Fig. 4: The IL-22 regulated transcriptome correlates with colonic neutrophil accumulation which is associated with resistance to ustekinumab therapy in ulcerative colitis.

a Relative expression of neutrophil attracting chemokines in sigmoid biopsies of UC patients participating to the UNIFI study (n = 550) and non-IBD controls (n = 18) (Mann–Whitney test, two-tailed, no multiple testing correction applied), b relative expression of the neutrophil attracting chemokines in the colonic mucosa of healthy controls (HC), UC patients with inactive and active disease (GSE50971), c non-parametric correlation (Spearman two-tailed) between the enrichment score for the IL-22 transcriptional program and the chemokine gene set (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8), r = 0.54, 95% CI (0.48, 0.60), d IL-22 enrichment scores stratified by the neutrophil subscore of the Geboes histology score in the epithelium and lamina propria in colonic biopsies sampled from the UNITI cohort prior to starting ustekinumab. A higher subscore reflects an increase in neutrophil infiltration (for lamina propria 0: no increase, 1: mild but unequivocal increase, 2: moderate increase, 3: marked increase; for epithelium 0: none, 1: <5% crypts involved, 2: <50% crypts involved, 3: >50% involved) (Kruskal–Wallis test with Dunn’s multiple comparisons test, ****p < 0.0001, ***p < 0.001, line denotes median, n = 550) e bioinformatically computed proportion of neutrophils (Cibersort) in mucosal biopsies of UC patients participating in the UNIFI trial correlates positively (Spearman correlation, two-tailed) with the IL-22 enrichment score (single sample gene set enrichment analysis-ssGSEA), f bioinformatically computed proportion of neutrophils (Cibersort) in mucosal biopsies of UC patients participating in the UNIFI trial stratified by response (mucosal healing, week 8) to ustekinumab and healthy controls (HC, n = 18). UC: UC patients n = 358, R responders, NR non-responders, *p < 0.0001 for NR vs. R and for UC vs. HC, Mann–Whitney test, two-tailed, box & whiskers representing interquartile range and overall range, median value depicted with horizontal line, g non-parametric correlation (Spearman, two-tailed) between the enrichment score for the IL-22 transcriptional program and the enrichment score for the gene set defining UC1 and UC2 populations by Czarnewski et al. (r = 0.79), 95% CI (0.77,0.83), (FDR false discovery rate). Source data for a, c, d–g are provided as a Source Data file.