Leveraging the Gut Microbiome to Regulate Hepatic Gluconeogenesis

项目摘要/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糖异生从而协调宿主营养的机制 健康和疾病的动态平衡。非酒精性脂肪性肝病是最常见的慢性肝病 这种疾病在全世界范围内流行，并可发展为肝硬变和肝癌。没有经过批准的药品 NALFD的治疗确定了一个重要的未得到满足的需求。虽然肠道微生物群对非酒精性脂肪肝有贡献， 潜在的机制没有得到完全的定义。我们公布的初步数据证明了这一点 微生物通过门静脉代谢产物在调节肝脏糖异生方面发挥关键作用，提供了明确的 这项研究的基本原理。我们提出了一个中心假设，即特定的生物活性微生物 代谢物通过门脉循环输送到肝脏，在那里它们下调肝脏的水平。 健康中的糖异生作用，而超加工的西方饮食破坏了这一途径，从而有助于 在NAFLD中观察到过量的葡萄糖产生。特定目标1将确定特定的微生物和下游 调节肝脏糖异生的代谢物。小鼠将被确定的微生物联盟和 体内葡萄糖产生试验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。饮食诱导的高血糖小鼠 NAFLD将在特定的微生物或代谢产物中定居，以恢复正常的肝脏 糖异生作用。具体目标2将定义肠道微生物群功能的不适应变化 人非酒精性脂肪性肝病患者肝脏糖异生过度。非酒精性脂肪肝患者和对照组的供体粪便 被用来创造具有人源化肠道微生物群的小鼠。门静脉血清代谢组学与微生物整体 基因组测序将被用来识别导致肝脏过剩的微生物和微生物代谢物 人非酒精性脂肪肝的糖异生作用。这项研究意义重大，因为它将通过以下方式识别新的机制 在健康和疾病中，肠道-肝轴的微生物成分调节肝脏的糖异生。 这一研究项目将在一个全面的职业发展计划的背景下进行，该计划将 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。这项工作将在威尔·康奈尔医学院进行，该学院与洛克菲勒 大学和纪念斯隆·凯特琳癌症中心构成极具刺激性的三个机构 研究网络。研讨会和专业课程将增强候选人的量身定做的指导 共同导师，以及来自具有互补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的研究人员，其研究计划整合了肠道中的专业知识 微生物组与肝脏代谢为了推进慢性代谢性疾病的治疗， 包括非酒精性脂肪肝。

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.