PT  - JOURNAL ARTICLE
AU  - Bedke, Tanja
AU  - Stumme, Friederike
AU  - Tomczak, Miriam
AU  - Steglich, Babett
AU  - Jia, Rongrong
AU  - Bohmann, Simon
AU  - Wittek, Agnes
AU  - Kempski, Jan
AU  - Göke, Emilia
AU  - Böttcher, Marius
AU  - Reher, Dominik
AU  - Franke, Anissa
AU  - Lennartz, Maximilian
AU  - Clauditz, Till
AU  - Sauter, Guido
AU  - Fründt, Thorben
AU  - Weidemann, Sören
AU  - Tiegs, Gisa
AU  - Schramm, Christoph
AU  - Gagliani, Nicola
AU  - Pelczar, Penelope
AU  - Huber, Samuel
TI  - Protective function of sclerosing cholangitis on IBD
AID  - 10.1136/gutjnl-2023-330856
DP  - 2024 Aug 01
TA  - Gut
PG  - 1292--1301
VI  - 73
IP  - 8
4099  - http://gut.bmj.com/content/73/8/1292.short
4100  - http://gut.bmj.com/content/73/8/1292.full
SO  - Gut2024 Aug 01; 73
AB  - 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.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.