原发性硬化性胆管炎 (PSC) 通常与炎症性肠病 (IBD) 相关，其病因涉及遗传、免疫和环境因素等多因素。 PSC-IBD 涉及肠道菌群失调和细菌易位，但其发病机制的确切机制仍然难以捉摸。在这里，我们描述了肠道病原体在由于细菌外膜囊泡（OMV）的释放而促进肝脏炎症和纤维化中的作用。除了导管类器官之外，还使用临床前小鼠模型来获取机制数据。进行了一项概念验证研究，包括对 PSC (n=22)、PSC-IBD (n=45) 和对照个体 (n=27) 患者队列进行血清和肝脏活检，以检测体循环中的 OMV在临床前模型系统和人类 PSC-IBD 患者中，OMV 易位至肝脏与增强的细菌感应和 NLRP3 炎性体的积累相关。使用导管类器官，我们能够精确地将 OMV 的促炎和促纤维化特性归因于依赖于 TLR4 和 NLRP3-GSDMD 的信号通路。 OMV 的免疫刺激潜力可以在巨噬细胞和肝星状细胞中得到证实。此外，当我们给 Mdr2-/- 小鼠施用肠道病原体衍生的 OMV 时，我们观察到肝脏炎症和纤维化显着增强。在转化方法中，我们使用 PSC-IBD 患者队列证实了 OMV 在严重纤维化的体循环和肝脏区域中的存在。这项研究证明了肠道病原体在释放穿过粘膜屏障的 OMV 方面的贡献，从而促进PSC-IBD 中的肝脏炎症和纤维化。 OMV 可能代表一种关键的新环境因素，它与其他疾病因素相互作用引起炎症，从而确定纤维化治疗的潜在新靶点。版权所有 © 2024 AGA Institute。由爱思唯尔公司出版。保留所有权利。

Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunological, and environmental factors. Gut dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs).Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n=22), PSC-IBD (n=45) and control individuals (n=27) was performed to detect OMVs in the systemic circulation and liver.In both, preclinical model systems and in human PSC-IBD patients, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on TLR4 and NLRP3-GSDMD. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2-/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort.This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier, and thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy.Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.