HISTOPATHOLOGICAL CHARACTERIZATION OF A CHRONIC DSS-INDUCED MOUSE MODEL OF IBD WITH INTESTINAL FIBROSIS

Abstract RATIONALE Inflammatory bowel disease (IBD) comprises a group of intestinal disorders, including ulcerative colitis and Crohn's disease. Intestinal fibrosis, as result of chronic inflammation, is a common complication in IBD. High treatment failure rates associated with existing interventions indicate a high unmet need for more effective drugs to improve the management and outcomes of IBD. Consequently, translational animal models of IBD demonstrating chronic, progressive colonic fibrosis are important tools in preclinical drug discovery for IBD. The aim of the present study was to characterize intestinal histopathology in a chronic DSS-induced mouse model of IBD. METHODS Ten-weeks-old male C57BL/6JRj mice were randomized into study groups based on body weight and received 3 cycles of DSS (2.5 % w/v) in the drinking water (DSS-IBD) or normal water (CTRL). Terminal endpoints included colon morphometry and quantitative histological markers of inflammation and fibrosis assessed in proximal, middle and distal colonic segments. Using RNA sequencing, transcriptome signatures were profiled in the middle colon segment. RESULTS Compared to healthy controls, the chronic DSS-IBD mouse model demonstrated hallmarks of IBD, including mild-to-moderate weight loss and colonic hypertrophy. Histopathological analysis indicated increased deposition of inflammatory (CD45 and CD11b), fibrogenesis (alpha-smooth muscle actin) and fibrosis markers (collagen 1a1, Picrosirius red) in the middle and distal colon. Severe fibrosis was observed throughout all layers of the middle colon. Histological findings were supported by significantly upregulated gene expression markers of inflammation and fibrosis. CONCLUSIONS The DSS-IBD mouse is a translational preclinical model suitable for testing novel drug therapies for IBD with intestinal fibrosis.