Paired transcriptomics reveals similarities between cytokine-stimulated organoids and ulcerative colitis epithelial responses

The intestinal epithelium mediates critical crosstalk between microbiota and immune cells in inflammatory bowel disease. While patient-derived intestinal organoids offer potential for modeling ulcerative colitis, their ability to replicate in vivo inflammation and utility for precision medicine remain unclear. By comparing transcriptomic profiles from microdissected colonic epithelium of ulcerative colitis patients with paired patient-derived organoids under various inflammatory conditions, we demonstrated that organoids established from uninflamed biopsies can effectively model epithelial inflammation. Combined IFNγ and TNF stimulation or a cocktail of pro- and anti-inflammatory signals induced inflammatory signatures matching in vivo ulcerative colitis patterns, including upregulation of interferon signaling, antigen presentation, and unfolded protein response pathways. Strong correlations between in vivo and in vitro expression of over 200 disease-relevant genes validate intestinal organoids as a suitable preclinical model. These findings substantiate intestinal epithelial organoids’ value for investigating ulcerative colitis pathogenesis and developing personalized medicine approaches.