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.

项目概要/摘要： 这个指导临床科学家职业发展奖的目的是阐明潜在的 肠道微生物调节肝脏新生并由此协调宿主营养的机制 健康和疾病的内稳态。非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病 这是一种全球性的疾病，可以发展为肝硬化和肝癌。缺乏批准的药物 NALFD的治疗确定了显著未满足的需求。而肠道微生物组有助于NAFLD， 根本的机制没有完全确定。我们发表的和初步的数据表明，肠道 微生物通过门静脉代谢物在调节肝硬化发生中起关键作用， 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 代谢物通过门静脉循环转运到肝脏，在那里它们下调肝细胞的增殖。 在健康方面，过度加工的西方饮食破坏了这一途径， 在NAFLD中观察到过量的葡萄糖产生。具体目标1将确定特定的微生物和下游 调节肝脏新生的代谢物。小鼠将被确定的微生物聚生体定殖， 体内葡萄糖产生测定和体外原代小鼠肝细胞培养将确定特异性 控制肝脏葡萄糖产生的微生物代谢成分。高血糖小鼠 和NAFLD将被特定的微生物定殖或施用代谢物以恢复正常的肝脏 异源发生具体目标2将定义肠道微生物组功能的适应不良变化， 与人类NAFLD中的过度肝再生有关。来自NAFLD患者和对照组的供体粪便将 用于制造具有人源化肠道微生物组的小鼠。门静脉血清代谢组学和微生物整体 基因组测序将被用来识别微生物和微生物代谢物，有助于过量的肝细胞， 人类NAFLD中的胚胎发生。这项研究意义重大，因为它将通过以下方式确定新的机制： 其中肠-肝轴的微生物组分调节健康和疾病中的肝再生。 该研究项目将在一个全面的职业发展计划的背景下进行， 允许研究者获得代谢组学，微生物组工程和生物信息学方面的专业知识 分析.这项工作将在威尔康奈尔医学院进行， 大学和纪念斯隆凯特琳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加从候选人的量身定制的指导， 共同导师以及具有互补专长的杰出咨询委员会。候选人的 最终目标是成为一名独立的调查员，其研究项目整合了肠道方面的专业知识 微生物组与肝脏代谢的关系，以推进慢性代谢性疾病的管理， 包括NAFLD。