Microbial regulation of intestinal lipid metabolism and its physiological consequences

摘要 众所周知，肠道微生物群可促进膳食脂肪的吸收并赋予对饮食诱发的易感性 肥胖。然而，我们对潜在机制的了解存在根本差距。我们的长期 目标是了解宿主-微生物相互作用和肠道脂质代谢的潜在机制 以及它们如何对人类生理和疾病做出贡献。我们在 gnotobiotic 和 传统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) 的肠上皮细胞 (IEC)，并确定潜在的上游微生物和转录调控 机制。我们对传统小鼠的遗传分析还证实，在 IEC 中特别阻断了 FAO 促进膳食脂肪吸收并调节肠道和全身能量代谢。总体目标 该项目的目的是了解微生物群如何调节 IEC 中的FAO，并定义肠道FAO 的影响 关于肠道和全身生理学。拟议的研究将检验具体的中心假设 细菌产物通过抑制FAO基因转录来下调IEC中的FAO，进而调节 IEC 燃料选择和区分并促进正能量平衡。我们的理由是，改进 了解微生物如何影响肠道FAO，以及FAO如何促进肠道生理学和 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机制，通过这些机制 微生物群抑制肠上皮中的FAO。在具体目标 2 中，我们将定义肠道粮农组织的作用 燃料选择和 IEC 分化，以及调节肠道微生物群对全身系统的影响 能量平衡。预期成果将从多个方面垂直推进该领域。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。其次，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引起的肥胖的显着抵抗力是由肠道FAO介导的。最后， 他们将提供一种新的控制肠道FAO的细菌-宿主信号通路。这些结果是预期的 产生重大影响，因为它们可能会导致新的针对微生物和宿主的策略 通过操纵FAO和相关基因来控制肥胖和营养不良情况下的能量平衡 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.