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

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Crohn's disease (CD) recurrence after ileocolonic resection (ICR) necessitates better predictive biomarkers.
• Molecular phenotyping can reveal disease mechanisms and identify therapeutic targets.

Purpose of the Study:

• Identify a molecular node predicting endoscopic disease recurrence post-ICR in CD.
• Validate a potential biomarker for disease recurrence.

Main Methods:

• Unbiased transcriptomics of postoperative ileum in CD patients with varying recurrence scores.
• Protein-level validation of a biomarker using quantitative confocal microscopy.
• Assessment of predictive value in three independent ICR cohorts (n=241).
• Functional investigation in mouse enteritis models.

Main Results:

• Reduced intestinal epithelial Glutathione peroxidase 4 (GPX4) expression characterized patients with CD recurrence.
• Low GPX4 expression at ICR predicted endoscopic recurrence, independent of clinical factors.
• GPX4 expression correlated inversely with ER stress and was not linked to genetic variants or inflammation severity.
• Reduced GPX4 fueled ER stress and enteritis in mice, which was reversed by selenium supplementation.

Conclusions:

• A druggable biomarker, intestinal epithelial GPX4, improves prediction of CD recurrence post-ICR.
• This finding may guide future patient management and therapeutic strategies.