Gut Microbiota and Cardiometabolic Diseases

肠道微生物群和心脏代谢疾病

• 批准号: 9790523
• 负责人: Stanley L Hazen
• 金额: $ 244.53万
• 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/9790523
• 关键词: Acute; Adverse event; Animal Model; Animals; Atherosclerosis; Bile Acids; Bioinformatics; Blood Platelets; Cardiovascular Diseases; Cardiovascular system; Choline; Clinical; Clinical Research; Collaborations; Communities; Complex; Couples Therapy; Cues; Data; Development; Diabetes Mellitus; Disease; Disease model; Endocrine Glands; Endocrinology; Engineering; Environment; Enzymes; Etiology; Event; FMO3; Gene Cluster; Generations; Genes; Genetic; Genetic Engineering; Germ-Free; Goals; Health; Hepatobiliary; High Fat Diet; Hormones; Human; Human Engineering; Investigation; Knockout Mice; Lead; Link; Lyase; Metabolic Diseases; Metabolic Pathway; Metabolism; Mission; Molecular; Mus; Nutritional; Obesity; Participant; Pathogenesis; Pathway interactions; Patient Care; Personal Satisfaction; Phenotype; Physiological Processes; Play; Predisposition; Preventive; Process; Production; Receptor Signaling; Regulation; Research; Research Personnel; Residual state; Risk; Role; Signal Transduction; Sterols; Structure; Study models; Testing; Thrombosis; Tissues; Transplantation; Unspecified or Sulfate Ion Sulfates; base; bench to bedside; biochemical model; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; chemical synthesis; clinical investigation; clinically relevant; commensal bacteria; community involvement; diabetes risk; disease phenotype; disorder risk; experimental study; gene product; gut microbes; gut microbiome; gut microbiota; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; loss of function; member; metabolic phenotype; metabolomics; microbial; microbial colonization; microbiome; microbiota; microbiota metabolites; mutant; novel; programs; receptor; tool; trimethyloxamine; virtual

Gut Microbiota and Cardiometabolic Diseases. Abstract: The overarching mission of our Program is to generate critical scientific discoveries in the field of gut microbiome and cardiometabolic diseases that lead to potential improvements in human health, wellbeing, and patient care. Substantial evidence has accrued demonstrating a critical role for gut microbiota in both human health and disease. Our Program will advance the concept of metaorganismal endocrinology – specifically – that gut microbes organize to form a key endocrine organ that converts nutritional cues from the environment into hormone-like signals that impact cardiovascular and metabolic phenotypes in the human host. Our Program is comprised of 3 Projects and 4 Cores. Project 1, seeks to discover and functionally interrogate novel gut microbial pathways linked to the development of CVD and its adverse events, with initial focus on the metaorganismal PhenylAcetyGlutamine (PAGln) pathway. Preliminary studies show PAGln is gut microbiota generated metabolite whose levels are strikingly linked to CVD that through numerous preliminary cellular, microbiota and animal model studies, contributes to CVD pathogenesis. Analytical, biochemical and disease model studies in mice and humans explore the functional impact of PAGln on in vivo thrombosis and atherosclerosis. Project 2 is thematically linked to Projects 1 and 3, and tests the hypothesis that the gut microbial co-metabolites TMA and TMAO are unique hormone-like drivers of high fat diet induced obesity and atherosclerosis. Through use of tools generated with Project 1 and 3, the role of microbial choline TMA lyase activity in enhancing susceptibility for high fat diet-driven obesity via a host TMA - Taar5 receptor signaling axis will be tested. The hypothesis that FXR-driven hepatobiliary secretion of TMAO initiates a newly discovered enterohepatic TMAO signaling axis that regulates gut microbiome community structure and host bile acid/sterol metabolism will also be explored. Project 3 is similarly interrelated to Projects 1 and 2, and leverages both human untargeted metabolomics data collaboratively discovered with Project 1, animal cardiometabolic disease phenotyping expertise of Project 2 investigators, and metabolic pathway discovery and microbiome gene editing expertise of Project 3 investigators to enabled studies of causality and mechanism for structurally specific members of two key classes of gut microbe-derived molecules, aryl sulfates and secondary bile acids. The role of specific microbial genes responsible for forming candidate CVD- and diabetes-associated metabolites will be examined for their involvement in enhanced thrombosis, atherosclerosis, obesity and other metabolic phenotypes. Four cores (Analytical/Clinical/Bioinformatics; Analytical and Chemical Synthesis; Microbial Engineering and Transplantation; and Cardiometabolic Disease Phenotyping) provide multi-project support, significantly strengthening the research Program. The proposed Program Project will yield greater understanding of the participation of the gut microbiome in cardiometabolic diseases, and help advance our long-term goal of developing potential improvements in human health, wellbeing, and patient care.

肠道微生物群和心脏代谢疾病。 我们计划的首要任务是在肠道领域产生关键的科学发现 微生物组和心脏代谢疾病可潜在改善人类健康、福祉和 大量证据表明肠道微生物群在人类中发挥着关键作用。 我们的计划将推进代谢内分泌学的概念——具体来说—— 肠道微生物组织形成一个关键的内分泌器官，可以将环境中的营养线索转化为 转化为影响人类宿主心血管和代谢表型的激素样信号。 计划由 3 个项目和 4 个核心项目 1 组成，旨在发现和功能性询问。 与 CVD 发生及其不良事件相关的新型肠道微生物途径，最初关注的是 初步研究表明 PAGln 是肠道微生物群的代谢途径。 产生的代谢物的水平与 CVD 显着相关，通过大量的初步细胞， 微生物群和动物模型研究有助于 CVD 发病机制的分析、生化和疾病。 小鼠和人类模型研究探索 PAGln 对体内血栓形成的功能影响 项目 2 在主题上与项目 1 和 3 相关，并检验了肠道的假设。 微生物共代谢物 TMA 和 TMAO 是高脂肪饮食引起的肥胖的独特激素样驱动因素 通过使用项目 1 和 3 生成的工具，微生物胆碱 TMA 裂解酶的作用。 通过宿主 TMA - Taar5 受体信号轴增强对高脂肪饮食导致的肥胖的易感性的活性 FXR 驱动的肝胆分泌 TMAO 引发了一种新发现的假设将得到检验。 调节肠道微生物群落结构和宿主胆汁酸/甾醇的肠肝TMAO信号轴 项目 3 也将与项目 1 和 2 类似地相互关联，并利用两者。 与项目 1 动物心脏代谢合作发现的人类非靶向代谢组学数据 项目 2 研究人员的疾病表型专业知识、代谢途径发现和微生物组 项目 3 研究人员的基因编辑专业知识能够研究结构性的因果关系和机制 两类关键肠道微生物衍生分子的特定成员：芳基硫酸盐和仲胆汁酸。 特定微生物基因在形成候选 CVD 和糖尿病相关基因中的作用 将检查代谢物是否参与增强血栓形成、动脉粥样硬化、肥胖和其他疾病 代谢表型四个核心（分析/临床/生物信息学；分析和化学合成； 微生物工程和移植；以及心脏代谢疾病表型分析）提供多项目 支持，显着加强研究计划 拟议的计划项目将产生更大的成果。 了解肠道微生物组在心脏代谢疾病中的参与，并有助于推进我们的研究 开发潜在改善人类健康、福祉和患者护理的长期目标。