Ulcerative colitis, but not Crohn's disease, displays demographically and clinically driven mucosal immune heterogeneity: implications for patient stratification.

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.