Microbial regulation of intestinal lipid metabolism and its physiological consequences

摘要 已知肠道微生物群促进膳食脂肪的吸收并赋予对膳食诱导的肥胖的易感性。 肥胖然而，在我们对基本机制的了解方面存在着根本性的差距。我们的长期 目的是了解肠道中宿主-微生物相互作用和脂质代谢的机制 以及它们对人类生理和疾病的影响我们对知生菌和 常规小鼠和斑马鱼揭示微生物群特异性抑制线粒体脂肪酸氧化 (FAO)在肠上皮细胞（IEC），并确定潜在的上游微生物和转录调控 机制等我们在常规小鼠中的遗传分析也证实了在IEC中特异性阻断FAO 促进膳食脂肪吸收，调节肠道和全身能量代谢。总体目标 本项目的目的是了解肠道微生物如何调节肠内微生物，并确定肠道微生物的影响。 对肠道和全身生理的影响拟议的研究将测试中心假设，具体 细菌产物通过抑制FAO基因转录下调IEC中的FAO，这反过来又调节 IEC燃料选择和区分，促进积极的能量平衡。我们的理由是， 了解微生物如何影响肠道粮农组织，以及粮农组织如何促进肠道生理学， 全身能量代谢可能导致控制脂肪代谢和能量平衡的新策略， 人类和其他动物。在具体目标1中，我们将确定宿主和微生物的机制， 微生物群抑制肠上皮中的FAO。在具体目标2中，我们将定义肠道FAO的作用 在IEC的燃料选择和分化中，以及在介导肠道微生物群对全身性 能量平衡预期成果将以几种方式垂直推进该领域。首先，他们将建立 肠道FAO是肠道和全身能量平衡的主要决定因素。第二，他们将提供 明确的新证据表明，肠上皮FAO是微生物调节的主要目标。第三，他们将 表明无菌小鼠对饮食诱导的肥胖的显著抵抗力是由肠道FAO介导的。最后， 它们将提供一种控制肠道FAO的新的细菌-宿主信号传导途径。这些结果是预期的 产生重大影响，因为它们可能导致新的微生物和宿主靶向策略， 在肥胖和营养不良的情况下，通过操纵FAO和相关基因来控制能量平衡 表达网络和肠道中的代谢途径。

ABSTRACT Intestinal microbiota are known to promote absorption of dietary fat and to confer susceptibility to diet-induced obesity. However, there exist fundamental gaps in our knowledge of the underlying mechanisms. Our long-term goal is to understand the mechanisms underlying host-microbe interactions and lipid metabolism in the intestine and how they contribute to human physiology and disease. Our preliminary studies in gnotobiotic and conventional mice and zebrafish reveal that microbiota specifically suppress mitochondrial fatty acid oxidation (FAO) in intestinal epithelial cells (IECs), and identify potential upstream microbial and transcriptional regulatory mechanisms. Our genetic analysis in conventional mice also establishes that blocking FAO specifically in IECs promotes dietary fat absorption and modulates intestinal and systemic energy metabolism. The overall objectives of this project are to understand how microbiota regulate FAO in IECs, and define the impact of intestinal FAO on intestinal and systemic physiology. The proposed research will test the central hypothesis that specific bacterial products downregulate FAO in IECs by suppressing FAO gene transcription, which in turn modulates IEC fuel selection and differentiation and promotes positive energy balance. Our rationale is that an improved understanding of how microbes influence intestinal FAO, and how FAO contributes to intestinal physiology and systemic energy metabolism could lead to new strategies for controlling fat metabolism and energy balance in humans and other animals. In Specific Aim 1, we will identify the host and microbial mechanisms by which microbiota suppress FAO in the intestinal epithelium. In Specific Aim 2, we will define the roles of intestinal FAO in fuel selection and differentiation of IECs, and in mediating the influence of the gut microbiota on systemic energy balance. The expected outcomes will vertically advance the field in several ways. First, they will establish intestinal FAO as a major determinant of intestinal and systemic energy balance. Second, they will provide definitive new evidence that intestinal epithelial FAO is a major target of microbial regulation. Third, they will show that the striking resistance of germ-free mice to diet-induced obesity is mediated by intestinal FAO. Finally, they will provide a novel bacteria-host signaling pathway governing intestinal FAO. These results are expected to have a significant impact because they are likely to lead to new microbe- and host-targeted strategies to control energy balance in the context of obesity and malnutrition by manipulating FAO and associated gene expression networks and metabolic pathways in the gut.