Modeling Chronic Colitis for Drug Development: Spatiotemporal Insights from Complementary Mouse Models of Ulcerative Colitis

Chronic inflammatory bowel disease presents a persistent challenge for translational drug development because disease drivers are neither static nor uniform. Immune signaling, epithelial responses, and tissue organization evolve as inflammation progresses, and these dynamics are not captured equally across commonly used preclinical models. As a result, therapeutic mechanisms that appear robust in one system may be attenuated, masked, or absent in another.

In a recent study by Fransson et al., published in Immunity (2026), the authors addressed this challenge by generating a high resolution, spatiotemporal atlas of chronic colitis across two widely used mouse models: CD45RB^hi adoptive T cell transfer colitis and Il10^-/- spontaneous colitis. By integrating longitudinal bulk RNA sequencing, single cell RNA sequencing, and spatial transcriptomics, the study tracked how immune, epithelial, and stromal compartments are progressively rewired during disease initiation and chronic progression.

Rather than treating colitis as a single inflammatory state, the authors show that distinct inflammatory programs emerge, expand, and persist over time, with both shared and model specific features. Across models, neutrophil associated inflammatory and cytokine responsive transcriptional programs represent some of the most consistently observed features between mice and human ulcerative colitis. However, the timing, cellular context, and spatial organization of these programs differ substantially depending on the underlying disease trigger.

In the CD45RB^hi T cell transfer model, inflammation follows a tightly coordinated trajectory dominated by adaptive CD4⁺ T cell activation, rapid induction of cytokine responsive gene programs, and synchronized expansion of innate immune populations. In contrast, Il10^-/- spontaneous colitis evolves more gradually and reflects loss of immune tolerance, with prominent involvement of B cells and plasma cells, progressive epithelial stress responses, and durable inflammatory programs that persist independently of acute cytotoxic T cell waves.

Spatial transcriptomic analysis further reveals that chronic colitis is regionally organized rather than uniform, with discrete epithelial and immune gene programs occupying defined tissue domains, including regions resembling tertiary lymphoid structures and epithelial antigen presentation niches. Importantly, these spatial patterns are observed across both models, demonstrating that tissue organization is an intrinsic feature of chronic inflammation rather than an artifact of experimental induction.

This Insight builds on those findings to examine how differences in immune drivers, chronicity, and spatial organization influence preclinical model selection and translational interpretation for ulcerative colitis drug development.

Choosing a Mouse Model for Preclinical IBD Drug Development

Selecting an appropriate mouse model for inflammatory bowel disease requires alignment between the therapeutic mechanism under investigation, the immune compartments involved, and the stage of disease being modeled. Induced systems often emphasize early inflammatory triggers, whereas spontaneous models more closely reflect chronic immune dysregulation, tissue remodeling, and durability of response.

Spatiotemporal profiling now makes it possible to distinguish which inflammatory programs arise early, which persist during chronic disease, and how these programs are organized within tissue. The comparison between CD45RB^hi T‑cell transfer colitis and Il10^-/- spontaneous colitis illustrates how model choice shapes both biological insight and translational confidence.

CD45RBhi T‑cell Transfer Colitis: Strengths for Defining Adaptive Immune Mechanisms

The CD45RB^hi CD4⁺ T‑cell transfer model is a widely used system for studying immune‑mediated intestinal inflammation. Transfer of naïve CD4⁺ T cells with limited regulatory T‑cell activity into immunodeficient recipients leads to progressive colitis driven by adaptive immune activation.

Spatiotemporal analysis shows a synchronized inflammatory trajectory characterized by early expansion of cytotoxic CD4⁺ T cells, coordinated recruitment of innate immune populations, and rapid induction of cytokine‑responsive transcriptional programs. These features make the model particularly powerful for dissecting adaptive immune drivers relevant to target validation.