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。摘要： 我们计划的首要使命是在肠道领域产生重要的科学发现。 微生物组和心脏代谢疾病，导致潜在的改善人类健康，福祉， 病人护理大量证据表明，肠道微生物群在人类和哺乳动物中起着关键作用。 健康和疾病。我们的计划将推进后生组织内分泌学的概念-特别是- 肠道微生物组织形成一个关键的内分泌器官， 转化为影响人类宿主心血管和代谢表型的类信号。我们 该计划由3个项目和4个核心组成。项目1，旨在发现和功能性询问 新的肠道微生物途径与心血管疾病的发展及其不良事件，最初的重点是 代谢物苯乙酰谷氨酰胺（PAGln）途径。初步研究表明PAGln是肠道微生物群 产生的代谢物，其水平与CVD显著相关，通过许多初步的细胞， 微生物群和动物模型研究，有助于CVD发病机制。分析、生化和疾病 小鼠和人的模型研究探索了PAGln对体内血栓形成的功能影响， 动脉粥样硬化项目2在主题上与项目1和项目3相关，并测试了肠道 微生物共代谢物TMA和TMAO是高脂肪饮食诱导的肥胖症的独特的脂肪样驱动因子， 动脉粥样硬化通过使用项目1和3产生的工具，微生物胆碱TMA裂解酶的作用 通过宿主TMA-Taar 5受体信号传导轴增强对高脂肪饮食驱动的肥胖症的易感性的活性 会得到考验FXR驱动TMAO的肝胆分泌启动新发现的TMAO的假说是： 调节肠道微生物群落结构和宿主胆汁酸/固醇的肝肠TMAO信号轴 还将探索新陈代谢。项目3与项目1和项目2类似地相互关联，并利用了两者 与项目1合作发现的人类非靶向代谢组学数据，动物心脏代谢 项目2研究人员的疾病表型鉴定专业知识，以及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，使研究的因果关系和机制， 两个关键类别的肠道微生物衍生分子的特定成员，芳基硫酸盐和二级胆汁酸。 负责形成候选CVD和糖尿病相关基因的特定微生物基因的作用 将检查代谢物在增强的血栓形成、动脉粥样硬化、肥胖和其他疾病中的参与。 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;和心脏代谢疾病表型）提供多项目 支持，大大加强了研究计划。该计划将产生更大的收益。 了解肠道微生物组在心脏代谢疾病中的参与，并帮助我们 长期目标是开发潜在的改善人类健康，福祉和病人护理。