炎症性肠病和胆道闭锁是由肠-肝免疫稳态失衡所致的、符合指南方向2的重大儿童疾病，防治困难。亟需回答的科学问题有：婴幼儿期肠-肝功能稳态如何维持？遗传环境因素如何破坏肠-肝稳态？稳态能否重建？团队前期发现cAMP第二信使通路缺陷促进巨噬细胞过度炎症，而PDE抑制剂可有效恢复炎症性肠病患儿肠道黏膜稳态（Cell，2019）。进一步研究发现：（1）新生儿肝脏造血及胆汁酸代谢异常促进胆道闭锁患儿肝脏衰竭（Cell待修回），而NLRP3（JACI已修回）、RADX等突变，促进肠道巨噬细胞炎症响应；（2）PDE抑制剂促进疾病模型鼠的肠-肝免疫修复。据此假设：基因突变、代谢紊乱等内外在因素交互促进婴幼儿肠道巨噬细胞过度炎症反应，破坏黏膜屏障，经肠肝循环导致肝脏功能紊乱。本课题拟采用遗传免疫及多组学手段，系统阐述儿童肠-肝免疫稳态的维持机制，验证PDE抑制剂治疗炎症性肠病及胆道闭锁的临床应用前景。

Biliary atresia (BA) and paediatric-onset inflammatory bowel disease (PIBD) affect the wellbeing of many infants and children. Poor understanding of disease pathogenesis and limited treatment regimens have prevented the prognosis of children with BA or PIBD. To improve diagnosis and treatment, it is critical to address the following key scientific questions: (1) What are the mechanisms maintaining gut-liver immune homeostasis in paediatric populations? (2) What environmental and genetic factors break gut-liver immune homeostasis? (3) How to restore gut-liver immune homeostasis? To answer these questions, we have previously profiled colonic mucosae of control and PIBD patients, and have uncovered that defects in the cAMP-response pathway promoted a cascade of immune deviation signified by macrophage hyper-inflammation. More importantly, we demonstrated that a pan-phosphodiesterase (PDE) inhibitor dipyridamole was able to restore gut immune homeostasis and alleviate clinical symptoms of children with PIBD (Cell, 2019). Preliminary studies further revealed that: (1) a blockade of enterohepatic circulation of bile acids in patients with BA, or genetic mutations in NLRP3 and RADX, promote colonic macrophage hyper-inflammation. (2) PDE inhibitor dipyridamole was effective in restoring gut-liver immune homeostasis in a mouse model of BA. Based on these results, we hypothesized that genetic predispositions and metabolic disorders promote macrophage hyper-inflammation in the guts of children with BA or PIBD, leading to gut leakiness. Pathogens or microbial-associated molecular patterns transport via the enterohepatic circulation and cause liver immune deviation and fibrosis. To consolidate this hypothesis, we will employ genetic and multi-omics methodology to systemically address the cellular and molecular mechanisms that govern gut-liver immune homeostasis. We will also use animal models and clinical trials to explore feasibility of using PDE inhibitors to treat PIBD and BA.