EPA、DHA调节杯状细胞黏液分泌影响溃疡性结肠炎发生作用及机制研究

溃疡性结肠炎影响患者生活质量、增加患肠癌风险。人群研究显示结肠n-3多不饱和脂肪酸水平与肠炎呈负相关，然而EPA、DHA对肠炎的确切作用尚不清楚。杯状细胞合成黏蛋白、分泌黏液对于肠上皮屏障至关重要，新近研究显示NLRP6炎症小体激活自噬是诱导黏液分泌的重要通路。课题组前期发现EPA显著升高杯状细胞黏蛋白含量、抑制小鼠肠炎形成，DHA无抑制作用。研究发现应用PPARγ激动剂可活化NLRP6、促进肠上皮修复，EPA可激活PPARγ、增强自噬，与DHA相比、EPA活化PPARγ能力更强。为此，我们提出假设“EPA、DHA通过PPARγ/NLRP6/自噬通路调节杯状细胞黏液分泌影响溃疡性结肠炎发生”，利用PPARγ敲除鼠和LS174T杯状样细胞探讨EPA、DHA能否拮抗葡聚糖硫酸钠诱导的肠炎，分析杯状细胞黏液分泌及PPARγ/NLRP6/自噬通路的作用，为探索有效的肠炎干预措施提供科学依据。

Colitis often leads to a decrease of the patient's quality of life and an increase of the risk for colon cancer. It has been shown that the intake of n-3 poly-unsaturated fatty acids is negatively related to colitis occurance. However, the precise role of EPA and DHA is still unclear. Previous data of our team showed that EPA intervention markedly inhibited the colitis of mice with a significant increase of mucin in goblet cells, while DHA did no show any protective effect. It is well known that goblet cells produce mucin and secrete it into lumen to make mucus layer, contributing to colon epithelium barrier. Recently, NLRP6 inflammasome has been found to activate autophagy and induce mucus secretion of goblet cells. In addition, application of PPARγ agonist was reported to activate NLRP6 inflammasome and promote the renewal of injured colon epithelium. It is reported that EPA activated PPARγ and promoted formation of autophagosome, moreover the efficiency of EPA to activate PPARγ is higher than DHA. Base on above evidences, it was proposed that EPA and DHA may influence colitis by regulating mucus secretion of goblet cells via PPARγ/NLRP6/autophagy pathway. The PPARγ knockout mice and LS174T goblet-like cell line will be used in the present study to clarify the effect of EPA and DHA on the DSS-induced colitis and uncover the role of mucus secretion as well as PPARγ/NLRP6/autophagy pathway to provide scientific evidence for develop the effective intervention measure of colitis.