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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2025; 31(41): 110955
Published online Nov 7, 2025. doi: 10.3748/wjg.v31.i41.110955
Published online Nov 7, 2025. doi: 10.3748/wjg.v31.i41.110955
Growth differentiation factor 15 alters intestinal barrier and increases permeability: A new molecular target in inflammatory bowel disease
Antonio J Ruiz-Malagón, Marina Herraiz-Vilela, Raquel Serrano-Pino, Paula García-Ávila, Luis Díaz- Suárez, Ada DM Carmona-Segovia, Victor M Becerra-Munoz, Manuel Jiménez-Navarro, Isabel Arranz-Salas, Juan A López-Villodres, Alejandra Fernández-Castañer, Fernando Gutiérrez-Martínez, Francisco J Rodríguez-González, Raquel Camargo-Camero, Guillermo Alcaín-Martínez, Cristina Rodríguez-Díaz, Eduardo García-Fuentes, María J Sánchez-Quintero, Carlos López-Gómez, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, Málaga 29590, Spain
Antonio J Ruiz-Malagón, Marina Herraiz-Vilela, Raquel Serrano-Pino, Paula García-Ávila, Alejandra Fernández-Castañer, Fernando Gutiérrez-Martínez, Francisco J Rodríguez-González, Raquel Camargo-Camero, Guillermo Alcaín-Martínez, Cristina Rodríguez-Díaz, Eduardo García-Fuentes, Carlos López-Gómez, Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
Luis Díaz- Suárez, Unidad de Gestión Clínica de Farmacia, Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
Ada DM Carmona-Segovia, Victor M Becerra-Munoz, Manuel Jiménez-Navarro, María J Sánchez-Quintero, Unidad de Gestión Clínica Área del Corazón, Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
Ada DM Carmona-Segovia, Victor M Becerra-Munoz, Manuel Jiménez-Navarro, María J Sánchez-Quintero, Centro de Investigación en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid 28029, Spain
Manuel Jiménez-Navarro, Departamento de Medicina y Dermatología, Facultad de Medicina, Universidad de Málaga, Málaga 29010, Spain
Isabel Arranz-Salas, Juan A López-Villodres, Unidad de Gestión Clínica Intercentros (UGCI) de Anatomía Patológica, Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
Isabel Arranz-Salas, Juan A López-Villodres, Departamento de Fisiología Humana, Histología Humana, Anatomía Patológica y Educación Física y Deportiva, Facultad de Medicina, Univer
Eduardo García-Fuentes, Carlos López-Gómez, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid 28029, Spain
Co-first authors: Antonio J Ruiz-Malagón and Marina Herraiz-Vilela.
Co-corresponding authors: María J Sánchez-Quintero and Carlos López-Gómez.
Author contributions: Ruiz-Malagón AJ and Herraiz-Vilela M contributed equally to this manuscript and are co-first authors. López-Gómez C and Sánchez-Quintero MJ contributed equally to this manuscript and are co-corresponding authors. Ruiz-Malagón AJ, Herraiz-Vilela M, Serrano-Pino R, García-Ávila P, Carmona-Segovia AdM, Becerra-Muñoz VM, Arranz-Salas I, López-Villodres JA, Fernández-Castañer A, Gutiérrez-Martínez F, Rodríguez-González FJ, Rodríguez-Díaz C, Sánchez-Quintero MJ and López-Gómez C acquired the data; Díaz-Suárez L, Jiménez-Navarro M, Camargo-Camero R, Alcaín-Martínez G, García-Fuentes E, Sánchez-Quintero MJ, and López-Gómez C analyzed and interpreted the data; García-Fuentes E, Sánchez-Quintero MJ, and López-Gómez C designed the research study and drafted the work; Ruiz-Malagón AJ, Herraiz-Vilela M, Serrano-Pino R, García-Ávila P, Díaz-Suárez L, Carmona-Segovia AdM, Becerra-Muñoz VM, Jiménez-Navarro M, Arranz-Salas I, López-Villodres JA, Fernández-Castañer A, Gutiérrez-Martínez F, Rodríguez-González FJ, Camargo-Camero R, Alcaín-Martínez G and Rodríguez-Díaz C substantively revised the work for intellectual content. All authors gave their final approval to the submitted version of the article.
