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, 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 or JAK-inhibitor therapies. Patients were assessed at 14 weeks to determine if they had achieved an endoscopic response, based on the SES-CD and the Mayo endoscopic sub-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 CD ustekinumab, 30 UC anti-TNF, 30 UC vedolizumab, and 30 UC tofacitinib), along with 30 healthy controls for comparison. Metabolomics analysis identified distinct baseline metabolic and lipoprotein signatures with significantly altered levels (p 0.05) in baseline urine and serum samples of subsequent responders compared with non-responders. Moreover, based on ROC curve analysis, several biomarkers showed good sensitivity and specificity for distinguishing responders from non-responders before each treatment (Figures 1 and 2). Only 12 of the 53 identified predictive biomarkers were shared between two treatment groups. The comparison with healthy controls revealed that, in some cases, responders showed a more preserved, healthy-like immunometabolic profile before treatment, whereas in others, response was associated with a more metabolically activated state that differed from healthy physiology, suggesting that each therapy depends on different metabolic conditions to achieve efficacy. Conclusion Baseline metabolic stratification may be a powerful predictor of treatment response in IBD, distinguishing subsequent responders from non-responders to biologic and JAK-inhibitor therapies. Although further validation is required, this study represents an important step toward the personalized selection of targeted therapies for patients with IBD. Conflict of interest: Ms. Martínez González, Paula Julia: No conflict of interest Baldan-Martin, Montserrat: No conflict of interest Gil-Redondo , Ruben: No conflict of interest Soleto, Irene: No conflict of interest Orejudo, Macarena: No conflict of interest Ramírez, Cristina: No conflict of interest Lucendo, Alfredo: No conflict of interest Rodríguez, Cristina: No conflict of interest Gutiérrez Casbas, Ana: No conflict of interest Martin Arranz, Eduardo: Personal Fees: Olympus and Janssen Non-financial Support: Support for conference attendance, education or research from Abbvie, Pfizer, Janssen Bujanda, Luis: Not Rodríguez-Lago, Iago: Financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Alfasigma, Biogen, Chiesi, Faes Farma, Ferring, Fresenius Kabi, Galapagos, Johnson & Johnson, Eli Lilly, Mirum Pharmaceuticals, Merck, Pfizer, Roche, Takeda, and Tillotts Pharma. Research support from AbbVie. Supported by a research grant from Gobierno Vasco-Eusko Jaurlaritza (Grant No 2020111061 and 2023222006). De Francisco Garcia, Ruth Maria: No conflict of interest Iglesias Flores, Eva: has served as a speaker, consultant and advisory member for or has received research funding from AbbVie, Janssen, Takeda, Gillead, Celgene, Pfizer, Lilly, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, and Adacyte, Bermejo San Jose, Fernando: No conflict of interest Van Domselaar, Manuel: No conflict of interest García, María José: Other: MJ García has received financial support for travelling and educational activities from Janssen, Pfizer, Abbvie, Takeda and Ferring. Fernández-Salazar, Luis: My institution has been granted by Johnosn & Johnson for investigation. I have been financed to attend IBD meetings by Ferring, Lilly and Sandoz. De Prado Santos, Ángel: No conflict of interest. Calvet Calvo, Xavier: Xavier Calvet has received grants for research from AbbVie Janssen, Kern and Vifor, and fees for advisory board services form Abbvie, MSD, Takeda and Vifor. He has also given lectures for Abbvie, Janssen and Takeda. Torrealba Medina, Leyanira: No conflict of interest Bastón Rey, Iria: Personal Fees: Iria Bastón Rey has received financial support for travelling and educational activities from or has served as an advisory board member for Abbvie, Johnson & Johnson, Takeda, Pfizer, Alfasigma, Ferring, Faes Farma and Otsuka Pharmaceutical and Adacyte. Pallarés-Manrique, Héctor: No conflict of interest Ber, Yolanda: Non Leo, Eduardo: No conflict of interest Casanova, María José: María José Casanova, has received education funding from Pfizer, Takeda, Janssen, MSD, Dr. Falk, Shire, Ferring, Galápagos and Abbvie, and research funding from Lilly. Millet, Óscar: No conflict of interest Mato, Jose María: No conflict of interest Chaparro, María: Grants: Pfizer, Janssen, Biogen, Abbvie, Lilly Personal Fees: Pfizer, Faes, Lilly, Abbvie, Janssen Gisbert, Javier: Grant: MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos/Alfasigma, Lilly, Sanofi, STADA, Teva, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, Italfarmaco, and Vifor Pharma. Personal Fees: MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos/Alfasigma, Lilly, Sanofi, STADA, Teva, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, Italfarmaco, and Vifor Pharma. Other: MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene/Bristol Myers, Gilead/Galapagos/Alfasigma, Lilly, Sanofi, STADA, Teva, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Norgine, Italfarmaco, and Vifor Pharma.
González et al. (Thu,) studied this question.