Identification of a Druggable Target That Predicts Postoperative Crohn's Disease Recurrence.
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Verstockt Sare, Schwärzler Julian, Willeit Peter, Bislenghi Gabriele, Meyer Moritz, Mayr Lisa, Machiels Kathleen, De Hertogh Gert, Lenfant Matthias, Scheffauer Laura, Grabherr Felix, Jans Deborah Sarah, Abdurahiman Saeed, Cleynen Isabelle, Jukic Almina, Zundel Luis, Moser Patrizia, Forer Lukas, Witsch-Baumgartner Martina, Ferrante Marc, Sabino João, D'Hoore André, Hess Michael, Kaser Arthur, Blumberg Richard S, Koch Robert, Le Bourhis Lionel, Hammoudi Nassim, Cazals-Hatem Dominique, Vermeire Séverine, Tilg Herbert, Allez Matthieu, Verstockt Bram, Adolph Timon E
Аннотация
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Collectively, our study identifies a druggable biomarker that improves the prediction of endoscopic CD recurrence, potentially guiding patient management and therapy in the future. One of the studied ICR cohorts was part of the REMIND (Groupe de Recherche sur les Maladies inflammatoires digestives) study, registered at ClinicalTrials.gov (NCT03458195).