Microbial regulation of intestinal lipid metabolism and its physiological consequences

摘要 已知肠道微生物区系可促进膳食脂肪的吸收，并增加对饮食诱导的敏感性。 肥胖。然而，我们对潜在机制的了解存在着根本的差距。我们的长期合作 目的是了解肠道中宿主-微生物相互作用和脂质代谢的潜在机制。 以及它们对人类生理和疾病的贡献。我们对诺生菌的初步研究和 传统的小鼠和斑马鱼表明，微生物区系特异性地抑制线粒体脂肪酸氧化 (FAO)在肠上皮细胞(IECS)中，并确定潜在的上游微生物和转录调控 机械装置。我们对常规小鼠的遗传分析也证实，在IECS中特异性地阻断FAO 促进膳食脂肪吸收，调节肠道和全身能量代谢。总体目标 这个项目的目的是了解微生物区系如何在IECS中调节FAO，并定义肠道FAO的影响 肠道和全身生理学。拟议中的研究将检验中心假设，即特定的 在IECS中，细菌产品通过抑制FAO基因转录而下调FAO，而FAO基因转录又反过来调节 IEC燃料选择和差异化，促进正能量平衡。我们的理由是，改进后的 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和 全身性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，我们将确定寄主和微生物机制 微生物区系抑制了肠上皮细胞中的FAO。在具体目标2中，我们将界定肠道粮农组织的作用 在IECS的燃料选择和分化以及肠道微生物区系对全身的影响方面 能量平衡。预期结果将在几个方面垂直推进这一领域。首先，他们将建立 肠道粮农组织作为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，肠道上皮粮农组织是微生物监管的主要目标。第三，他们会 表明无菌小鼠对饮食诱导的肥胖的显著抵抗力是由肠道粮农组织介导的。最后， 它们将提供一条新的细菌-宿主信号通路来管理肠道粮农组织。这些结果是意料之中的 产生重大影响，因为它们可能导致新的以微生物和宿主为目标的战略 通过操纵粮农组织及其相关基因控制肥胖和营养不良背景下的能量平衡 肠道中的表达网络和代谢途径。

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.