleotidesPeptidoglycanPhenotypePlasmaPlayPositioning AttributePredispositionProcessProductionProteinsResearch PersonnelResistanceResourcesRoleSignal PathwaySystemTestingToll-like receptorsToxinValidationWorkblood glucose regulationcardiometabolismcardiovascular disorder therapycardiovascular risk factorcytokinedesigndisorder preventiondysbiosisfollow-upgenetic approachgut bacteriagut microbesgut microbiomegut microbiotahost microbiotaimprovedinsightinterleukin-22interleukin-23intestinal barrierintestinal homeostasismacrophagemicrobialmicrobial hostmicrobiomemicrobiome compositionmicrobiome researchmouse modelnoveloverexpressionpreventreceptorskillstargeted treatmenttraittrimethylaminetrimethyloxaminevector
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
人类和小鼠的研究发现,肠道微生物群的变化与糖尿病的进展有关
动脉硬化。虽然肠道微生物为宿主提供了许多好处(例如,提供代谢能力而不是
在我们的人类基因组中),它们也可能是有害的。与我们的肠道微生物共存在很大程度上
由肠道屏障实现--由腔粘液层、上皮细胞和内部功能
免疫屏障--限制毒素和微生物促炎分子的进入。上一首
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已经将肠道微生物群的变化与肠道屏障功能和
心脏代谢疾病。然而,肠屏障功能在动脉粥样硬化发生和发展中的作用
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被探索。将打开定义这些内容
疾病预防和治疗的新途径,因为饮食和肠道微生物群都可以改变。我们
已经确定了与肠道内稳态、炎症和
动脉硬化。简单地说,我们研究了100多种不同遗传多样性的近交系小鼠。
(称为杂交小鼠多样性小组,HMDP)研究动脉粥样硬化易感性和肠道微生物区系
组成。在这个筛选中,我们确定了几个与动脉粥样硬化保护和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--肠玫瑰草杆菌,它的效果取决于
促进其生长和丁酸盐生产的饲料底物(即纤维)的可用性。此外,我们
表明肠黄的有益作用与改善肠道屏障功能和
降低血浆内毒素水平。此外,通过将丁酸盐输送到远端肠道来模拟这些影响。
我们的HMDP研究还发现了一种知之甚少的蛋白质,主要表达于肠道树突状细胞和
巨噬细胞,亚当样Decysin-1(Adamdec1),作为一种对微生物组组成和
促进肠道动态平衡、葡萄糖动态平衡和全身炎症。在此应用程序中,我们
建议对这些令人兴奋的观察结果进行后续研究,以获得新的机制洞察力
饮食-丁酸产生菌相互作用和Adamdec1影响肠道内环境平衡
动脉硬化。我们为总体方法提供了强有力的验证,工作将分两个阶段完成
技能互补的实验室:雷伊博士(微生物学、灵知生菌小鼠模型)和卢西斯博士
(遗传学、动脉粥样硬化)。调查人员在一起工作了几年。我们期待着新的发现
肠道细菌调节动脉粥样硬化发展的新机制,这应该为
针对肠道微生物组的新型心血管疾病治疗方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Aldons Jake Lusis其他文献
Aldons Jake Lusis的其他文献
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{{ truncateString('Aldons Jake Lusis', 18)}}的其他基金
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
- 批准号:
10392355 - 财政年份:2020
- 资助金额:
$ 65.97万 - 项目类别:
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
- 批准号:
10600832 - 财政年份:2020
- 资助金额:
$ 65.97万 - 项目类别:
Systems genetics dissection of non-alcoholic steatohepatitis
非酒精性脂肪性肝炎的系统遗传学解析
- 批准号:
10205047 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
Gut microbiota and metabolite interactions in atherosclerosis
肠道微生物群和代谢物在动脉粥样硬化中的相互作用
- 批准号:
10063553 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
Systems genetics approach to inflammatory mechanisms in atherosclerosis
动脉粥样硬化炎症机制的系统遗传学方法
- 批准号:
9975217 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
Gut microbiota and metabolite interactions in atherosclerosis
肠道微生物群和代谢物在动脉粥样硬化中的相互作用
- 批准号:
10308700 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
Systems genetics approach to inflammatory mechanisms in atherosclerosis
动脉粥样硬化炎症机制的系统遗传学方法
- 批准号:
9797558 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
Systems genetics approach to inflammatory mechanisms in atherosclerosis
动脉粥样硬化炎症机制的系统遗传学方法
- 批准号:
10171611 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
Systems genetics dissection of non-alcoholic steatohepatitis
非酒精性脂肪性肝炎的系统遗传学解析
- 批准号:
10434833 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
Systems genetics approach to inflammatory mechanisms in atherosclerosis
动脉粥样硬化炎症机制的系统遗传学方法
- 批准号:
10406279 - 财政年份:2019
- 资助金额:
$ 65.97万 - 项目类别:
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