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.

肠道菌群和心脏代谢疾病。抽象的： 我们计划的总体使命是在肠道领域产生批判性的科学发现 微生物组和心脏代谢性疾病可导致人类健康，福祉和 病人护理。大量证据已经积累了证明肠道菌群在两个人中的关键作用 健康与疾病。我们的计划将推进元生物内分泌学的概念 - 特别是 - 肠道微生物组织形成一个关键的内分泌器官，可转化环境的营养线索 进入类似马的信号，影响人宿主的心血管和代谢表型。我们的 计划完成了3个项目和4个核心。项目1，试图发现并在功能上进行询问 与CVD的发展及其不良事件有关的新型肠道微生物途径，最初的重点是 元有机苯甲酰谷氨酰胺（PAGLN）途径。初步研究表明，PAGLN是肠道菌群 产生的代谢产物，其水平与CVD相关，该水平通过许多初步的细胞， 微生物群和动物模型研究有助于CVD发病机理。分析，生化和疾病 小鼠和人类的模型研究探索了PAGLN对体内血栓形成和 动脉粥样硬化。项目2主题与项目1和3相关，并检验了肠道的假设 微生物合作代谢物TMA和TMAO是高脂肪饮食诱导肥胖和 动脉粥样硬化。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饮食驱动物体的敏感性的活性 将进行测试。 FXR驱动的TMAO的肝动物分泌的假设启动了新发现的假设 调节肠道微生物组群落结构和宿主胆汁酸/固醇 还将探索代谢。项目3与项目1和2相似，并利用两者 人类非靶向代谢组学数据与项目1，动物心脏代谢合作发现 项目2研究者的疾病表型专业知识以及代谢途径发现和微生物组 项目3调查人员的基因编辑专业知识，以实现对偶然性和结构上的机制的研究 肠道微生物衍生分子，芳基硫酸盐和继发胆汁酸的两种关键类别的特定成员。 负责形成候选CVD和糖尿病相关的特定微生物基因的作用 将检查代谢物是否参与了增强的血栓形成，动脉粥样硬化，肥胖和其他 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；和心脏代谢性疾病型）提供多项目 支持，大大加强研究计划。拟议的计划项目将产生更大的 了解肠道微生物组参与心脏代谢性疾病，并帮助我们促进我们的 长期目标是发展人类健康，福祉和患者护理的潜在改善。