Cytokine Responsive Networks in Human Colonic Epithelial Organoids Unveil a Novel Molecular Stratification of Inflammatory Bowel Disease

Interactions between the epithelium and the immune system are critical in the pathogenesis of inflammatory bowel disease (IBD). In this study, we provide new insights into the gut immune-epithelial interactome by mapping the transcriptional landscape of human colonic epithelial organoids in response to different cytokines responsible for mediating canonical mucosal immune responses. By profiling the transcriptome of human colonic organoids treated with the canonical cytokines: interferon gamma, interleukin 13, 17A and tumour necrosis factor alpha with next generation sequencing we unveil previously unrecognised levels of shared and distinct regulation of epithelial function by different cytokines. An integrative analysis of cytokine responses in diseased tissue from IBD patients (n=1,084) reveals a new molecular stratification of IBD defined by gradients of cytokine responsive transcriptional signatures. Utilising a systems biology approach, we also detect signalling bottlenecks in cytokine responsive networks and highlight their translational potential as theragnostic targets in intestinal inflammation.