Understanding heterogeneity in the pathogenesis and drug responses of ulcerative colitis through single-cell and spatial transcriptomics

Introduction: Ulcerative colitis (UC) is driven by mucosal inflammation and epithelial injury. Single cell RNA sequencing (scRNA-seq) enables high resolution profiling of immune, stromal and epithelial compartments in UC, whilst spatial transcriptomic (ST) and proteomic (SP) enable interrogation of cell-cell interactions, niche-specific expression profiles, and spatially restricted pathological processes. Although scRNA-seq, ST, and SP technologies have been rapidly evolved in the past ten years, relatively limited clinical applications have been demonstrated. This systematic review aims at comprehensively analysing current evidence in UC studies as an approach to identifying key limitations and proposing recommendations for strengthening future spatial research towards translations into clinics. Methods: A comprehensive search of Embase, Medline, and grey literature was conducted to identify studies using scRNA-seq or spatial transcriptomic or proteomic technologies in adult UC cohorts. Outcomes of interest included insights into disease pathogenesis or treatment response. Results: scRNA-seq studies revealed alterations across the innate and adaptive immune systems, as well as stromal and epithelial compartments in UC colonic tissue. Spatial studies provided insights into: (i) cellular composition of the UC microenvironment; (ii) inflammatory features in treatment responders versus non-responders; and (iii) ligand-receptor interactions as potential spatial biomarkers and therapeutic targets. Conclusion: Overall, single-cell and spatial studies are deepening our understanding of UC pathogenesis and treatment response. However, they are often limited by small sample sizes and heterogeneous UC phenotypes. Future studies should prioritise robust cohort design and careful sample stratification. This will be critical to generating mechanistically precise, reproducible, and clinically meaningful insights into the heterogeneity of UC pathogenesis and treatment response. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024601628.