The TNF^ΔAREmouse as a model of intestinal fibrosis

ABSTRACTBackground & AimsCrohn’s disease (CD) is a highly morbid chronic inflammatory disease. The majority of CD patients also develop fibrostenosing complications. Despite this, there are no medical therapies for intestinal fibrosis. This is in part due to lack of high-fidelity biomimetic models to enhance understanding and drug development. There is a need to developin vivomodels of inflammatory bowel disease-related intestinal fibrosis. We sought to determine if the TNFΔAREmouse, a model of ileal inflammation, may also develop intestinal fibrosis.MethodsSeveral clinically relevant outcomes were studied including features of structural fibrosis, histological fibrosis, and gene expression. These include the use of a luminal casting technique we developed, traditional histological outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNFΔAREmice as well as in cohorts of numerous ages.ResultsAt ages of 24+ weeks, TNFΔAREmice develop structural, histological, and genetic changes of ileal fibrosis. Genetic expression profiles have changes as early as six weeks, followed by histological changes occurring as early as 14-15 weeks, and overt structural fibrosis delayed until after 24 weeks.DiscussionThe TNFΔAREmouse is a viable and highly tractable model of intestinal fibrosis. This model and the techniques employed can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis.