ECCO Grant Analysis of the tolerogenic role of the liver in controlling intestinal inflammation

Abstract

Abstract Background and Aims There is a close anatomical connection between the liver and the intestine. This connection is further highlighted by the association between Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease (IBD). Interestingly, PSC-associated IBD (PSC/IBD) presents with milder colitis symptoms compared to Crohn's disease and Ulcerative Colitis. We hypothesize that PSC has a protective impact on IBD, which is mediated by Foxp3+ regulatory T cells. This hypothesis is supported by our preliminary data. However, the mechanism by which PSC induces tolerance in the intestine remains unknown and answering this question is the aim of this proposal. Methods In Objective 1, we will test the hypothesis that changes in the intestinal microbiota mediate the protective effects of PSC on IBD. We will compare the intestinal microbiota in patients with PSC/IBD and IBD. This analysis will be complemented by functional experiments. Specifically, we aim to engraft germ-free wild type (WT) mice with fecal microbiota from PSC/IBD and IBD patients, as well as from Mdr2-deficient and WT mice. In these mouse models, we will analyze the effect of the microbiota on effector and regulatory T cells and on colitis susceptibility. In Objective 2, we will test whether changes in the composition of bile acids mediate the protective effects of PSC on IBD. To test this, we will deliver specific bile acids identified by us into Il10-deficient mice and analyze their impact on colitis severity and the intestinal T cell repertoire. Moreover, we will decipher how those bile acids impact the intestinal microbiota. Using in vitro assays, we will further test the direct effect of specific bile acids on T cell differentiation. Anticipated Impact Finally, our long-term aim is to understand how the liver induces immunological tolerance in the intestine. This knowledge could pave the way for new targeted therapies for inflammatory diseases.