Comprehensive characterization of local cytokine signatures in ulcerative colitis in deep remission

Background: Ulcerative colitis (UC) is a chronic relapsing-remitting disease characterized by distinct molecular patterns and proinflammatory pathways. Through advances in therapy and monitoring-strategies, long lasting remission can be achieved in an increasing number of patients. Our aim was to investigate cytokine signatures in the interstitial microenvironment at protein and RNA level in UC patients showing deep remission (DR) to better understand the response to existing therapies. We hypothesize that the DR forms a distinct group that differs in its local intestinal cytokine profile from mild activity and non-IBD controls.

Methods: Two cohorts of UC patients along with non-IBD controls were characterized. We isolated interstitial fluid (IF) from the rectum and colonic mucosa of 14 UC patients in DR (UCEIS 0+Mayo 0), 11 in mild activity (UCEIS 1-4 and/or Mayo 1-4) and 25 non-IBD controls as part of the InFlame study (DRKS00031203). IF was used for multiplex immunoassays of 18 proinflammatory cytokines in the same way as plasma cytokines of this cohort. RNA isolates of colonic biopsies of the other cohort (IBDome) (DR n=22; mild activity n=14, non-IBD controls n=18) underwent bulk RNA sequencing.

Results: RNA expression of genes corresponding to IL-15, IL-17 and VEGF were significantly upregulated in DR versus non-IBD samples in colonic samples. 14 out of 18 (78%) genes were differentially expressed between DR and mild activity. Cytokine levels of IL-8, IL-10, IL-15, IL-16, IL-17, IFN-gamma and TNF-a were simultaneously upregulated in IF and RNA analysis. VEGF and IL-12B were only significantly upregulated at the protein level. DR and non-IBD controls could not be distinguished in PCA clustering based on interstitial cytokines or the corresponding gene expression. However, PCA clustering could separate DR from mild activity in both datasets. Within the mild activity group, patients with a higher clinical score clustered further away from DR. Overall, the characterization of disease activity in the interstitial space was more robust in the rectum than in the descending colon. At the plasma level, DR could not be distinguished from mild activity, and non-IBD controls.

Conclusion: Cytokines in the IF can reliably differentiate between UC in different activity stages. Furthermore, RNA expression of corresponding cytokines is correlating. Nevertheless, DR with stringent criteria resembles non-IBD controls more than UC with mild activity.

Publication History

Article published online:
04 September 2025