Supported by the Ministerio de Ciencia, Innovación y Universidades (Spain), No. IJCI-2017-31466; the Consejería de Salud y Familia de la Junta de Andalucía, Spain, No. PI-0244-2021, No. PI-0245-2021, and No. PI-0131-2020; FEDER funds/Consejería de Economía y Conocimiento, Empresas y Universidad, de la Junta de Andalucía (“A way to make Europe”) (“Andalucía se mueve con Europa”, University of Málaga, No. UMA20-FEDERJA-081 and No. UMA20-FEDERJA-074; the Consejería de Empleo, Empresa y Trabajo Autónomo de la Junta de Andalucía (Investigo program), No. MA-INV-0031-2022-04; Sara Borrell grant from the Instituto de Salud Carlos III (ISCIII), No. CD23/00117; PFIS contract from the ISCIII, No. FI23-00016; Juan Rodés contract from the ISCIII, No. JR22/00067; the Miguel Servet program from the ISCIII, No. CP23/00088; the Nicolas Monardes Program from the Consejería de Salud de la Junta de Andalucía (Spain), No. RC-0005-2020; the Consejería Salud y Familias-Junta de Andalucía, No. RH-0078-2021; and the University of Málaga (Incorporación de Doctores del II Plan Propio de Investigación, Transferencia y Divulgación Científica de la Universidad de Málaga en 2023); the Miguel Servet program from ISCIII, Spain, No. CP22/00050.
Institutional review board statement: All participants gave their written informed consent. The study protocol was carried out in accordance with the ethical guidelines of the Declaration of Helsinki, and the study was approved by the Málaga Provincial Research Ethics Committee, Málaga, Spain (No. PI0244-2021, No. ORG-Digest_2021, and No. PI-131-2020). All subjects were older than 18 years.
Conflict-of-interest statement: Fernández-Castañer A has received honoraria from AbbVie, Pfizer, Galapagos, and Janssen. Gutierrez-Martínez F has received honoraria from AbbVie, Pfizer, Galapagos, and Janssen. Rodríguez-González FJ has received honoraria from AbbVie, Pfizer, Galapagos, and Janssen; Alcain-Martínez G has received honoraria from AbbVie, Pfizer, Kern Pharma, Takeda, Galapagos, Amgen, MSD, and Janssen. The remaining authors have nothing to declare.
Data sharing statement: The datasets used and analyzed during the current study are available at Zenodo (https://zenodo.org/records/15124854) (DOI:10.5281/zenodo.15124854). Authors will grant access to files upon request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Carlos López-Gómez, PhD, Researcher, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina, IBIMA Plataforma BIONAND, c/Severo Ochoa 35, Málaga 29590, Spain. carlos.lopez@ibima.eu
Received: June 20, 2025
Revised: July 24, 2025
Accepted: September 24, 2025
Published online: November 7, 2025
Processing time: 140 Days and 0.3 Hours
Revised: July 24, 2025
Accepted: September 24, 2025
Published online: November 7, 2025
Processing time: 140 Days and 0.3 Hours
Core Tip
Core Tip: Mitochondrial dysfunction in intestinal mucosa is emerging as a novel mechanism in inflammatory bowel disease pathogenesis. In the present study, we show that growth differentiation factor 15 (GDF15), a marker of mitochondrial stress, is elevated in plasma from both ulcerative colitis and Crohn’s disease patients. Furthermore, levels of GDF15 correlate with markers of inflammation and intestinal permeability. In vitro assays using colonic organoids further showed that GDF15 alters the intestinal barrier, reducing the levels of zonula occludens 1 and claudin 1, and subsequently increases intestinal permeability. Targeting GDF15 may offer a promising strategy to prevent disruption of the intestinal barrier, potentially reducing immune overactivation.