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.

摘要 肠道微生物群在人类健康和疾病过程中的作用越来越受到重视。此外，委员会认为， 肠道微生物组现在被认为是一个可以产生生物活性的大型内分泌器官 代谢物，其在吸收到宿主中时，通常具有专用受体，并且影响生理学上的 过程和疾病易感性。在这个项目中，我们研究了特定肠道微生物群途径的作用， 心血管疾病（CVD）发病机制。我们采用非靶向代谢组学作为一种发现， 平台，再加上细胞和动物模型研究，以确定额外的/新的潜在肠道微生物群- 2型糖尿病中依赖性途径增强，这两种途径都与糖尿病相关， CVD的贡献者。患有2型糖尿病的受试者发生糖尿病的风险不成比例地增加。 然而，血糖控制的总体水平与CVD风险不一定相关。因此， 糖尿病的葡萄糖中心观点之外的代谢途径导致该高危人群中的CVD。 大规模临床研究用于将研究注意力集中在候选代谢物上， 循环水平可重复地与不良心血管事件的发生相关， 心脏病发作、中风和死亡。在验证关联之后（通常 观察候选代谢物预测糖尿病和非糖尿病受试者的风险），我们继续前进 机制研究旨在确定观察到的相关性是否与CVD和代谢有关， 疾病相关表型，通过细胞和动物模型研究。初步细胞、动物模型和 使用基因工程人类胚胎的微生物移植相关研究（获得和丧失 功能突变体）用于询问特定微生物群衍生的代谢物的作用，并且微生物 负责其产生的酶在宿主中引发相关表型，如增强的 血栓形成的可能性或对动脉粥样硬化的易感性。我们提出的研究有望发现新的 肠道微生物群可能导致CVD的机制。它们还将有助于提高识别 那些有CVD及其不良事件风险的人，否则可能无法识别。他们还将提供 这将促进CVD新疗法的潜在发展。