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，许多人的发病率正在上升 人口。IBD的确切病因尚不清楚。 我们的兴趣集中在组织中与炎症相关的变化的识别上 炎症活动时的新陈代谢。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和 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 与炎症中的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)，我们确定了一组有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。这是丁酸引发的 上皮基因签名可作为了解宿主-微生物相互作用的模板 分子水平。 在这项提案中，我们将定义微生物来源的SCFA如何对整合至关重要 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(S)参与屏障形成和伤口愈合。目标2将定义亲属 HIF稳定和/或HDAC抑制在SCFA诱导的粘膜屏障功能中的作用 和伤口愈合。具体目标3将确定丁酸诱导的信号和 急、慢性黏膜炎症模型体内基因表达的研究。来自这些的结果 实验将为粘膜屏障的先天调节和扩展提供新的见解 共生菌产生单链脂肪酸的生理作用。我们希望这一点的延长 将导致确定粘膜炎症性疾病的新治疗靶点

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