Journal Article Epublish
PubMed: 42851492 DOI: 10.3389/fimmu.2026.1965046
Ulcerative colitis, but not Crohn's disease, displays demographically and clinically driven mucosal immune heterogeneity: implications for patient stratification.
Front Immunol 17:1965046
Authors: Ángel De Prado, Irene Soleto, Carolina G de Castro, Montse Baldán-Martín, Alejandro G Del Hierro, Paula J Martínez, Elisa Arribas-Rodríguez, Fabio Suarez-Trujillo, Aida Fiz-López, Álvaro Martín-Muñoz, Alfredo J Lucendo, Cristina Rodríguez Gutiérrez, Ana Gutiérrez-Casbas, Eduardo Martín Arranz, Luis Bujanda, Iago Rodríguez-Lago, Ruth M de Francisco García, Eva Iglesias-Flores, Fernando Bermejo, Manuel Van Domselaar, María José García, Luis Fernández-Salazar, Francisco J García-Alonso, Xavier Calvet Calvo, Leyanira Torrealba, Iria Bastón-Rey, Héctor Pallares Manrique, Yolanda Ber Nieto, Eduardo Leo Carnerero, María Chaparro, Javier P Gisbert, David Bernardo
Affiliations
- Mucosal Immunology Lab, Institute of Biomedicine and Molecular Genetics from Valladolid (IBGM Universidad de Valladolid-CSIC), Valladolid, Spain.
- Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
- Flow Cytometry Unit, Institute of Biomedicine and Molecular Genetics (IBGM), Universidad de Valladolid-CSIC, Valladolid, Spain.
- Hospital General de Tomelloso, Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), CIBEREHD, Dept. de Gastroenterology, Ciudad Real, Spain.
- Hospital Universitario de Navarra, Instituto de Investigación de Navarra IdiSNAP, Pamplona, Spain.
- Hospital Universitario Dr Balmis de Alicante, Spain (Gastroenterology Department), ISABIAL, CIBEREHD, Alicante, Spain.
- Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz (IdiPaz), Gastroenterology Unit, Madrid, Spain.
- Department of Hepatology and Gastroenterology, Biogipuzkoa Health Research Institute - Donostia University Hospital, Universidad del País Vasco (EHU), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), San Sebastián, Spain.
- Hospital Universitario de Galdakao, Biocruces Bizkaia HRI, Gastroenterology, Vizcaya, Spain.
- Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
- Servicio de Aparato digestivo, Hospital Universitario Reina Sofía, IMIBIC, UCO, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Córdoba, Spain.
- Hospital Universitario de Fuenlabrada, Gastroenterology, Madrid, Spain.
- Hospital Universitario de Torrejón, Madrid, Spain.
- Hospital Universitario Marqués de Valdecilla and IDIVAL, Gastroenterology, Santander, Spain.
- Hospital Clínico Universitario de Valladolid, Universidad de Valladolid, Valladolid, Spain.
- Instituto de Investigación Biosanitaria de Valladolid (IBioVALL), Valladolid, Spain.
- Hospital Universitario Rio Hortega, Valladolid, Spain.
- Gastroenterology Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació, Parc Taulí (I3PT-CERCA), Sabadell, Catalunya, Departament de Medicina, Universitat Autònoma de Barcelona, CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
- Hospital Universitario Dr. Josep Trueta, Girona, Spain.
- Hospital Clínico Universitario de Santiago, Gastroenterology and Hepatology, Santiago de Compostela, Spain.
- Hospital Juan Ramón Jiménez, Huelva, Spain.
- Hospital San Jorge, Huesca, Spain.
- Hospital Universitario Virgen del Rocío, Sevilla, Spain.
- Centro de Investigaciones Biomédicas en Red de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain.
Abstract
BACKGROUND
Inflammatory bowel disease (IBD) encompasses Crohn's disease (CD) and ulcerative colitis (UC), two conditions with distinct immunopathological profiles despite shared inflammatory pathways. Comparative mucosal and systemic immune characterisation across disease subtypes and clinical variables remains limited. This study aimed to map leukocyte dysregulation in tissue and blood from patients with CD and UC compared to controls.
METHODS
Intestinal tissue and blood samples were obtained from 35 controls and endoscopically active IBD patients, including 54 with CD and 74 with UC. Leukocyte subsets were identified using a 29-marker spectral cytometry panel combining hierarchical gating with unsupervised clustering and dimensionality reduction. Immune composition was stratified by disease location, biological sex, age and endoscopic severity.
RESULTS
Hierarchical gating identified 41 mucosal and 42 circulating immune subsets; unsupervised clustering resolved 51 mucosal and 62 blood clusters. Both diseases displayed dysregulated mucosal immunity relative to controls but with distinct signatures: while CD was mainly T-cell biased, UC showed a mixed infiltrate with an increased relative proportion of NK, NKT and IgG + B-cells. UC also exhibited substantially greater immunological heterogeneity than CD when stratified by biological sex, age and severity, with effects predominantly confined to the mucosa. Ileal and colonic CD showed minor immunological differences.
CONCLUSIONS
UC displayed more prominent subgroup-associated mucosal immune heterogeneity than CD, particularly according to biological sex, age and endoscopic severity. These findings support tissue-resolved patient stratification in UC and highlight the limited sensitivity of blood-based biomarkers to reflect mucosal immune alterations.
MeSH
Cells, Colitis, Blood, Crohn Disease, Immunophenotyping, Immune System Diseases, Inflammatory Bowel Diseases, Cluster Analysis, Sex, Tissues, Mucous Membrane, Colitis, Ulcerative