Keratinocytes as driver of Crohn’s disease associated fistulas

Abstract Background and aims Perianal fistulas are a debilitating complication of Crohn’s disease (fCD) with limited treatment options and poorly understood mechanisms. The lack of robust experimental models has long hindered progress in understanding fistula formation and developing targeted therapies. Through a previous ECCO Pioneer Award of our team, we established a novel fistulizing gut model in human xenografts. By inducing psoriatic dermatitis and gut mucosal inflammation, we reliably generated enterocutaneous fistulas that closely mimic human disease. We demonstrated that fistula tracts are formed by mouse basal keratinocytes and found resident keratinocytes in human gut samples from our model system and fCD patients. Based on our preliminary results we hypothesize that in the gut mucosa of fCD patients, fistula tracts are initiated, formed and progress by “wound healing mechanisms” activated in resident basal keratinocytes. Aims (1) To establish a keratinocyte-driven perianal disease model (KDPD), (2) To study the role of gut microbiome in the pathogenesis of KDPD, (3) To demonstrate the role of keratinocytes-driven mechanisms and microbiome in the pathogenesis of human fCD. Methods Murine colitis and perianal psoriasis model systems will be used to study keratinocytes-driven perianal disease. Manipulation of the gut microbiome will enable us to better understand its role in fCD. Rectal and anal biopsy samples from UC, CD and fCD patients and fresh curettage material will be screened for keratinocytes and analyzed using advanced multi-omics technologies. Anticipated impact By the developing KDPD model in mice and eliminating the need for human fetal tissue, our model represents a significant ethical and practical advancement in experimental research of fCD. By demonstrating the relevance of this novel disease mechanism in fCD patients. Basal keratinocytes and wound healing mechanisms will open a new field for the development of novel therapeutic targets to be tested in the KDPD model and in patients.