基于HIF-1α对肠上皮细胞自噬的调控探讨短链脂肪酸治疗IBD的作用及机理

肠上皮细胞自噬功能的维持是肠屏障发挥功能、肠道菌群平衡的保障。探讨维持自噬功能的分子机制可为治疗肠炎提供新依据。我们前期发现缺氧诱导因子-1α (hypoxia-inducible factor-1α, HIF-1α)可诱导肠上皮细胞自噬相关蛋白高表达，促进自噬小体形成。肠上皮细胞特异性敲除HIF-1α后肠道炎症明显加重，肠道菌群紊乱。新近研究表明，益生菌代谢产物短链脂肪酸（short-chain fatty acids, SCFA）是从肠腔激活HIF-1α的理想分子。因此我们假设：肠炎条件下口饲SCFA可以刺激HIF-1α，从而增强自噬，维持肠屏障稳态。本研究拟采用体内外研究模型，通过SCFA口饲、缺氧、自噬抑制等手段，利用细胞和动物模型，阐明SCFA通过激活HIF-1α对自噬产生调控，为SCFA治疗肠炎提供理论依据。

The autophagy pathway has been increasingly recognized as an important mechanism for regulating homeostasis of gut microbiota and host defense. The discovery of molecular mechanism for autophagy has provided exciting advances in our understanding of inflammatory bowel disease treatment. Our preliminary data showed that hypoxia-inducible factor-1α (HIF-1α) could induce autophagy and autophagy-related proteins. Absence of intestinal epithelial HIF-1α affects microbial assemblage and increases susceptibility to dextran sulfate sodium-induced colitis. Recent study revealed that microbiota-derived short-chain fatty acids (SCFA) promote intestinal epithelial O2 consumption to the extent that HIF is stabilized and the expression of barrier-protective HIF target genes. Therefore, we hypothesize that the intestinal epithelial HIF-1α is a target of SCFA through its actions on the autophagy, thus determining states of host defense and microbial assembly. In this study, we would like to confirm the above mentioned hypothesis by using technology of HIF-1α-knockout mice and hypoxic cell model, and test whether SCFA upregulates the autophagy-related proteins through HIF-1α. These findings provide profound insight for the development of therapies to treat IBD.