Response to Anti-α4β7 Blockade in Patients With Ulcerative Colitis Is Associated With Distinct Mucosal Gene Expression Profiles at Baseline

Background: Improving treatment outcomes with biological therapy is a demanding current need for patients with inflammatory bowel disease. Discovery of pretreatment prognostic indicators of response may facilitate patient selection and increase long-term remission rates. We aimed to identify baseline mucosal gene expression profiles with predictive value for subsequent response to or failure of treatment with the monoclonal antibody against integrin alpha 4 beta 7, vedolizumab, in patients with active ulcerative colitis (UC). Methods: Mucosal expression of 84 immunological and inflammatory genes was quantified in RNA extracted from colonic biopsies before vedolizumab commencement and compared between patients with or without response to treatment. Significantly differentiated genes were further validated in a larger patient cohort and within available public data sets, and their functional profiles were studied accordingly. Results: In the discovery cohort, we identified 21 genes with a statistically significant differential expression between 54-week responders and nonresponders to vedolizumab. Our validation study allowed us to recognize a core mucosal profile that was preserved in both discovery and validation cohorts and in the public database. The applied functional annotation and analysis revealed candidate dysregulated pathways in nonresponders to vedolizumab, including immune cell trafficking, TNF receptor superfamily members mediating noncanonical NF-kappa B pathway, in addition to interleukin signaling, MyD88 signaling, and toll-like receptors (TLRs) cascade. Conclusions: Nonresponse to vedolizumab in UC is associated with specific pretreatment gene-expression mucosal signatures and dysregulation of particular immunological and inflammatory pathways. Baseline mucosal and/or systemic molecular profiling may help in the optimal stratification of patients to receive vedolizumab for active UC.

Automated summary

This study aimed to explore the baseline mucosal gene expression profiles in patients with active ulcerative colitis (UC) before vedolizumab treatment, in order to predict their response to the therapy. The results revealed specific differential gene expression in nonresponders to vedolizumab, indicating dysregulation of immunological and inflammatory pathways. These findings provide potential molecular markers for optimal treatment strategies in patients with active UC.