Microbial regulation of host nutrient metabolism

 描述（由申请人提供）：在我们对肠道微生物群如何影响其动物宿主收获富含能量的膳食脂肪的能力的理解方面存在根本性的差距。此外，微生物和营养信号和响应主机转录机制，控制宿主基因在肠上皮细胞的表达，仍然没有得到解决。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确定肠道微生物群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改变如何调节肠上皮细胞（IEC）中的基因表达程序。我们的初步研究 gnotobiotic斑马鱼和小鼠揭示了微生物群在促进肠上皮细胞中长链和中链脂肪酸（FA）吸收中的新作用，并涉及FA调节的转录因子家族肝核因子4（Hnf 4）介导对微生物群的IEC转录反应。拟议的研究将解决核心假设，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Hnf 4转录因子的活性，以减少IEC中宿主靶基因的表达。我们的基本原理是，更好地了解宿主FA吸收和肠道转录调控程序的细菌控制可能会导致新的微生物群为基础的策略，用于控制人类和其他动物的脂肪代谢和能量平衡。在具体目标1，我们将确定宿主和细菌的机制，细菌刺激饮食中的FA吸收在肠上皮。在具体目标2中，我们将确定Hnf 4在肠道上皮中响应微生物定植的调节和功能。预期成果将以几种方式垂直推进该领域。首先，它们将产生关于肠道细菌如何调节宿主对富含能量的膳食脂肪的同化的基本机制见解。其次，他们将首次将Hnf 4转录因子确定为肠道中宿主微生物共生的关键介质。第三，它们将提供一种新的分子途径，将微生物刺激宿主FA吸收与肠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膳食脂肪同化和肠上皮细胞中的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.