胆管细胞糖萼降解促进原发性硬化性胆管炎的发生

Friederike Klein, Freya Wellhoener, Anika Freise, Kristina M Niculovic, Howard Junca, Manuel Vicente, Elina Katz, Luiz G dos Anjos Borges, Leonard Knegendorf, Karsten Cirksena, Antonia M Triefenbach, Franziska Woelfl, Helin F Abdullah, Meike Schulz, Iris Plumeier, Silke Kahl, Iris Albers, Martijn Zoodsma, Marius Vital, Torsten Voigtlaender, Henrike Lenzen, Jessica Schmitz, Anna Saborowski, Michael P Manns, Philipp Solbach, Jan H Braesen, Gisa Gerold, Cheng-Jian Xu, Heiner Wedemeyer, Anja K Muenster-Kuehnel, Dietmar H Pieper, Benjamin Heidrich
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摘要

原发性硬化性胆管炎(PSC)是一种胆道炎症性疾病,最终会导致胆管破坏、肝功能衰竭、胆管细胞腺癌和/或死亡。目前尚无改变疾病的治疗方法。特别是胆汁酸的细胞毒性,被认为是疾病进展的潜在驱动因素。胆管细胞受到糖萼形成的碳酸氢盐保护伞的保护,糖萼是一层致密的膜结合多聚糖,延伸至细胞外空间。PSC患者的胆汁中蕴藏着独特的微生物群。在这里,我们发现了 PSC 发病机制中的一个新因素。通过细胞培养实验、个体化类器官模型和肝脏活组织切片,我们发现细菌降解硅酸和半乳糖与 PSC 患者的无事件生存率低下有关,并确定细菌释放硅酸是胆管细胞损伤的关键因素。这项研究拓宽了胆管相关疾病中细菌与宿主相互作用的视野。细菌群落的功能模式对 PSC 患者的胆管破坏至关重要。这为诊断工具、改变疾病的治疗方案和识别高危患者开辟了新的领域。
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Cholangiocyte glycocalyx degradation boosts primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tract eventually leading to bile duct destruction, liver failure, cholangiocellular adenocarcinoma and/or death. No disease modifying treatments are available. Especially cytotoxicity of bile acids, are discussed as potential driver of disease progression. Cholangiocytes are protected by a bicarbonate umbrella formed by the glycocalyx, a dense layer of membrane bound polyglycans extending into the extracellular space. Bile of PSC patients harbors a unique microbiome. Here we identified a new factor in the pathogenesis of PSC. The bacterial degradation of sialic acid and galactose are associated with a poor event free survival of PSC patients and could identify bacterial liberation of sialic acid as crucial element in cholangiocyte damage using cell culture experiments, individualized organoid models and liver biopsies. With this study the view on bacteria-host interactions in bile duct associated diseases is widened. Functional patterns of the bacterial community are crucial for bile duct destruction in PSC patients. This opens a new field of diagnostic tools, disease modifying treatment options and identification of patients at risk.
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