Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disease characterized by substantial heterogeneity in histologic activity, which is frequently uncoupled from clinical symptoms and endoscopic findings. Persistent microscopic inflammation is increasingly recognized as a critical determinant of relapse, therapeutic failure, and long-term disease outcomes, underscoring the need for molecular frameworks that align directly with tissue-level immune dysregulation. Interleukins (ILs) represent central regulators of mucosal immunity in UC, integrating innate and adaptive immune responses that govern epithelial injury and resolution. In this narrative review, we synthesize mechanistic, translational, genetic, and clinical evidence examining IL networks associated with histologic disease activity and persistence. Particular emphasis is placed on IL-23-driven inflammatory pathways, which consistently align with histologic severity, sustained microscopic inflammation, and resistance to immune resolution. In contrast, preserved IL-10-mediated regulatory signaling characterizes histologic remission and effective mucosal healing, whereas its insufficiency permits ongoing tissue-level inflammation. Downstream effector ILs, including IL-6, IL-1β, IL-8, and IL-17A, are discussed as mediators translating upstream immune imbalance into neutrophil recruitment and epithelial injury. Throughout this review, the term “prognostic” is used to denote alignment with histologic disease behavior rather than validated prediction of clinical outcomes. Collectively, the evidence supports the concept that coordinated IL patterns reflect distinct immunopathologic states underlying microscopic inflammation in UC, providing a biologically coherent framework for interpreting histologic activity and disease persistence beyond symptom-based assessment.

Background/Objectives: Deep remission, defined as the coexistence of endoscopic remission and histologic healing, has emerged as an advanced therapeutic target in ulcerative colitis (UC). However, reliable non-invasive biomarkers capable of accurately reflecting histologic inflammatory status remain limited. We aimed to evaluate the association between serum interleukin-10 (IL-10) concentrations and deep remission in UC and to assess its discriminatory performance. Methods: In this prospective single-center observational study, consecutive adult patients with ulcerative colitis undergoing clinically indicated colonoscopy were enrolled. Serum IL-10 concentrations were measured prior to endoscopy using an enzyme-linked immunosorbent assay. Histologic healing was defined as a Geboes score < 2.0, and deep remission as the coexistence of endoscopic remission and histologic healing. Associations were evaluated using Firth penalized logistic regression. Discrimination was assessed using receiver operating characteristic analysis with bootstrap internal validation (500 resamples). Results: Among 44 patients, 18 (40.9%) achieved deep remission. Serum IL-10 levels were significantly higher in patients with histologic healing compared with those with active histologic inflammation (p < 0.001). Log-transformed IL-10 was independently associated with deep remission in both univariable and multivariable models. The primary multivariable model demonstrated apparent good discrimination (apparent AUC 0.88; optimism-corrected AUC 0.85). Among patients in endoscopic remission, non-detectable IL-10 identified persistent histologic activity with high sensitivity (92.9%) and negative predictive value (94.4%), although these findings are exploratory. Conclusions: Serum IL-10 concentrations were independently associated with deep remission and showed potentially promising internally validated discriminatory performance within this cohort. These findings are hypothesis-generating and require external validation in larger cohorts before clinical application.

