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

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。据估计 超过150万美国人患有IBD，许多国家的发病率在上升， 人口。IBD的确切病因尚不清楚。 我们的兴趣集中在组织中炎症相关变化的识别上 在活跃的炎症过程中代谢。特别是，我们的目标是更好地了解微生物- 衍生因子，如短链脂肪酸（SCFA），有助于粘膜屏障功能， 伤口愈合我们正在进行的工作集中在定义分子途径和微生物 与炎症中代谢变化相关的靶点。在正在进行的工作中，使用无偏见的单一 细胞RNA测序（scRNAseq），我们确定了一组丁酸诱导的基因， 在屏障功能和粘膜伤口愈合反应中的重要性。这种丁酸盐引起的 上皮基因签名作为一个模板，以了解宿主微生物的相互作用， 分子水平。 在本提案中，我们将定义微生物来源的SCFA对于整合 促进屏障功能和协调伤口愈合的上皮功能反应。三 提出了协同增效的具体目标。在目标1中，我们将阐明丁酸盐的贡献- 诱导靶基因以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将确定丁酸诱导的信号传导的相关性， 体内急性和慢性粘膜炎症模型中的基因表达。从这些 实验将为粘膜屏障的先天调节提供新的见解， SCFA的生理作用。我们希望， 将导致粘膜炎性疾病的新治疗靶点的确定

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