P154 Histological disease progression and ALK5i therapeutic efficacy in a chronic DSS-induced mouse model of IBD with intestinal fibrosis

Abstract

Abstract Background Inflammatory bowel disease (IBD) comprises a group of intestinal disorders, including ulcerative colitis and Crohn's disease. Intestinal fibrosis, as a result of chronic inflammation, is a common complication in IBD. Many patients do not respond or do not have a sustained response to existing treatments, highlighting the large unmet need for more effective drugs in the management of IBD. Translational animal models demonstrating chronic, progressive colonic fibrosis are important tools in preclinical drug discovery for IBD. The aim of the present study was to characterize histological disease progression and therapeutic efficacy of a TGF-β type I receptor inhibitor (ALK5i) in a novel chronic DSS-induced mouse model of IBD. Methods 10 week old male C57BL/6JRj mice received 3 cycles of DSS (2% w/v) administration in the drinking water (DSS-IBD) or normal water (CTRL). Study groups were terminated at week 1, 3 or 6. Groups terminated at week 6 received twice daily oral dosing with vehicle or ALK5i (30 mg/kg, BID). Terminal endpoints included distal colon morphometry, quantitative histological markers of inflammation and fibrosis as well as colon transcriptomics. Results Compared to healthy controls, the chronic DSS-IBD mouse model demonstrated clinical and histological hallmarks of progressive IBD, including mild-to-moderate weight loss, colonic hypertrophy with sustained inflammation and fibrosis in the mucosa and submucosa areas. ALK5i treatment increased colon weight/length ratio while significantly reducing fractional (%) area of alpha-1 type I collagen in the colonic mucosa and submucosa. The histopathological phenotype was supported by corresponding regulations in gene expression markers of colonic inflammation including ptprc (cd45), tnf and nos2. Alk5i therapy did not influence gene expression markers of fibrosis, suggesting that improved relative (%) levels of collagen were driven by Alk5i-stimulated tissue volume increases. Further studies are needed to establish if TGF-beta inhibitors have antifibrotic effects in the chronic DSS model of IBD complicated by fibrosis. Conclusion The DSS-IBD mouse model is a preclinical model with features of progressive IBD suitable for testing novel anti-fibrotic drug therapies targeted for IBD patients.