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Objective: There is a strong clinical association between IBD and primary sclerosing cholangitis (PSC), a chronic disease of the liver characterised by biliary inflammation that leads to strictures and fibrosis. Approximately 60%-80% of people with PSC will also develop IBD (PSC-IBD). One hypothesis explaining this association would be that PSC drives IBD. Therefore, our aim was to test this hypothesis and to decipher the underlying mechanism., Design: Colitis severity was analysed in experimental mouse models of colitis and sclerosing cholangitis, and people with IBD and PSC-IBD. Foxp3 + Treg-cell infiltration was assessed by qPCR and flow cytometry. Microbiota profiling was carried out from faecal samples of people with IBD, PSC-IBD and mouse models recapitulating these diseases. Faecal microbiota samples collected from people with IBD and PSC-IBD were transplanted into germ-free mice followed by colitis induction., Results: We show that sclerosing cholangitis attenuated IBD in mouse models. Mechanistically, sclerosing cholangitis causes an altered intestinal microbiota composition, which promotes Foxp3 + Treg-cell expansion, and thereby protects against IBD. Accordingly, sclerosing cholangitis promotes IBD in the absence of Foxp3 + Treg cells. Furthermore, people with PSC-IBD have an increased Foxp3 + expression in the colon and an overall milder IBD severity. Finally, by transplanting faecal microbiota into gnotobiotic mice, we showed that the intestinal microbiota of people with PSC protects against colitis., Conclusion: This study shows that PSC attenuates IBD and provides a comprehensive insight into the mechanisms involved in this effect., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Primary sclerosing cholangitis (PSC) is a chronic liver disease marked by inflammation of the bile ducts and results in the development of strictures and fibrosis. A robust clinical correlation exists between PSC and inflammatory bowel disease (IBD). At present, published data are controversial, and it is yet unclear whether IBD drives or attenuates PSC., Methods: Mdr2 -deficient mice or DDC-fed mice were used as experimental models for sclerosing cholangitis. Additionally, colitis was induced in mice with experimental sclerosing cholangitis, either through infection with Citrobacter rodentium or by feeding with DSS. Lastly, fibrosis levels were determined through FibroScan analysis in people with PSC and PSC-IBD., Results: Using two distinct experimental models of colitis and two models of sclerosing cholangitis, we found that colitis does not aggravate liver pathology, but rather reduces liver inflammation and liver fibrosis. Likewise, people with PSC-IBD have decreased liver fibrosis compared to those with PSC alone., Conclusions: We found evidence that intestinal inflammation attenuates liver pathology. This study serves as a basis for further research on the pathogenesis of PSC and PSC-IBD, as well as the molecular mechanism responsible for the protective effect of IBD on PSC development. This study could lead to the discovery of novel therapeutic targets for PSC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stumme, Steffens, Steglich, Mathies, Nawrocki, Sabihi, Soukou-Wargalla, Göke, Kempski, Fründt, Weidemann, Schramm, Gagliani, Huber and Bedke.)