Functional characterization of Zonulin, a positive regulator of intestinal epithelial permeability, in inflammatory bowel disease (IBD).

The project involves an in-depth study of the functional role of Zonulin in inflammatory bowel disease (IBD), a disease characterized by chronic inflammation of the gastro-intestinal tract. We will also study its possible use as target for future treatment options (translational research).

Inflammatory bowel disease (IBD) (Crohn's disease (CD) and ulcerative colitis (UC)) is a multifactorial disease characterized by a chronic inflammation of the gut. Although an increased intestinal permeability (IP) has been shown to play a central role in its pathogenesis1, it is unclear whether this dysfunction is a cause or consequence of the mucosal inflammation. We have previously shown that the HP2 allele of the Haptoglobin (HP) gene is overrepresented in CD and UC patients versus healthy controls2. The same is observed in other immune diseases like Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Type 1 Diabets (T1D). Interestingly, it was discovered only recently that the pre-form of human HP2 (pre-haptoglobin-2, pre-HP2), which first was thought to be just an inactive precursor, is actually Zonulin. Zonulin is an important regulator of intestinal permeability (IP). It modulates the small intestinal tight junction (TJ) permeability, and is found upregulated in different immune diseases like Celiac disease and T1D. We hypothesize on a role for Zonulin in IBD pathogenesis. The general aim of this project is therefore to study if and how Zonulin expression is correlated with intestinal permeability, and if we can target it for treatment of IBD.