Spatiotemporal analysis reveals distinct inflammatory programs underlying chronic colitis.

Abstract

Inflammatory bowel disease (IBD) is a complex disorder that is often resistant to immunomodulatory treatments. Here, to understand how immune, epithelial, and stromal compartments are rewired during disease initiation and progression, we leveraged T cell transfer and Il10^-/- spontaneous colitis models, including anti-IL-12p40 intervention, and integrated time-course transcriptomic analyses at bulk, single-cell, and spatial resolution. These well-established models exhibited conserved features of chronic inflammation, including neutrophil infiltration, and impaired tissue regeneration. Comparison of murine transcriptional programs and human IBD datasets revealed neutrophil-associated inflammation and cytokine signaling as the most conserved pathways across species. We identified spatial heterogeneity in inflammatory modules and described three gene programs with differential spatial and temporal distributions, including one corresponding to tertiary lymphoid structures. When used together, these models recapitulate complementary aspects of human disease at both cellular and transcriptional levels. This high-resolution spatiotemporal atlas will guide future translational research aimed at optimizing therapeutic strategies for IBD.