Disease duration impacts intestinal gene expression profiles in Crohn’s disease but not in ulcerative colitis

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BACKGROUND: Disease duration is associated with lower treatment response and accrual of bowel damage in Crohn's disease (CD), but not in ulcerative colitis (UC). We aimed to understand intestinal transcriptomic changes associated with disease duration in CD and UC. METHODS: We analyzed intestinal tissue RNA sequencing data from two independent prospective cohorts of CD and UC patients, the Mount Sinai Crohn's and Colitis Registry (MSCCR; nCD = 498, nUC = 421), and the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD; nCD = 777, nUC = 440). We conducted differential expression analysis and subsequent pathway analyses of significantly up- or down-regulated genes, and examined cell type-specific expression of significant genes and pathways in ileal single-cell RNA sequencing data from CD patients (n = 18). We then assessed the association of significant pathways with treatment response in an infliximab-treated CD cohort. RESULTS: Significantly more genes were differentially expressed with increasing disease duration in CD compared to UC in both cohorts (MSCCR: nCD = 1472, nUC = 227; SPARC: nCD = 1248, nUC = 25; q-value < 0.05). A shared gene signature with 263 down- and 135 up-regulated genes in longer standing disease was identified. Pathway analyses revealed significant enrichment in pathways related to oxidative phosphorylation, mitochondrial dysfunction, cholesterol biosynthesis, liver X receptor/retinoid X receptor (LXR/RXR) activation, and protein modifications. Pre-treatment intestinal gene expression of four disease duration-related pathways were associated with non-response to infliximab. CONCLUSION: Disease duration influences intestinal gene expression in CD but significantly less so in UC. The identified pathways and genes may inform development of differing biomarkers and treatment strategies in shorter versus longer standing CD.

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