P0093 Identification of metabolic predictive biomarkers of response to Inflammatory Bowel Disease treatment
Authors: Martínez González P J , Baldán-Martín M , Gil-Redondo R , Soleto I , Orejudo M , Ramírez C , Alfredo J L , Rodríguez C , Gutiérrez-Casbas A , Martín-Arranz E , Bujanda L , Rodríguez-Lago I , De Francisco R , Iglesias-Flores E , Bermejo F , Van Domselaar M , García M J , Fernández-Salazar L , Jesús B , Calvet X , Torrealba L , Bastón-Rey I , Pallares Manrique H , Ber Nieto Y , Leo-Carnerero E , Casanova M J , Millet O , Mato J M , Chaparro M , Gisbert J P ,   *Authors share co-senior authorship
Published: January 2025

Abstract

Background
The therapeutic goal in inflammatory bowel disease (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), is the control of the inflammatory process frequently through biologic and JAK-inhibitor therapies, which are generally expensive and may induce adverse effects. Unfortunately, only one-third of patients respond to these treatments, and there are no markers that accurately predict this response. The aim of this study was to identify potential serum and urinary metabolic biomarkers predictive of IBD response to different drugs at baseline (before treatment), which could facilitate the selection of the most appropriate therapy for each patient.

Methods
A prospective multicenter study was conducted including CD and UC patients who initiated biologic (anti-TNF, ustekinumab or vedolizumab) or JAK-inhibitor (tofacitinib) therapies. Patients were assessed at 14 weeks to determine if they had achieved an endoscopic response, based on the SES-CD and on the endoscopic sub-score of the Partial Mayo Score. The analyses of the serum and urine metabolome, along with the deconvolution of the serum lipoprotein profile into 110 subfractions, were performed using nuclear magnetic resonance for a quantitative differential analysis comparing the baseline serum samples of responders and non-responders.

Results
A total of 150 patients were included (30 CD anti-TNF, 30 UC anti-TNF, 30 CD ustekinumab, 30 UC vedolizumab and 30 UC tofacitinib). Metabolomics analysis identified 55 potential predictive biomarkers of IBD treatment response (11 common and 44 drug-specific), with significantly altered levels (p&lt;0.05) in the baseline urine and serum samples of subsequent responders compared to non-responders (Figure 1). Moreover, based on ROC curves, some of these biomarkers showed good sensitivity and specificity for distinguishing between responders and non-responders before treatment (Figure 2). Finally, metabolite set enrichment analysis identified different biological pathways associated with the response to each of the treatments for IBD. Among the common ones, the citrate cycle and the metabolism of butanoate, alanine, aspartate, glutamate, and arginine stood out.

Conclusion
The present study represents a step towards personalized medicine in the selection of targeted therapies for IBD patients, addressing an important unmet need. Although further validation is needed, we have identified serum and urinary metabolic biomarkers with the potential to predict response to biologic and JAK-inhibitor therapies.