肠道菌群介导的胆汁酸代谢异常在NEC病变中的作用及发病机制研究

坏死性小肠结肠炎（NEC）是早产儿常见的严重疾病，病死率高。目前NEC致病因素不明，病理机制不清。我们前期发现NEC患儿肠道菌群紊乱，次级胆汁酸减少，次级胆汁酸转化菌丰度下降。由此提出假设：①肠道菌群介导的胆汁酸代谢异常，次级胆汁酸减少是NEC发病的主要因素；②其发病机制是胆汁酸代谢异常-FXR通路改变激活NLRP3致肠道炎症；③特定肠道菌结合胆汁酸可靶向胆汁酸FXR代谢通路成为诊断、防治NEC的有效途径。本项目拟采用宏基因组学和代谢组学，找到早产儿NEC和非NEC的差异菌、差异胆汁酸，分离获得次级胆汁酸高效转化菌。通过比较FXR-/-与野生型NEC动物模型的肠道病理变化，检测肠道菌群和胆汁酸，分析胆汁酸-FXR-NLRP3信号通路在NEC发生发展中的作用，探讨NEC的发病机制，确定NEC诊断标记物，探索出一条NEC早期诊断和有效防治的新途径。本研究对提高NEC诊断和防治有重要的科学价值。

Necrotizing enterocolitis (NEC) is a common and serious disease in preterm infants with high mortality. At present, the pathogenic factors and pathological mechanisms of NEC are unclear. We have previously discovered that NEC neonates have intestinal flora disorders, accompanied by the reduced level of secondary bile acids due to a marked reduction in the abundance of secondary bile acid converting bacteria. Based on the above reasons, the following hypotheses are put forward: ① Abnormal bile acid metabolism and the reduction of secondary bile acids mediated by intestinal flora are the main factors in the pathogenesis of NEC. ② The pathogenesis of NEC is due to the abnormal bile acid metabolism-mediated through FXR pathway, which activates the NLRP3 pathway and leads to intestinal inflammation. ③ Bile acid profile and the specific bacteria that can target the bile acid metabolic pathway may become an effective way to diagnose and prevent NEC. This project intends to use metagenomics and metabolomics to analyze the NEC and non-NEC differential microbiome and the distinct bile acids in NEC preterm infants and normal preterm infants in order to isolate probiotics that can efficiently transform secondary bile acids. In this study, we aim to compare the intestinal pathological changes between FXR-/- and wild-type NEC animal models and to examine the intestinal flora and bile acids while analyzing the role of the bile acid-FXR-NLRP3 pathway in the development of NEC. Moreover, this study will further explore the pathogenesis of NEC, determine the NEC diagnostic markers, and will appraise the bile acid FXR signaling pathway as an important drug intervention target. Based on the above research direction, we will explore a new strategy for early diagnosis and effective prevention of NEC. This study has significant scientific value for improving the diagnosis and treatment of NEC.