Analysis of the connection between inflammatory bowel disease and primary sclerosing cholangitis (PSC)

• Applicant: Professor Dr. Samuel Huber
• Subject Area: Gastroenterology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278045702

Primary sclerosing cholangitis (PSC) is highly associated with inflammatory bowel disease (IBD). However, it is unclear, whether PSC favors the development of IBD or vice versa. This knowledge is critical in order to understand PSC and to develop novel treatments. Interestingly, polymorphisms in the IL2RA gene, a key gene for Foxp3+ Treg, are associated with both PSC and IBD. Also, the fecal microbiota is known to impact Foxp3+ Treg and is altered in patients with PSC and IBD, suggesting a further role of the intestinal microbiota. We hypothesize that the connection of PSC and IBD is due to impaired Treg function, which initiates a vicious circulus, which then drives both diseases. Indeed, our preliminary findings show that IBD protects from PSC and vice versa in different mouse models. This protection was dependent on Foxp3+ Treg. However, so far we have used mouse models in which Foxp3+ Treg were completely depleted or absent. Therefore, it is unclear, if these data could explain the association seen in humans. To overcome this caveat, we will analyze human samples and use mouse models which recapitulate IL2RA gene mutations. Finally, we will use patient-specific gnotobiotic mice to assess the role of the intestinal microbiota. Therefore, this study will clarify the influence of an impaired Foxp3+ Treg function and an altered microbiota on the association of PSC with IBD. Thus, if successful this study could build the basis for future therapies aiming at restoring or promoting Foxp3+ Treg function in PSC and IBD.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 306: Primär Sklerosierende Cholangitis
• Co-Investigator: Dr. Penelope Pelczar