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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要