Gut Microbiota and Cardiometabolic Diseases

肠道微生物群和心脏代谢疾病

• 批准号: 10206249
• 负责人: Stanley L Hazen
• 金额: $ 242.39万
• 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/10206249
• 关键词: Acute; Adverse event; Animal Model; Animals; Atherosclerosis; Bile Acids; Bioinformatics; Blood Platelets; Cardiometabolic Disease; 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; Sulfate; Testing; Thrombosis; Tissues; Transplantation; 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; diet-induced obesity; 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; thrombotic; 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.

肠道微生物群与心脏代谢疾病。文摘: