KFO 306: Primär Sklerosierende Cholangitis

原发性硬化性胆管炎（PSC）是一种相对罕见的胆管慢性进行性疾病，可导致肝硬化和胆管癌。迄今为止，还没有有效的治疗方法来改变疾病的进展过程。肝硬化和肝胆恶性肿瘤的高风险限制了患者的生存，此外，psc相关的并发症（如骨质疏松症）往往会损害健康相关的生活质量。PSC的特点是肝内和/或肝外胆管的炎症和纤维化，并与炎症性肠病密切相关，最常见的是PSC相关性全结肠炎。这些疾病的特征强调了粘膜表面对疾病发病机制的重要性。近年来，微生物群在维持和破坏粘膜免疫稳态中起着至关重要的作用。在CRU306中，我们假设微生物组及其相关的免疫和代谢变化决定了疾病的发病机制和病程。在之前的工作中，我们可以证明PSC与肠道微生物群组成的变化有关，这在不同地理区域得到了验证，最近也与胆道微生物群的变化有关。我们已经证明PSC与血液和肝脏中免疫细胞群的改变有关，PSC患者的T细胞在热灭活细菌刺激后显示促炎细胞因子的产生增加。CRU306汇集了许多肝病学、免疫学、微生物组研究和生物信息学方面的临床和基础科学专家。在下一个资助期，我们将重点关注在人类和相应小鼠模型中观察到的psc相关微生物群、免疫和代谢模式与疾病发病机制、表型和病程相关的变化的功能意义。

Primary Sclerosing Cholangitis (PSC) is a relatively rare, chronic progressive disease of bile ducts which leads to liver cirrhosis and cholangiocarcinoma. To date there is no effective therapy to alter the progressive course of disease. Patient survival is limited by the high risk of cirrhosis as well as hepatobiliary malignancy, but in addition health related quality of life is often impaired by PSC-associated complications such as osteoporosis.PSC is characterized by inflammation and fibrosis of intra- and/or extrahepatic bile ducts and by its strong association with inflammatory bowel disease, most often PSC-asssociated pancolitis. These disease features underline the importance of the mucosal surface for disease pathogenesis. In recent years it has become clear that the microbiome is critical for the maintenance and breach of mucosal immune homeostasis. Within the CRU306 we hypothesize that the microbiome and its associated immunological and metabolic changes determine disease pathogenesis and course. In previous work we could show that PSC is associated with changes in intestinal microbiota composition, which were validated across geographical regions, and recently also with changes in the biliary microbiota. We have shown that PSC is associated with altered immune cell populations in blood and liver and that T cells from patients with PSC showed increased pro-inflammatory cytokine production after stimulation with heat-inactivated bacteria. The CRU306 brings together a number of clinical and basic science experts in hepatology, immunology, microbiome research and bioinformatics. In the next funding period we will focus on the functional meaning of the observed changes in PSC-associated microbiota, immunological and metabolic patterns with regard to disease pathogenesis, phenotype and disease course in humans and respective mouse models.