Leveraging the Gut Microbiome to Regulate Hepatic Gluconeogenesis

利用肠道微生物组调节肝脏糖异生

• 批准号: 10449804
• 负责人: Tibor Krisko
• 金额: $ 16.99万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449804
• 关键词: Advisory Committees; Amino Acids; Bioinformatics; Biological Assay; Blood Circulation; Chronic; Cirrhosis; Citric Acid Cycle; Clinical; Complex Mixtures; Data; Development Plans; Diet; Disease; Engineering; Equilibrium; Feces; Gluconeogenesis; Glucose; Goals; Health; Hepatic; Hepatocyte; Homeostasis; Human; Human Microbiome; Human body; Hyperglycemia; Hyperglycemic Mice; In Vitro; Investigation; K-Series Research Career Programs; Liver; Malignant neoplasm of liver; Memorial Sloan-Kettering Cancer Center; Mentors; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Microbe; Microbial Genome Sequencing; Mission; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; Obesity; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmacologic Substance; Play; Portal vein structure; Process; Production; Public Health; Publishing; Regulation; Research; Research Personnel; Research Project Grants; Role; Scientist; Serum; Testing; Therapeutic; Transplantation; Tricarboxylic Acids; Universities; Volatile Fatty Acids; Work; blood glucose regulation; career development; chronic liver disease; disorder control; dysbiosis; euglycemia; experimental study; genome sequencing; glucose metabolism; glucose production; gut microbes; gut microbiome; gut microbiota; gut-liver axis; hepatic gluconeogenesis; host-microbe interactions; in vivo; liver metabolism; medical schools; metabolomics; microbial; microbiome; microbiota; mouse model; non-alcoholic fatty liver disease; novel; programs; western diet; whole genome

Project Summary/Abstract: The objective of this Mentored Clinical Scientist Career Development Award is to elucidate the underlying mechanisms by which gut microbes regulate hepatic gluconeogenesis and thereby coordinate host nutrient homeostasis in health and disease. Non-alcoholic fatty liver disease (NAFLD) is the most-prevalent chronic liver disease worldwide and can progress to cirrhosis and liver cancer. The absence of approved pharmaceutical treatments for NALFD identifies a significant unmet need. Whereas the gut microbiome contributes to NAFLD, the underlying mechanisms are incompletely defined. Our published and preliminary data demonstrate that gut microbes play a key role in regulating hepatic gluconeogenesis through portal vein metabolites, providing a clear rationale for this research. We propose the central hypothesis that specific biologically-active microbial metabolites are transported by the portal circulation to the liver, where they downregulate hepatic gluconeogenesis in health, and that ultra-processed western diets disrupt this pathway to contribute to the excess glucose production observed in NAFLD. Specific Aim 1 will identify the specific microbes and downstream metabolites that regulate hepatic gluconeogenesis. Mice will be colonized with defined microbial consortia and in vivo glucose production assays and in vitro primary mouse hepatocyte cultures will determine the specific microbial metabolic components that control hepatic glucose production. Mice with diet-induced hyperglycemia and NAFLD will be colonized with specific microbes or administered metabolites to restore normal hepatic gluconeogenesis. Specific Aim 2 will define the maladaptive changes in gut microbiome function that contribute to excess hepatic gluconeogenesis in human NAFLD. Donor stool from patients with NAFLD and controls will be used to create mice with humanized gut microbiomes. Portal vein serum metabolomics and microbial whole genome sequencing will be used to identify microbes and microbial-metabolites that contribute to excess hepatic gluconeogenesis in human NAFLD. This research is significant because it will identify novel mechanisms by which the microbial component of the gut-liver axis regulates hepatic gluconeogenesis in health and disease. This research project will be performed in the context of a comprehensive career development plan that will permit the investigator to acquire expertise in metabolomics, microbiome engineering, and bioinformatics analysis. The work will be conducted at Weill Cornell Medical College, which together with The Rockefeller University and Memorial Sloan Kettering Cancer Center constitutes the highly stimulating Tri-Institutional research network. Seminars and specialized coursework will augment tailored guidance from the candidate’s co-mentors, as well as from a distinguished advisory committee with complementary expertise. The candidate’s ultimate goal is to become an independent investigator whose research program integrates expertise in the gut microbiome with hepatic metabolism in order to advance the management of chronic metabolic diseases, including NAFLD.

项目摘要/摘要： 这个受过指导的临床科学家职业发展奖的目的是阐明基础 肠道微生物调节肝麸质的机制，从而协调宿主营养素 健康和疾病中的稳态。非酒精性脂肪肝疾病（NAFLD）是最先进的慢性肝 全球疾病，可以发展为肝硬化和肝癌。缺乏批准的药物 NALFD的治疗方法确定了很大的未满足需求。而肠道微生物组有助于NAFLD，但 基本机制未完全定义。我们发布的初步数据表明肠道 微生物在通过门户静脉代谢物回合肝麸质中发挥着关键作用，提供了清晰的 这项研究的理由。我们提出了一个中心假设，即特定的生物活性微生物 代谢物被门户流通运输到肝脏，在那里它们下调了肝 健康中的糖生成，并且超得加工的西方饮食破坏了这一途径，以促进 在NAFLD中观察到的葡萄糖产生过多。特定目标1将识别特定的微生物和下游 调节肝葡萄糖发生的代谢产物。小鼠将通过定义的微生物联盟和 体内葡萄糖生产测定和体外原发性小鼠肝细胞培养物将确定特定 控制肝葡萄糖产生的微生物代谢成分。饮食引起的高血糖的小鼠 NAFLD将用特定的微生物或施用的代谢物殖民以恢复正常肝 糖异生。具体目标2将定义肠道微生物组功能的不良适应性变化 在人Nafld中过量的肝麸质。来自NAFLD和对照患者的供体粪便将 用于用人源肠道微生物组创建小鼠。门静脉血清代谢组学和微生物整体 基因组测序将用于识别有助于肝过量的微生物和微生物 - 代谢产物 人Nafld中的糖异生。这项研究很重要，因为它将通过 肠肝轴的微生物成分调节健康和疾病中的肝脏谷胱甘肽生成。 该研究项目将在一项全面的职业发展计划的背景下执行 允许研究人员获得代谢组学，微生物组工程和生物信息学方面的专业知识 分析。这项工作将在Weill Cornell医学院与洛克菲勒一起进行 大学和纪念斯隆·凯特林癌症中心构成了高度刺激的三机构 研究网络。研讨会和专业课程将增强候选人的量身定制指导 联合委员会以及具有完善专业知识的杰出咨询委员会。候选人的 最终目标是成为一名独立研究者，其研究计划将专业知识纳入肠道 与肝脏代谢的微生物组，以促进慢性代谢疾病的治疗， 包括nafld。