早产儿肠外营养相关肝损害（parenteral nutrition-associated liver disease，PNALD）发生比例高、机制不清、临床防治困难。研究证实肠道菌群参与婴幼儿肠炎等多种疾病发病过程，迄今尚未报道肠道菌群对早产儿PNALD作用。肠屏障损伤及肝内胆汁淤积是PNALD重要原因。前期研究显示PNALD患儿肠杆菌增多、乳杆菌减少。肠杆菌增多可能激活肠道JNK-2-CUGBP1通路，导致肠屏障损伤进而造成肠道细菌移位；乳杆菌减少可能抑制FXR-FGF19通路，导致胆汁酸代谢异常进而造成肝内胆汁淤积。为验证以上假说，本项目拟利用早产小猪模型研究：肠杆菌在肠屏障损伤中的作用及机制；乳杆菌在肝内胆汁淤积中的功能和机制；调节肠杆菌、乳杆菌对早产儿PNALD发生的干预作用。通过以上研究可能为早产儿PNALD临床防治提供新的靶点。

Parenteral nutrition-associated liver disease (PNALD) is one of the most common complications in preterm infants with long-term parenteral nutrition (PN) support. However, it still lacks effective strategies for prevention and treatment, since the etiology of PNALD has not been fully understood. Bacterial translocation and intrahepatic cholestasis have been identified as the main causes of PNALD. Our preliminary studies revealed that long-term PN support in preterm infants resulted in significant changes in microbial community, typically an increase in enterobacteriaceae abundance and a decrease in lactobacillaceae abundance. On one hand, elevation of enterobacteriaceae abundance may activate JNK-2-CUGBP1 pathway, leading to the disruption of intestinal barrier and consequent bacterial translocation; On the other hand, diminish of lactobacillaceae abundance may repress FXR-FGF19 pathway, leading to the aberrant metabolism of bile acids and consequent intrahepatic cholestasis. To verify these hypothesis, we use the preterm-piglet model to study 1) the effects and mechanisms of enterobacteriaceae in the disruption of intestinal barrier; 2) the role of lactobacillaceae in intrahepatic cholestasis; 3) the interventional effects of optimization of microbiota on the pathogenesis and development of PNALD. Our study will provide potential therapeutic targets for PNALD in preterm infants.