Gut Microbiota and Cardiometabolic Diseases

肠道微生物区系与心脏代谢性疾病。摘要： 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性疾病可能会改善人类的健康、福祉和 病人护理。大量证据表明，肠道微生物区系在人类 健康和疾病。我们的计划将推进超生物内分泌学的概念-具体地说- 肠道微生物组织起来形成一个关键的内分泌器官，将来自环境的营养线索转化为 转化为荷尔蒙样信号，影响人类宿主的心血管和代谢表型。我们的 该方案由3个项目和4个核心组成。项目1，寻求发现并从功能上审问 新的肠道微生物途径与心血管疾病的发展及其不良事件有关，最初的重点是 代谢苯乙酸谷氨酰胺(PAGln)途径。初步研究表明PAGln是肠道微生物区系 所产生的代谢物的水平与心血管疾病密切相关，通过许多初步的细胞， 微生物区系和动物模型的研究，有助于CVD的发病机制。分析、生化和疾病 小鼠和人类模型研究探讨PAGln对体内血栓形成和功能的影响 动脉硬化。项目2在主题上与项目1和项目3相关联，并测试了这样的假设 微生物共代谢产物TMA和TMAO是高脂饮食诱导肥胖和肥胖的独特激素样驱动因素 动脉硬化。通过使用项目1和项目3产生的工具，微生物胆碱TMA裂解酶的作用 通过宿主TMA-Taar5受体信号轴增加高脂饮食所致肥胖的易感性 将会受到考验。FXR驱动的TMAO肝胆分泌物启动新发现的 调节肠道微生物群落结构和宿主胆汁酸/甾醇的肠肝型TMAO信号轴 我们还将探索新陈代谢。项目3与项目1和项目2类似地相互关联，并利用这两个项目 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专长，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结构上的因果关系和机制研究成为可能 肠道微生物衍生分子的两个关键类别的特定成员，芳基硫酸盐和次级胆汁酸。 特定微生物基因在形成候选心血管疾病和糖尿病相关疾病中的作用 将检查代谢物是否参与血栓形成、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；以及心脏代谢性疾病表型)提供多个项目 支持，大大加强了研究计划。建议的计划项目将产生更大的收益 了解肠道微生物群在心脏代谢性疾病中的参与，并有助于推动我们的 在人类健康、福祉和病人护理方面发展潜在改善的长期目标。

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.