Abstract
Abstract Background Primary sclerosing cholangitis (PSC), a cholestatic liver disease highly associated with inflammatory bowel disease (IBD), is characterized by progressive inflammatory destruction of bile ducts. Bacterial membrane vesicles (bEVs) derived from gut pathobionts may play a significant role in the pathogenesis of PSC-IBD by disrupting the biliary barrier, promoting liver inflammation and contributing to liver fibrosis. A deeper understanding of how bEVs influence bile duct homeostasis is crucial for unraveling the mechanisms behind PSC-IBD and developing targeted therapeutic strategies. Methods Bile duct organoids were generated from WT mice and PSC-IBD patients. BEVs were isolated from commensals or PSC-associated gut pathobionts following MISEV guidelines. To assess the role of bEVs to ductal barrier dysfunction and inflammation, we employed an organoid based permeability assay, immunofluorescence staining, qPCR and bulk RNA sequencing. Furthermore, to investigate whether the presence and amount of bEVs in the systemic circulation were associated with PSC-IBD, we analyzed serum-derived EVs from either healthy control, as well as PSC and PSC-IBD patients using Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and a TLR4-Receptor based reporter assay. Results Our results demonstrate that particularly bEVs isolated from gut pathobionts trigger signaling pathways associated with inflammation in both murine and human biliary epithelial cells. Furthermore, we observed a disease and strain specific fingerprint after bEV treatment, which was characterized by several significantly enriched terms related to PSC-related inflammation, including genes involved in T-helper 17 cell differentiation, and tumor necrosis factor (TNF) signaling. However, we did not observe a direct impact of bEVs on biliary barrier function. Consistent with this, we detected increased levels of bEVs in the systemic circulation of PSC-IBD patients, but not in those with PSC alone or in healthy controls, suggesting that these bacterial components may translocate across a compromised intestinal barrier into the bloodstream. Conclusion Overall, our study suggests that bEVs may contribute to biliary inflammation, but not barrier dysfunction and thereby may represent a novel player in the pathogenesis of PSC-IBD. Additionally, it underscores the critical role of bEVs in host-microbe communication, suggesting their potential as diagnostic biomarkers and highlighting, that therapeutic strategies targeting bEVs could offer promising avenues for managing PSC-IBD.
Published Version
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