Gut Liver axis: The interrelated role of regulated ‐ necrosis as keydriver of gastrointestinal and hepatic inflammation

肠道内环境平衡失调是炎症性肠病(IBD)的典型特征，是全身炎症发生和发展的重要因素，最终可导致多器官受累和损害。高达30%的IBD患者表现出肝脏损伤的生化体征，而原发性硬化性胆管炎(PSC)和自身免疫性肝炎(AIH)等肝胆疾病在IBD中相对常见[4]。肠道菌群失调和细菌跨肠上皮屏障移位，通过促进肝细胞损伤和炎症，被广泛认为是慢性肝病进展的主要因素。然而，事件的顺序和潜在的分子机制还没有明确的定义。本课题组最近的研究揭示了程序性坏死在胃肠道和肝脏炎症的发病机制中的重要作用，并提示程序性坏死可能与许多人类炎症性疾病的发病机制有关。这项拟议的项目旨在通过一种多学科的方法来表征肠道程序性坏死与肝脏炎症的发生/发展之间的联系。这个综合性的项目将通过一个跨学科的方法取代以器官为中心的观点，包括对受影响的器官(肝脏和肠道)的分析，来促进我们对肠道稳态失稳与肝脏炎症之间联系的机制的理解。这将为临床/生化指征为肝胆受累的IBD患者开发更有效、更安全的治疗方法提供基础。

Failure of gut homeostasis as a typical feature of inflammatory bowel disease (IBD) is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ involvement and damage. Up to 30% of IBD patients show biochemical signs for liver injury and hepatobiliary diseases such as primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are relatively common in IBD [4]. Enteric dysbiosis and translocation of bacteria across the gut epithelial barrier have been widely recognized as major factors in the progression of chronic liver disease by promoting hepatocellular injury and inflammation. However, the sequence of events and the underlying molecular mechanisms are poorly defined. Recent studies by our group have revealed important functions for programmed necrosis in the pathogenesis of gastrointestinal and hepatic inflammation and implicated that programmed necrosis could be implicated in the pathogenesis of many human inflammatory diseases. The proposed project aims at a multidisciplinary approach to characterize the association between programmed necrosis in the gut and the initiation/progression of hepatic inflammation. This comprehensive project will advance our understanding of mechanisms linking failure of gut homeostasis to hepatic inflammation by replacing the organ centered point of view by an interdisciplinary approach that includes analysis in both affected organs (liver and gut). This will provide the basis for the development of a more efficient and safer therapy for IBD patients with clinical/biochemical indications for hepatobiliary involvement.