Tu138 - A Rat Model of Chronic Colitis with Fibrosis Induced by Repeated Intrarectal TNBS Administration

Abstract Text: Intestinal fibrosis is a frequent complication associated with chronic inflammation in patients with Inflammatory Bowel Diseases (IBD) such as Crohn’s Disease (CD). While therapies exist for inflammation related to IBD, there are no approved therapeutics for intestinal fibrosis. Additionally, most animal models for IBD do not effectively model the chronic transmural inflammation or intestinal fibrosis observed in CD. With the goal of establishing a rodent model to test novel therapeutics for intestinal fibrosis, we induced colitis/inflammation with weekly intrarectal TNBS administration and tracked the progression of colitis and fibrosis. TNBS-administered animals demonstrated significantly reduced body weight gain and significant increases in Disease Activity Index scores compared to naive rats. Additionally, significant levels of colitis were observed by video endoscopy following TNBS, and terminal measures of colon weight:length ratios were significantly increased in diseased animals on Day 39. Colon samples were processed for histopathology analysis, showing significant increases in inflammation, necrosis/gland loss, and epithelial hyperplasia in TNBS-dosed animals. Importantly, erosions and ulcerations were successfully induced, with significantly increased mural (submucosal and tunica muscularis) inflammation. Granulation tissue and collagen I/III protein (IHC) deposition were associated with erosions and ulcerations; submucosal collagen I/III immunolabeling normalized to colon length was significantly increased in diseased animals. Collectively, these data show that repeated TNBS administration provides a validated approach to induce clinically-relevant features of intestinal mural fibrosis associated with chronic inflammation, allowing for assessment of novel therapeutics for this clinically unmet need.