岩藻糖调控肠上皮细胞自噬在肠黏膜屏障中的作用

Increasing intestinal mucosa barrier function plays a key role in the prevention and treatment of severe illness. Our results demonstrated that fucose could improve the function of intestinal mucosal barrier, but its mechanism is not clear. Further study showed that intestinal mucosal barrier could be repaired by regulating the autophagy level of intestinal epithelial cells. Therefore, regulation of autophagy level of intestinal epithelial cells may be a key target to maintain the function of mucosal barrier. Our study takes the intestinal mucosa barrier function as a target, using fucose for tool to discuss the effect and mechanism between fucose and autophagy. By building a specific knock out of intestinal epithelial cells FUT2 genes and type I interferon receptor IFN - a/β mouse model in mice, we will discuss the relationship bwtween the fucose and intestinal epithelial cell autophagy level through the fucose-PI3K/AKT/mTOR direct pathway and fucose-interferon-PI3K/AKT/mTOR indirect way. A better understanding of intestinal mucosa barrier function would potentially provide important insights into pathogenesis and may generate new therapeutic approaches.

维持肠道黏膜屏障功能是临床防治危重疾病的重要措施。我们前期研究发现岩藻糖可以改善肠黏膜屏障功能，但其机制尚不清楚。已有的基础证实调节肠上皮细胞自噬水平可以修复肠黏膜屏障，因此对肠上皮细胞自噬水平的调控可能是维持黏膜屏障功能的关键手段。本课题以肠道黏膜屏障为切入点，以岩藻糖为干预手段，拟构建特异性敲除肠上皮细胞FUT2基因小鼠以及I型干扰素受体IFN-a/βR小鼠模型，通过岩藻糖-PI3K/AKT/mTOR直接途径以及岩藻糖-干扰素-PI3K/AKT/mTOR间接途径探讨岩藻糖与肠上皮细胞自噬水平的关系，这对深入了解肠道黏膜屏障功能的调控，为肠道炎性疾病及其它危重症的治疗提供新思路。

肠黏膜屏障是防止肠内细菌、毒素等有害物质进入机体的重要防线。但目前维持肠道黏膜屏障功能的措施很少。溃疡性结肠炎患者肠黏膜屏障功能受损尤其严重。而肠道菌群有害菌是重要原因之一。我们通过体内外研究发现，具核梭杆菌可明确加重溃疡性结肠炎小鼠肠道炎症及黏膜屏障功能的破坏，而给予有益菌鼠李糖乳酸杆菌干预以后，通过PCR、WB、免疫荧光、免疫组化等多种实验方法发现，李糖乳酸杆菌可以显著缓解具核梭杆菌导致的肠道黏膜炎症反应，其机制是具核梭杆菌通过抑制肠道自噬流来加重结肠炎，而益生菌鼠李糖乳酸杆菌可以通过恢复被具核梭杆菌所抑制的自噬流来缓解肠道炎症反应。另一方面，具核梭杆菌同样也是引起溃疡性结肠炎相关性结肠癌的致病菌，实验进一步研究发现，外源性给予岩藻糖后，岩藻糖可显著缓解具核梭杆菌在多种结肠癌细胞系中的促增殖、促迁移、促侵袭的肿瘤特性，其机制可能是通过激活jak2/stat3通路以及上皮间充质转化，从而达到岩藻糖抑制炎症抑制肿瘤的作用。这对于深入了解肠道炎症及肠道肿瘤的防治，具有重要的意义。