Microbial regulation of host nutrient metabolism

 描述(由申请人提供)：在我们对肠道微生物区系如何影响动物宿主获取能量丰富的饮食脂肪的能力的理解上存在着根本的差距。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反应性宿主转录机制仍未解决。我们的长期目标是了解肠道内宿主-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确定肠道微生物区系成员促进膳食脂肪吸收的机制，以及微生物诱导的脂肪代谢变化如何调节肠道上皮细胞(IECS)的基因表达程序。我们的初步研究是在 共生斑马鱼和小鼠揭示了微生物区系在促进肠上皮细胞对长链和中链脂肪酸(FA)吸收方面的新作用，并暗示FA调节的转录因子家族肝核因子4(Hnf4)参与介导IEC对微生物区系的转录反应。这项拟议的研究将解决这一中心假设，即肠道细菌的可溶性产物刺激宿主对膳食FA的吸收，并降低Hnf4转录因子的活性，从而减少宿主靶基因在IECs中的表达。我们的理论基础是，对细菌对宿主FA吸收和肠道转录调控程序的了解的提高，可能会导致基于微生物区系的新策略，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，我们将确定宿主和细菌刺激肠道上皮吸收膳食FA的潜在机制。在特定的目标2中，我们将确定Hnf4在肠道上皮细胞中的调节和功能，以响应微生物的定植。预期结果将在几个方面垂直推进这一领域。首先，他们将对肠道细菌如何调节宿主对富含能量的饮食脂肪的同化产生基础性的机械性见解。其次，他们将首次建立HNF4转录因子作为肠道内宿主-微生物共生的关键媒介。第三，它们将提供一种新的分子途径，将微生物对宿主FA吸收的刺激与肠道上皮中重要的宿主转录程序联系起来。这些结果预计将产生重大影响，因为它们可能导致通过操纵饮食脂肪同化和肠道上皮基因表达程序来治疗肥胖和营养不良等人类疾病的新策略。

 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.