丁酸-HDAC-巨噬细胞轴在溃疡性结肠炎黏膜损伤修复中的作用及机制研究

菌群失调和肠屏障受损是溃疡性结肠炎（UC）发病机制中的主要因素，修复屏障、促进黏膜愈合是目前UC治疗的热点和难点。近期研究发现，响应菌群信号调控的巨噬细胞在肠上皮再生和稳态维持中扮演重要角色，但具体作用和机制不明。申请者前期发现UC患者肠道产丁酸菌及产物丁酸明显减少，补充丁酸及丁酸处理后的巨噬细胞均可促进UC小鼠肠黏膜愈合，表明巨噬细胞很可能介导了菌群产物丁酸促进UC黏膜损伤修复的获益效应；进一步研究发现,丁酸具有调控巨噬细胞M2极化的作用,而巨噬细胞M2极化受阻和对凋亡损伤细胞清除能力减弱是UC愈合延迟的重要机制,那么,丁酸是如何调控巨噬细胞的上述促修复功能的？本研究拟在动物、类器官、细胞和分子水平，采用过继回输、荧光示踪及基因干预等方法，深入探讨以组蛋白去乙酰化酶(HDAC)为核心的丁酸-HDAC-巨噬细胞轴在肠上皮损伤修复中的具体机制，从肠稳态角度为UC的治疗提供新靶点和新路径。

The microbial dysbiosis and gut barrier disorders are important factors in the pathogenesis of ulcerative colitis (UC). Intestinal barrier re-establishment and mucosal healing have become a focus in current research of UC. Recent studies have found that macrophages, regulated by microbial signals, play an important role in tissue regeneration and intestinal homeostasis, however the specific role and mechanism are not yet clear. Our previous studies have confirmed that there was microbial dysbiosis with a decrease of butyrate-producing bacteria and their product butyrate in UC patients. Both butyrate supplementation and butyrate-treated macrophages could promote intestinal mucosal healing following experimentally induced colitis, indicating that macrophages may mediate the beneficial effect of microbial metabolite butyrate on mucosal repair. Furthermore, butyrate could skew macrophages toward a M2-like phenotype, and obstruction of M2 macrophage polarization and weakened ability to eliminate apoptotic cells are the important mechanisms for the delay of wound healing in UC. So, how does butyrate regulate the above pro-repair function of macrophages? In this project, we try to answer these questions at animal, organoid, cell and molecular level. We will apply a series of adoptive transfer of immune cells, fluorescent cell tracing and genetic manipulation methods to investigate the mechanism of butyrate-HDAC-macrophage axis with histone deacetylase (HDAC) as the core in the repair of intestinal epithelial damage, further providing new targets and paths for clinical treatment of UC in the perspective of gut homeostasis.