Background: Endoscopic remission is a central therapeutic target in inflammatory bowel disease (IBD); however, histologic inflammation may persist despite apparent mucosal healing. The biological mechanisms underlying endoscopic–histologic discordance remain incompletely defined. We aimed to characterize systemic cytokine patterns associated with discordant disease. Methods: In this prospective cross-sectional study, 59 patients with IBD undergoing clinically indicated colonoscopy underwent concurrent endoscopic and histologic assessment. Endoscopic remission was defined as a Mayo endoscopic subscore ≤ 1 for ulcerative colitis and SES-CD ≤ 2 for Crohn’s disease. Histologic healing was defined as a Geboes score < 2.0. Patients were classified into concordant remission, discordant disease (endoscopic remission with persistent histologic activity), and concordant active disease. Circulating interleukin (IL)-10, IL-23, and C-reactive protein (CRP) levels were compared across phenotypes using nonparametric methods. Associations with discordant disease were evaluated using Firth penalized logistic regression, and model discrimination was assessed using receiver operating characteristic (ROC) analysis with bootstrap internal validation. Results: Among 36 patients in endoscopic remission, 14 (38.9%) exhibited persistent histologic activity. Discordant patients demonstrated significantly lower IL-10 and higher IL-23 concentrations compared with concordant remission (both p < 0.001), whereas CRP did not differ significantly. Across phenotypes, IL-10 decreased progressively, while IL-23 increased stepwise (both p < 0.001). In multivariable analysis, lower IL-10 (OR 0.0014; 95% CI 0.000003–0.576; p = 0.032) and higher IL-23 (OR 16.94; 95% CI 1.90–151.32; p = 0.011) were independently associated with discordant disease. A model incorporating IL-10 and CRP demonstrated strong discrimination (AUC 0.925), with further improvement after inclusion of IL-23 (AUC 0.994), although these estimates should be interpreted with caution given the limited sample size. Conclusions: Endoscopic–histologic discordance is associated with a distinct systemic cytokine profile characterized by reduced IL-10 and elevated IL-23 levels, despite low CRP concentrations. These findings suggest incomplete restoration of immune regulatory balance and highlight the potential role of circulating cytokines, particularly IL-10, in identifying ongoing microscopic inflammation. These results are exploratory and hypothesis-generating and require validation in larger, prospective cohorts before clinical application.

Background: Persistent histologic inflammation may remain present in patients with inflammatory bowel disease (IBD) despite endoscopic remission. This study evaluated a clinically interpretable cytokine-based framework for risk stratification of residual histologic activity. Methods: In this prospective cohort study, 59 patients with IBD undergoing colonoscopy were included. Primary analyses were restricted to patients with ulcerative colitis (UC) in endoscopic remission (n = 31). Histologic activity was assessed using the Geboes score. Serum interleukin-10 (IL-10), interleukin-23 (IL-23), and C-reactive protein (CRP) were measured prior to endoscopy. Receiver operating characteristic (ROC) analysis and ROC-derived thresholds were used to evaluate biomarker performance and construct a cytokine-based risk stratification framework. Results: Among patients with UC in endoscopic remission, 14/31 (45.2%) demonstrated persistent histologic activity. IL-10 showed the strongest discriminatory performance for histologic activity (AUC 0.850), with a threshold < 3.9 pg/mL associated with sensitivity of 84.6% and specificity of 77.8%. Similar performance was observed using raw assay-reported IL-10 values (AUC 0.906). IL-23 showed limited overall discrimination (AUC 0.615). A combined IL-10/IL-23 framework stratified patients into progressively higher-risk subgroups, with histologic activity observed in 1/14 patients (7.1%) in the low-risk subgroup, 1/2 patients (50.0%) in the Intermediate A subgroup, 9/12 patients (75.0%) in the Intermediate B subgroup, and 3/3 patients (100%) in the high-risk subgroup (p < 0.001), although estimates for smaller subgroups should be interpreted cautiously. Reduced IL-10 levels were independently associated with histologic activity, whereas IL-23 primarily refined subgroup classification without substantially improving discrimination. Conclusions: An exploratory cytokine-based framework incorporating IL-10 and IL-23 may support risk stratification of residual histologic activity in UC during endoscopic remission. Larger multicenter studies are required to validate these findings and define their clinical utility.

