Metabolic Regulation of Inflammation by Microbial-Derived Short Chain Fatty Acids

微生物衍生的短链脂肪酸对炎症的代谢调节

基本信息

批准号：
10375388
负责人：
Sean P Colgan
金额：
$ 37.7万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375388
关键词：
Acute American Anatomy Animals Antigens Bacteria Butyrates Cell Line Cell physiology Chronic Colon Crohn&apos s disease Digestive System Disorders Disease Disease model Energy-Generating Resources Engineering Epithelial Epithelial Cells Escherichia coli Essential Fatty Acids Etiology Formulation Gene Expression Gene Expression Regulation Genes Genetic Germ-Free Goals Health Histone Deacetylase Histone Deacetylase Inhibitor Hypoxia Hypoxia Inducible Factor Immune response In Vitro Incidence Individual Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Intestinal Diseases Intestinal Mucosa Metabolic Metabolic Pathway Metabolism Microbe Modeling Molecular Mucositis Mucous Membrane Mus Oxygen Pathway interactions Pharmacology Physiological Population Positioning Attribute Regulation Resolution Role Signal Transduction Submucosa TNF gene Testing Tissues Ulcerative Colitis Volatile Fatty Acids Western World Work base cohort commensal bacteria design epithelial wound experimental study gain of function genetic signature gut inflammation gut microbiota healing host-microbe interactions in vivo in vivo Model insight interest intestinal epithelium microbial microbial community microbial host microbiota new therapeutic target novel response single-cell RNA sequencing tool transcription factor tributyrin wound healing

项目摘要

The Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis, remain among the most debilitating inflammatory disorders of the western world. It is estimated that more than 1.5 million Americans suffer with IBD, with incidence rates on the rise in many populations. The precise etiology of IBD is not known. Our interest is focused on the identification of inflammation-associated changes in tissue metabolism during active inflammation. In particular, we aim to better understand how microbial- derived factors, such as short chain fatty acids (SCFA), contribute to mucosal barrier function and wound healing. Our work in progress has focused on defining molecular pathways and microbial targets associated with metabolic shifts in inflammation. In ongoing work using unbiased single cell RNA sequencing (scRNAseq), we identified a cohort of butyrate-induced genes with potential importance in barrier function and mucosal wound healing responses. This butyrate-elicited epithelial gene signature serves as a template to understand host-microbial interactions at a molecular level. In this proposal, we will define how microbe-derived SCFA are essential for integrated epithelial functional responses that promote barrier function and coordinate wound healing. Three synergistic specific aims are proposed. In Aim 1, we will elucidate the contribution of butyrate- induced target gene(s) to barrier formation and wound healing. Aim 2 will define the relative contribution of HIF stabilization and/or HDAC inhibition to SCFA-elicited mucosal barrier function and wound healing. Specific Aim 3 will determine the relevance of butyrate-induced signaling and gene expression in acute and chronic mucosal inflammation models in vivo. Results from these experiments will provide new insights into innate regulation of mucosal barrier and an expanded physiological role for SCFA produced by commensal bacteria. It is our hope that extensions of this will lead to the identification of new therapeutic targets for mucosal inflammatory disease

炎症性肠病（IBD），包括克罗恩病和溃疡性结肠炎，仍然是西方世界最令人衰弱的炎症性疾病之一。估计超过 150 万美国人患有 IBD，并且许多国家的发病率呈上升趋势人口。 IBD 的确切病因尚不清楚。我们的兴趣集中在识别组织中与炎症相关的变化活动性炎症期间的新陈代谢。特别是，我们的目标是更好地了解微生物如何- 衍生因子，例如短链脂肪酸（SCFA），有助于粘膜屏障功能和伤口愈合。我们正在进行的工作重点是定义分子途径和微生物与炎症代谢变化相关的目标。在正在进行的工作中使用无偏见的单一细胞 RNA 测序 (scRNAseq)，我们鉴定了一组具有潜在潜力的丁酸诱导基因屏障功能和粘膜伤口愈合反应的重要性。这种丁酸盐引发上皮基因特征作为了解宿主-微生物相互作用的模板分子水平。在本提案中，我们将定义微生物衍生的短链脂肪酸 (SCFA) 如何对于整合至关重要促进屏障功能和协调伤口愈合的上皮功能反应。三提出了协同的具体目标。在目标 1 中，我们将阐明丁酸盐的贡献- 诱导靶基因形成屏障和伤口愈合。目标 2 将定义相对 HIF 稳定和/或 HDAC 抑制对 SCFA 引起的粘膜屏障功能的贡献和伤口愈合。具体目标 3 将确定丁酸诱导信号传导的相关性和体内急性和慢性粘膜炎症模型中的基因表达。这些结果实验将为粘膜屏障的先天调节提供新的见解，并扩大共生细菌产生的 SCFA 的生理作用。我们希望这一举措能够得到扩展将导致粘膜炎症疾病新治疗靶点的确定