Microbial regulation of host nutrient metabolism

微生物对宿主营养代谢的调节

• 批准号: 9118963
• 负责人: John F Rawls
• 金额: $ 46.11万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118963
• 关键词: ANGPTL4 gene; Address; Adipose tissue; Animals; Assimilations; Bacteria; Carbohydrates; Chromatin; Colon; Conditioned Culture Media; Data; Diet; Dietary Fats; Dietary Fatty Acid; Dietary intake; Disease; Energy Metabolism; Enhancers; Environmental Risk Factor; Epithelial; Epithelial Cells; Etiology; Family; Fatty Acids; Fatty acid glycerol esters; Foundations; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genomics; Gnotobiotic; Goals; HNF4A gene; Harvest; Health; Hepatic; Human; Intestines; Knowledge; Lead; Ligands; Link; Malnutrition; Mediating; Mediator of activation protein; Medium chain fatty acid; Microbe; Mission; Modeling; Molecular; Mus; Nuclear; Nuclear Receptors; Nutrient; Nutritional; Obesity; Outcome; Pathway interactions; Physiological Processes; Platelet Factor 4; Process; Proteins; Public Health; Regulation; Research; Role; Signal Transduction; Symbiosis; Testing; Time; Tissues; Transcript; Volatile Fatty Acids; Zebrafish; absorption; base; burden of illness; energy balance; fatty acid oxidation; functional genomics; gut microbiota; human disease; improved; insight; intestinal epithelium; lipid metabolism; lipoprotein lipase inhibitor; member; microbial; microbial colonization; microbiota; microorganism; novel; novel therapeutic intervention; novel therapeutics; nutrient metabolism; programs; public health relevance; response; transcription factor; uptake

 DESCRIPTION (provided by applicant): There exists a fundamental gap in our understanding of how intestinal microbiota impact the ability of their animal hosts to harvest energy-rich dietar fats. Moreover, the microbial and nutritional signals and responsive host transcriptional mechanisms that control host gene expression in the intestinal epithelium, remain unresolved. Our long-term goal is to understand the mechanisms underlying host-microbe interactions in the intestine and how those interactions impact human health and disease. The overall objectives of this project are to define the mechanisms by which members of the intestinal microbiota promote absorption of dietary fats, and how microbe-induced alterations in fat metabolism regulate gene expression programs in intestinal epithelial cells (IECs). Our preliminary studies in gnotobiotic zebrafish and mice reveal a novel role for microbiota in promoting absorption of long- and medium-chain fatty acids (FA) in intestinal epithelial cells, and implicate the FA-regulated transcription factor family Hepatic nuclear factor 4 (Hnf4) in mediating IEC transcriptional responses to microbiota. The proposed research will address the central hypothesis that soluble products from gut bacteria stimulate host absorption of dietary FA and reduce activity of Hnf4 transcription factors to reduce expression host target genes in IECs. Our rationale is that an improved understanding of bacterial control of host FA absorption and transcriptional regulatory programs in the intestine could lead to new microbiota-based strategies for controlling fat metabolism and energy balance in humans and other animals. In Specific Aim 1, we will identify host and bacterial mechanisms underlying bacterial stimulation of dietary FA absorption in the intestinal epithelium. In Specific Aim 2, we will define the regulatio and function of Hnf4 in the intestinal epithelium in response to microbial colonization. The expected outcomes will vertically advance the field in several ways. First, they will generate foundational mechanistic insights into how gut bacteria regulate host assimilation of energy-rich dietary fats. Second, they will establish Hnf4 transcription factors for the first time as key mediators of host-microbe commensalism in the intestine. Third, they will provide a novel molecular pathway linking microbial stimulation of host FA absorption to important host transcriptional programs in the intestinal epithelium. These results are expected to have a significant impact because they are likely to lead to new strategies for treating human diseases such as obesity and undernutrition by manipulating dietary fat assimilation and gene expression programs in the intestinal epithelium.

 描述（通过应用程序提供）：我们对肠道菌群如何影响其动物宿主收获富含能量丰富的饮食脂肪的能力的理解存在一个基本差距。此外，控制肠道上皮中宿主基因表达的微生物和营养信号以及响应式宿主转录机制仍未解决。我们的长期目标是了解肠道中宿主 - 微生物相互作用的机制，以及这些相互作用如何影响人类健康和疾病。该项目的总体目标是定义肠道菌群成员促进饮食脂肪的滥用的机制，以及微生物诱导的脂肪代谢变化如何调节肠上皮细胞（IEC）中的基因表达程序。我们在 gnotobiotic斑马鱼和小鼠揭示了微生物群在促进肠上皮细胞中长长和中链脂肪酸（FA）方面的新作用，并暗示了FA调节的转录因子家族肝核因子4（HNF4）介导IEC转录响应的肝脏核因子4（HNF4）。拟议的研究将解决以下核心假设：肠道细菌的固体产物刺激了饮食FA的宿主缓解，并降低了HNF4转录因子的活性，以减少IEC中的表达宿主靶基因。我们的理由是，对肠道中宿主FA抽象的细菌控制和肠道调节计划的控制有了改进的理解，可能会导致新的基于微生物群的策略，以控制人类和其他动物的脂肪代谢和能量平衡。在特定的目标1中，我们将确定肠道上皮饮食FA抽象的细菌模拟的宿主和细菌机制。在特定的目标2中，我们将根据微生物定植来定义肠上皮上HNF4的调节和功能。预期的结果将以几种方式垂直地推进该领域。首先，他们将对肠道细菌如何调节能量丰富的饮食脂肪的宿主同化产生基本的机理见解。其次，他们将首次建立HNF4转录因子，作为肠中宿主 - 微叶片的关键介体。第三，他们将提供一种新型的分子途径，将宿主FA滥用的微生物模拟与肠上皮中重要的宿主转录程序联系起来。预计这些结果将产生重大影响，因为它们可能会导致新的策略来治疗人类疾病，例如通过操纵肠道上皮中的饮食脂肪同化和基因表达程序来治疗肥胖和营养不良。