DOP81 Unaffected ileal transcriptomics in Crohn's disease is associated with the response to anti-TNF therapy

Background We aimed to assess the gene expression profiles of uninflamed small bowels in patients with Crohn’s disease (CD) to identify its accompanying molecular alterations. Methods We performed RNA sequencing of the uninflamed small bowel tissues obtained from 70 patients with ileal CD, and 9 patients with colon cancer (non-CD controls) during bowel resection. Differentially expressed gene (DEG) analyses were performed using DESeq2. Gene set enrichment, correlation, and cell deconvolution analyses were applied to identify modules and functionally enriched transcriptional signatures of CD. Results A comparison of CD patients and non-CD controls revealed that of the 372 DEGs, 49 protein-coding genes and 5 lncRNAs overlapped with the IBD susceptibility loci. The pathways related to immune and inflammatory reactions were upregulated in CD, while metabolic pathways were downregulated in CD. Compared with non-CD controls, CD patients had significantly higher proportions of immune cells, including plasma cells (P=1.15×10-4), and a lower proportion of epithelial cells (P=1.12×10-4). Co-upregulated genes (M14 module) and co-downregulated genes (M9 module) were identified in CD patients. The M14 module was enriched in immune-related genes and significantly associated with the responses to anti-TNF therapy. Intestinal tissue transcriptomic analysis of 3 independent cohorts, identified M14 module upregulation in non-responders at baseline, which was predictive of response with acceptable discrimination ability (area under the curve of 77~83%). Conclusion The differences in gene expression and cellular composition between CD patients and non-CD controls imply significant molecular alterations, which are associated with the response to anti-TNF treatment.