Identification of a Druggable Target That Predicts Postoperative Crohn's Disease Recurrence.

Abstract

Molecular phenotyping of Crohn's disease (CD) trajectories after ileocolonic resection (ICR) enables the identification of evolving disease mechanisms and related biomarker discovery. Here, we aimed at identifying a pathogenic node with predictive value for endoscopic disease recurrence after ICR in CD. We performed unbiased transcriptomics of the postoperative ileum, comparing patients with an endoscopic Rutgeerts' score i0 vs those with ≥i2b (n = 36). A potential biomarker from this analysis was then validated at the protein level by quantitative confocal microscopy on tissue slides, and its value for predicting endoscopic recurrence at resection was assessed in 3 independent ICR cohorts (total N = 241). Functional implications and therapeutic potential were investigated in mouse enteritis models. Patients with endoscopic CD recurrence exhibited a transcriptional node characterized by reduced glutathione peroxidase 4 (GPX4) expression, which was confined to the intestinal epithelium. Reduced intestinal epithelial GPX4 expression was already observed at the time of ICR and predicted endoscopic recurrence in addition to established clinical risk factors in a patient-level meta-analysis. Intestinal epithelial GPX4 expression was a surrogate of its enzymatic activity, inversely correlated with a mucosal endoplasmic reticulum stress signature, but was unrelated to a GPX4 genetic variant associated with CD susceptibility, histologic severity of inflammation, or clinical risk factors for recurrence. In mice, reduced intestinal epithelial Gpx4 expression fueled endoplasmic reticulum stress and enabled severe enteritis, which was ameliorated by restoration of epithelial GPX4 expression with selenium supplementation. Collectively, our study identifies a druggable biomarker that improves the prediction of endoscopic CD recurrence, potentially guiding patient management and therapy in the future. This REMAND (Groupe de Recherche sur les Maladies inflammatoires digestives) study was registered at ClinicalTrials.gov (NCT03458195).