Project 1: Discovery of gut microbiota dependent pathways contributing to cardiovascular disease in type 2 diabetes

项目 1：发现肠道微生物群依赖性途径导致 2 型糖尿病心血管疾病

• 批准号: 10447069
• 负责人: Stanley L Hazen
• 金额: $ 52.33万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447069
• 关键词: Adverse event; Agonist; Animal Model; Antibiotics; Area; Atherosclerosis; Attention; Bile Acids; Bioinformatics; Blood Platelets; Cardiac; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cecum; Cell model; Cells; Cessation of life; Clinical; Cloning; Collagen; Communities; Coupled; Development; Diabetes Mellitus; Disease; Disease susceptibility; Endocrine Glands; Enzymes; Essential Amino Acids; Event; Family; Feces; Fostering; Generations; Genes; Genetic Engineering; Germ-Free; Glucose; Goals; Health; Human; Human Engineering; Hyperglycemia; In Vitro; Insulin Resistance; Link; Metabolic; Metabolic Diseases; Metabolic Pathway; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral Ingestion; Participant; Pathogenesis; Pathway interactions; Phenotype; Phenylacetates; Phenylalanine; Physiological Processes; Plasma; Populations at Risk; Predisposition; Process; Production; Publications; Reporting; Research; Research Personnel; Research Project Grants; Risk; Role; Serum; Stable Isotope Labeling; Stroke; Study models; Sulfate; Testing; Thrombin; Thrombosis; Tracer; Transplantation; Validation; absorption; base; blood glucose regulation; cardiovascular disorder risk; clinical investigation; cohort; diabetes mellitus therapy; diabetic; gain of function; glycemic control; gut microbes; gut microbiome; gut microbiota; improved; in vivo; indexing; liquid chromatography mass spectrometry; loss of function; metabolomics; microbial; microbial colonization; microbial host; microbiota metabolites; microbiota transplantation; mouse model; multidisciplinary; mutant; non-diabetic; novel; platelet function; receptor; stable isotope; treatment response; trimethyloxamine

Abstract The role of gut microbiota in human health and disease processes is increasingly recognized. Moreover, the gut microbiome is now recognized as a large endocrine organ that can generate biologically active metabolites, which upon absorption into the host, often have dedicated receptors, and impact physiological processes, and disease susceptibility. In this Project, we examine the role of specific gut microbiota pathways in cardiovascular disease (CVD) pathogenesis. We have employed untargeted metabolomics as a discovery platform, coupled with cellular and animal model studies, to identify additional/new potential gut microbiota- dependent pathways enhanced in type 2 diabetes mellitus that are both associated with, and potentially a contributor to CVD. Subjects with type 2 diabetes are at a disproportionately increased risk for development of CVD, and yet, the overall level of glycemic control is not necessarily related to CVD risks. There thus are metabolic pathways beyond the glucocentric view of diabetes that contribute to CVD in this at risk population. Large-scale clinical investigations are used to focus research attention on candidate metabolites whose circulating levels are reproducibly associated with incident development of adverse cardiovascular events like heart attack, stroke and death in this at risk population. After validating the associations (and often typically observing the candidate metabolite predicts risks in diabetic and non-diabetic subject alike), we move forward with mechanistic studies aimed at defining whether observed associations are linked to CVD and metabolic disease relevant phenotypes, through cellular and animal model studies. Preliminary cell, animal model and microbial transplantation related studies using genetically engineered human commensals (gain and loss of function mutants) are used to interrogate the role of specific microbiota derived metabolites, and the microbial enzyme(s) responsible for their generation, in eliciting relevant phenotypes in the host like enhanced thrombosis potential, or susceptibility to atherosclerosis. Our proposed studies promise to identify new mechanisms through which gut microbiota may contribute to CVD. They also will help improve identification of those at risk for CVD and its adverse events who otherwise might not be identified. They also will provide enabling discoveries that will foster potential development of novel treatments for CVD.

抽象的 肠道微生物群在人类健康和疾病过程中的作用越来越多地认识到。而且， 现在，肠道微生物组被认为是可以产生生物活性的大型内分泌器官 在吸收到宿主后，代谢物通常具有专用受体，并影响生理 过程和疾病易感性。在这个项目中，我们检查了特定肠道菌群途径的作用 在心血管疾病（CVD）发病机理中。我们已经利用不靶向的代谢组学作为发现 平台，再加上细胞和动物模型研究，以鉴定其他/新的潜在肠道微生物群 既增强的2型糖尿病的依赖途径 CVD的贡献者。患有2型糖尿病的受试者的发展风险不成比例 CVD，但是，血糖控制的总体水平不一定与CVD风险有关。这样就有了 超出了糖尿病的血糖视图的代谢途径，这些糖尿病在这一风险人群中有助于CVD。 大规模的临床研究用于将研究注意力集中在候选代谢物上 循环水平与不良心血管事件的事件发展相关 在这一风险人群中，心脏病发作，中风和死亡。验证关联后（通常通常 观察候选代谢物可以预测糖尿病和非糖尿病学科的风险），我们向前迈进 通过旨在定义观察到的关联是否与CVD和代谢相关的机械研究 通过细胞和动物模型研究，疾病相关的表型。初步细胞，动物模型和 微生物移植相关的研究使用基因工程人类共生（增益和丧失） 功能突变体）用于询问特定微生物衍生的代谢产物的作用，而微生物的作用 酶负责产生的酶，在宿主中引起相关表型，例如增强 血栓形成潜力或对动脉粥样硬化的敏感性。我们提出的研究有望确定新的 肠道微生物群可能会导致CVD的机制。他们还将有助于提高对 那些有CVD风险及其不良事件的人可能无法确定。他们还将提供 能够促进CVD的新型治疗方法的潜在发展。