Microbial regulation of intestinal lipid metabolism and its physiological consequences

肠道脂质代谢的微生物调控及其生理后果

• 批准号: 10533800
• 负责人: John F Rawls
• 金额: $ 68.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-03 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533800
• 关键词: Ablation; Affect; Animals; Bacteria; Biological Assay; Carbohydrates; Cells; Cellularity; Chromatin; Chylomicrons; Colon; Consumption; Development; Dietary Fats; Digestion; Disease; Energy Intake; Energy Metabolism; Environmental Risk Factor; Enzymes; Epithelial Cells; Esterification; Fatty Acids; Fatty acid glycerol esters; Fermentation; Foundations; Gene Expression; Genetic; Genetic Transcription; Germ-Free; Gnotobiotic; Goals; HNF4A gene; Health; High Prevalence; Homeostasis; Human; Intestines; Knowledge; Lipids; Lipoproteins; Malnutrition; Mediating; Mediator; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Microbe; Mission; Mitochondria; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Physiological; Physiological Processes; Physiology; Predisposition; Process; Public Health; Regulation; Research; Resistance; Role; Ruminococcus; Signal Pathway; Small Intestines; Symbiosis; Testing; Time; Tissues; Triglycerides; United States National Institutes of Health; Zebrafish; absorption; burden of illness; diet-induced obesity; energy balance; fatty acid oxidation; functional genomics; genetic analysis; gut bacteria; gut microbiota; host-microbe interactions; human disease; improved; innovation; intestinal epithelium; lipid metabolism; meetings; microbial; microbial colonization; microbiota; microorganism; novel; novel therapeutic intervention; response; transcription factor; uptake

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.

抽象的 已知肠道菌群促进饮食脂肪的吸收，并赋予饮食诱发的敏感性 肥胖。但是，我们对基本机制的了解存在基本差距。我们的长期 目标是了解肠相互作用的机制和肠道中的脂质代谢 以及它们如何促进人类的生理和疾病。我们在gnotobiotic和 常规小鼠和斑马鱼表明，微生物群特异性抑制线粒体脂肪酸氧化 （粮农组织）在肠上皮细胞（IEC）中，并鉴定潜在的上游微生物和转录调节 机制。我们在常规小鼠中的遗传分析还确定，在IEC中特别阻止粮农组织 促进饮食脂肪的吸收并调节肠道和全身能量代谢。总体目标 该项目的内容是了解微生物群如何调节IEC中的粮农组织，并定义肠道粮农组织的影响 关于肠道和全身生理学。拟议的研究将检验一个中心假设，即特定于 细菌产物通过抑制粮农组织基因转录在IEC中下调粮农 IEC燃料选择和分化并促进正能量平衡。我们的理由是改善 了解微生物如何影响肠道粮农组织，以及粮农组织如何对肠道生理和 系统性能源代谢可能会导致控制脂肪代谢和能量平衡的新策略 人类和其他动物。在特定目标1中，我们将确定宿主和微生物机制 微生物群抑制肠上皮的粮农组织。在特定的目标2中，我们将定义肠道粮农组织的作用 在IEC的燃料选择和差异化以及介导肠道菌群对系统性的影响方面 能量平衡。预期的结果将以几种方式垂直地推进该领域。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 确切的新证据表明，肠上皮粮农组织是微生物调节的主要目标。第三，他们会的 表明无菌小鼠对饮食诱导的肥胖症的抗药性是由肠道疫儿介导的。最后， 他们将提供一种新型的细菌宿主信号传导途径，管理肠道粮农组织。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微生物和主机策略 通过操纵粮农组织和相关基因来控制肥胖和营养不良的环境中的能量平衡 肠道中的表达网络和代谢途径。