Abstract Background Clinical success of therapies in inflammatory bowel disease (IBD) is capped at a 30-40% remission rate after one year, highlighting the need for new therapeutics. Robust preclinical in vivo models are essential to investigate novel drugs in IBD. Several studies describe rodent models recapitulating certain features of ulcerative colitis (UC) and Crohn’s disease (CD). However, systematic cross-model characterization with shared and translatable endpoints is limited. Here, we aim to establish and compare different in vivo IBD models with harmonized pathological, molecular and imaging readouts to improve understanding of IBD pathogenesis and accelerate drug discovery. Methods We established and characterized four in vivo models of colitis: acute DSS, anti-CD40, CD45RBhi CD4+ T cell transfer and chronic DSS. Shared endpoints across models included the assessment of body weight loss, gross pathology, histology, local and systemic inflammation, and bulk colon RNA-sequencing (RNA-seq). Fibrosis and colon wall thickening were determined by Picrosirius Red assessment with AI segmentation and Magnetic Resonance Imaging (MRI), respectively. Finally, standard of care (SoC) treatments in IBD were used to confirm pharmacological responsiveness. Results Our systematic comparison of endpoints and disease kinetics highlighted the complementary features of each of the models that reflect the complexity of IBD patients. Acute DSS produced transient self-resolving inflammation mirroring UC flares with major innate immune involvement. Anti-CD40 induced UC-like mucosal injury driven by innate cytokines with colon immune cell infiltration and goblet cell loss. CD4+ T cell transfer recapitulated Crohn’s features including transmural inflammation, with small and large intestine involvement. Chronic DSS showed relapsing-remitting inflammation with submucosal thickening and increased collagen deposition. RNA-seq highlighted shared and model-specific pathways across models overlapping with patient datasets. MRI-based wall thickness measurements correlated with disease stage and terminal readouts, enabling monitoring on live animals. Notably, SoC treatments differentially improved inflammation across models. Conclusion This integrated platform delivers reproducible kinetics, inflammatory and fibrotic readouts, and SoC validation. Together, these models capture distinct features of UC and CD, enabling selection of the most appropriate in vivo setting to investigate novel targets and accelerating preclinical-to-clinical translation for next-generation IBD therapeutics. References: Read S, Powrie F. Induction of inflammatory bowel disease in immunodeficient mice by CD45RBhigh CD4+ T cells. Immunol Rev. 2001;182:168-176. Wirtz S, Neurath MF. Mouse models of intestinal inflammation. Cell Mol Gastroenterol Hepatol. 2017;3(2):166-176. doi:10.1016/j.jcmgh.2016.12.003. Uhlig HH, McKenzie BS, Hue S, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006;25(2):309-318. doi:10.1016/j.immuni.2006.05.017. Conflict of interest: Dr. Preite, Silvia: AstraZeneca employee and and may have stocks/stock options. Adelöf, Julia: AstraZeneca employee and and may have stocks/stock options. Bretin, Alexis: AstraZeneca employee and and may have stocks/stock options. Burgueno, Juan: Employee at AstraZeneca Sorini, Chiara: AstraZeneca employee and and may have stocks/stock options. Bölükbas, Deniz: AstraZeneca employee and and may have stocks/stock options. Preti, Max: AstraZeneca employee and and may have stocks/stock options Hofving, Tobias: AstraZeneca employee and and may have stocks/stock options. Eyassu, Filmon: AstraZeneca employee and and may have stocks/stock options. Peris, Eduard: AstraZeneca employee and and may have stocks/stock options. Markou, Thomais: AstraZeneca employee and and may have stocks/stock options. Strömberg, Anneli: AstraZeneca employee and and may have stocks/stock options. Ulenius, Lisa: AstraZeneca employee and and may have stocks/stock options. Das, Devashish: AstraZeneca employee and and may have stocks/stock options. Bidar, Abdel: AstraZeneca employee and and may have stocks/stock options. Sand, Elin: AstraZeneca employee and and may have stocks/stock options. Piras, Antonio: AstraZeneca employee and and may have stocks/stock options. Ort, Tatiana: AstraZeneca employee and and may have stocks/stock options. Borde, Annika: AstraZeneca employee and and may have stocks/stock options. Birrell, Mark: AstraZeneca employee and and may have stocks/stock options.
Preite et al. (Thu,) studied this question.