Spatiotemporal analysis reveals distinct inflammatory programs underlying chronic colitis

Introduction

Despite recent advances in therapies for Inflammatory Bowel Disease (IBD) (Crohn’s Disease and Ulcerative Colitis), many patients still show a lack of response/loss of response to prescribed treatments and require surgical interventions to control their disease.  In this article, Fransson et al. describe their work to enhance the understanding of IBD pathogenesis through investigating the temporal and spatial nature of transcriptional changes occurring during disease progression in both animal models and patients. The authors hope that their disease “atlas” constructed from these data will support the development of improved treatment and better clinical outcomes for IBD patients.

Main Points

• Bulk RNAseq, scRNA sequencing and spatial analysis demonstrated conserved transcriptional changes in models of chronic colitis (Il10^-/- mice and T cell transfer to SCID mice or to Rag2^-/- mice) with upregulation of genes controlling inflammation and proliferation and downregulation of genes controlling tissue regeneration.
• Although there was commonality in the gene sets being regulated, each model had a unique time course for the colitis-associated transcriptional changes; also, in the response to treatment (in relation to the T cell transfer models). Some proinflammatory transcriptional change were conserved also in DSS-induced acute colitis, with 853 differentially expressed genes (DEGs) common to all models.
• Comparison of the mouse model DEGs that had human homologues, with DEGs identified in ulcerative colitis patients (vs. healthy controls), identified a subset of 138 genes, including tnf, ifng, il1b, mmp3, cxcl10. Immune cells were a main source of upregulated pro-inflammatory gene expression.
• In T cell transfer models, 4 genes showing time-dependent increase in expression were common to both SCID and Rag2^-/- (Ccr5, Ccr6, Ccl5, Gzmk).
• Analysis of Il10^-/- mice identified B cell-specific transcriptional changes in germinal centre cells and a B cell subpopulation associated with mucosal damage/healing (first identified by the authors in mice recovering from DSS-induced colitis). Upregulation of genes associated with tertiary lymphoid structures was also a late event in T cell transfer colitis.
• Neutrophils were a particular source of upregulated genes. Colitis progression was associated with altered transcriptional profiles of neutrophils, to a cytotoxic genotype (Sell^hi Cxcl3^hi) from an immunosuppressive one (Siglecf^hi).
• Spatial transcriptomics revealed regional differences in gene expression between proximal and distal colon. Specific gene clusters were associated with tertiary lymphoid structures (TLS), immune and stromal cells and epithelial cells and fibroblasts. Some gene grouping demonstrated no specific localisation.

Conclusion

The authors provide a comprehensive analysis of the transcriptional changes that accompany the progression of chronic colitis in animal models.  It defines groups of DEGs that are conserved in the different models and in human disease, highlighting potential areas for the focus of developing new therapies. The importance of TLS in fibrostenosis in Crohn’s disease was recently highlighted [DOI: 10.1002/path.70019].

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