肠道Th17细胞在MCD饮食诱导NAFLD中的作用及相关机制研究

Nonalcoholic fatty liver disease (NAFLD) has become a main cause of the chronic liver disease and one of the important reasons for the liver cirrhosis. More and more evidence show that the intestinal flora were closely related to NAFLD. Our previous studies showed that patients with cirrhosis exist the change of intestinal microflora, The severity of the disease were closely related with the degree of flora imbalance, but the specific mechanism is still unknown. Recent studies have found intestinal Th17 cells maybe the key factor to maintain the balance in the intestinal immune barrier function, but Role of the Th17 cells in NAFLD development has not been reported. Our hypothesis is dysfunction of Th17 cells caused by the change of intestinal flora maybe one of the pathogenesis of NAFLD; Regulator of intestinal microecology could improve the liver damage in NAFLD through regulation of intestinal Th17 cells. In order to confirm the above speculation, we establish the NAFLD mice model used by feeding MCD, use 16SrRNA gene PCR technique to analysis the intestinal flora of mice with NAFLD; meanwhile we also detect of body and intestinal Th17 cells and the related cytokine levels so as to explore whether Th17 cells involved in the pathogenesis of liver injury and disorders of the intestinal flora. We want to prove that the influence of the intestinal flora on the regulation of Th17 cells is a new target to reduce liver damage and improve the disease prognosis.

非酒精性脂肪性肝病（NAFLD）已成为导致慢性肝病乃至肝硬化的重要原因之一。越来越多的证据表明肠道菌群与NAFLD发病密切相关。我们前期研究表明，肝硬化患者存在肠道菌群改变，病情严重程度与菌群失衡程度相关，但具体机制不明。最近研究发现，肠道Th17细胞可能是维持肠道免疫屏障功能中关键的因素，但其在NAFLD发生发展中的作用尚未见报道。我们的假说是肠道菌群改变致肠道Th17细胞功能失调为NAFLD的发病机制之一，肠道微生态调节剂可调节肠道Th17细胞来改善NAFLD中肝脏损伤。为证实上述推测，我们拟在用MCD喂养小鼠建立NAFLD动物模型的基础上，以针对16SrRNA基因的PCR技术对NAFLD小鼠肠道菌群进行分析；检测机体和肠道Th17细胞及相关的细胞因子水平，探讨Th17细胞参与了肝损伤和肠道菌群紊乱的发病机制，以期证明通过肠道菌群对Th17细胞的干预调节是减轻肝损伤及改善预后的新靶点。

非酒精性脂肪性肝病（NAFLD）已成为导致慢性肝病乃至肝硬化的重要原因之一。肠道菌群改变在NAFLD的发病过程中发挥重要作用。前期研究表明，肝硬化患者存在肠道菌群改变，病情严重程度与菌群失衡程度相关。本课题组按照计划任务书的要求，设计并开展各项研究，研究发现，NAFLD模型中，同一小组小鼠个体间肠道菌群差异不明显，存在明显的相似性，而MCD饮食诱导下小鼠肠道菌群结构特征与正常对照组相比较存在着明显差异。研究发现在NAFLD模型中，肠道菌群改变可以影响肝损伤的严重程度。分别口服益生菌和乳梨醇能够明显减轻肝损伤，减低脏器的细菌异位以及血清细胞因子水平（TNF-α, IL-6, IL-10 and IL-12)。发现不同肠道菌群改变对肝损伤进程有着不同的影响。研究发现（1）机体Th17细胞相关的细胞因子网络可能参与了肝损伤和肠道菌群紊乱的发病过程，Th17细胞可以作为急性肝损伤严重程度的间接指标之一，而对其的干预和调节可能是干预急性肝病和肠道菌群紊乱的发生发展及改善预后的新思路。（2）服用乳梨醇、双歧杆菌和乳酸杆菌能明显调节肠道菌群紊乱，可在一定程度上保护肝损伤和肝功能。我们推测可能通过对Th17细胞的调节改善机体免疫功能。