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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270661 | GEO | 2025/07/16

REPOSITORIES: GEO

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Project description:The course of Crohn's disease (CD) is heterogeneous, confounding effective personalized therapy. A previous analysis of differences in gene expression between patients with versus without CD groups revealed 2 subsets of patients with CD -- a group characterized by genes more highly expressed in the colon (colon-like CD) and a group with increased expression of ileum marker genes (ileum-like CD). We compared differences in microRNAs between these groups. We performed genome-wide microRNA profile analyses of colon tissues from 18 adults with CD and 12 adults without CD (controls). We performed principal component analyses to associate levels of microRNAs with CD subtypes. Colonic epithelial cells and lamina propria immune cells were isolated from intestinal tissues and levels of microRNA 31 (miR-31) were measured by real-time quantitative PCR. We validated the differential expression of miR-31 between the subtypes by measuring miR-31 levels in an independent cohort of 32 adult patients with CD and 23 controls. We generated epithelial colonoid cultures from controls and patients with CD, and measured levels of miR-31 in crypts. We performed genome-wide microRNA profile analyses of formalin-fixed paraffin-embedded colon and ileum biopsies from 76 treatment-naive pediatric patients with CD and 51 controls (234 samples) and collected data on disease features and outcomes. In comparing miRNA expression profiles between 9 patients with colon-like CD and 9 patients with ileum-like CD, we identified 19 miRNAs with significant differences in levels. We observed a 13.5-fold difference in level of miR-31-5p between tissues from patients with colon-like vs. ileum-like CD (Padj = 1.43 x 10-18). Principal component analysis found miR-31 to be the top contributor to the variance observed. Levels of miR-31 were increased 60-fold in tissues from patients with ileum-like CD compared with controls (Padj = 2.59 × 10-51). We validated the differential expression of miR-31 between the subtypes in the independent set of tissues. Colonoids derived from patients with CD had significantly higher levels of miR-31 than colonoids derived from control tissues (day 2 P=.041 and day 6 P=.0095). Levels of miR-31 were significantly increased in colon tissues from pediatric patients with CD compared with controls (~7.8-fold, P=4.64 ×10-7) and in ileum tissues from patients with CD patients vs. controls (~1.5-fold, P=9.97 × 10-7). A high level of miR-31 in index biopsies from pediatric patients with only inflammation and no other complications at time of diagnosis associated with development of fibrostenotic ileal CD. We identified differences in miR-31 levels in colon tissues from adult and pediatric patients with CD compared with controls, and in patients with ileum-like CD compared with colon-like CD. Further studies are needed to determine the mechanisms by which miR-31 might contribute to pathogenesis of this subtype of CD, or affect response to therapy.

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

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