Characterisation of the regulatory landscape in Crohn’s disease reveals miRNA-associated alterations that shape anti-TNF response (CIBER-120)

MicroRNAs (miRNAs) play a key role in regulating gene expression in Crohn’s disease (CD). Although several studies have identified miRNAs with biomarker potential, an exhaustive characterisation of the miRNAome in CD is still lacking. We performed the largest miRNA profiling effort to date to analyse miRNA variability across intestinal tissues, disease activity status, and infliximab treatment in CD. We generated 120 transcriptomic profiles from terminal ileum and left colon biopsies of 30 individuals (10 with active CD, 10 with quiescent CD, and 10 healthy controls). Half of the samples were cultured ex vivo with infliximab, and the remaining half with basal medium. Using variance analyses and linear mixed differential expression models, we explored the determinants of miRNAome variability in CD. We also generated infliximab response signatures to identify candidates and examine interactions between miRNAs and the coding transcriptome. Tissue location was the main factor in miRNA variability in CD, although with a relevant contribution from patient-specific effects. We identified nine miRNAs with treatment-responsive behaviour particular to the terminal ileum of active CD cases. Incubation with infliximab restored the miRNA-mRNA interactome, although the changes observed in active CD cases suggest that many miRNA alterations are not offset by treatment. Finally, we identified 13 miRNAs-mRNA pairs with potential involvement in the transcriptomic changes induced by anti-TNF treatment. A comprehensive miRNA profiling revealed significant intestinal tissue-specific variability and identified key alterations in the miRNA-mRNA interactome that might be involved in therapeutic response to anti-TNF in CD.