Background: Ulcerative colitis (UC) is driven by a dysregulated mucosal immune response. Interleukins (ILs) orchestrate both pro-inflammatory and regulatory pathways, but their systemic profiles before therapeutic intervention remain unclear. Identifying early cytokine signatures may help stratify disease and guide precision immunotherapy. This meta-analysis aimed to characterise the serum interleukin landscape of treatment-naïve adult UC. Methods: A systematic review and meta-analysis was conducted in accordance with PRISMA. PubMed, Scopus, Embase and Web of Science were searched from database January 1995 to September 2025 for studies assessing serum interleukins in untreated UC versus healthy controls. Inclusion criteria: adults ≥18 years; confirmed UC; treatment-naïve at sampling; extractable mean, SD and sample size for IL-17A, IL-8, IL-23 or IL-10; and healthy controls. Exclusion criteria: paediatric cohorts, tissue-only cytokine assays, interventional studies, unavailable quantitative data, and studies on IL-6, IL-1β or IL-33 due to predefined heterogeneity. Standardised mean differences (SMDs) with 95 % confidence intervals (CIs) were pooled using random-effects models (DerSimonian–Laird). Between-study heterogeneity (I²) and publication bias (Egger’s test) were assessed. Analyses were conducted in IBM SPSS Statistics v30.0. Results: Eighteen studies met eligibility criteria (5 IL-17A, 5 IL-8, 4 IL-23, 4 IL-10). Compared with healthy controls, treatment-naïve UC showed: • IL-23: SMD 4.08 (95% CI 3.30–4.86; p<0.0001; I²=46%) • IL-17A: SMD 2.07 (1.48–2.66; p<0.0001; I²=60%) • IL-8: SMD 2.03 (1.27–2.79; p<0.0001; I²=0%) • IL-10: SMD −2.57 (−3.27—1.88; p<0.0001; I²=0%) These findings indicate a reproducible pattern of increased IL-23, IL-17A and IL-8, accompanied by reduced IL-10, in untreated UC across independent cohorts. Conclusion: Across available studies, treatment-naïve UC demonstrates consistent serum cytokine changes characterised by higher IL-23, IL-17A and IL-8 and lower IL-10 compared with healthy controls. This pattern may reflect upstream immune pathway activity in early disease and could support further evaluation of serum interleukins as potential non-invasive biomarkers in UC. References: 1. Liu X, Chen H, Shao L, et al. Updated cytokine profiling in ulcerative colitis. Front Immunol. 2023;14:1123456. 2. Lucaciu O, Copotoiu C, Copotoiu R, et al. Serum cytokine profiles in inflammatory bowel disease. J Immunol Res. 2021;2021:1-10. 3. Akpinar H, Yilmaz B, Dogruel N, et al. Serum IL-23 and IL-10 levels differentiate ulcerative colitis from controls. Eur J Gastroenterol Hepatol. 2020;32(8):1032-1040. 4. Zuo L, Li Y, Wang H, et al. Serum inflammatory cytokines in ulcerative colitis. World J Gastroenterol.2015;21(27):8271-8281. Conflict of interest: Dr. Martinos, Nikolaos: No conflict of interest Lazaris, Andreas C.: No conflict of interest Kroupis, Christos: No conflict of interest Kranidiotis, Georgios: No conflict of interest Stefanidis, Gerasimos: No conflict of interest Vasileiadis, Konstantinos: No conflict of interest Karakoidas, Christos Andreas: No conflict of interest Spyridon, Sgouros: No conflict of interest Thomopoulou, Georgia-Eleni: No conflict of interest

Background/Objectives: Histologic mucosal healing is an increasingly recognized therapeutic target in inflammatory bowel disease (IBD), yet reliable non-invasive correlates remain limited. This study aimed to evaluate circulating cytokine patterns as detectability-based immune signals across the spectrum of histologic disease activity. Methods: In this prospective cross-sectional study, 59 patients with IBD and 36 healthy controls were enrolled. Serum interleukin-10 (IL-10) and interleukin-23 (IL-23) were quantified by ELISA. Histologic activity was graded using the Geboes score. Associations were assessed using non-parametric methods and multivariable logistic regression with Firth penalization. Results: IL-10 demonstrated apparent separation across histologic states, primarily driven by reduced detectability in active inflammation, and was inversely associated with histologic severity. IL-10 remained associated with histologic status, although estimates should be interpreted cautiously. Detectable IL-23 was confined to moderate-to-severe inflammation and did not show graded discrimination, with interpretation limited by the small number of detectable observations. Conclusions: IL-10 and IL-23 exhibit complementary patterns, reflecting detectability-based regulatory signaling and a severity-dependent inflammatory threshold, respectively, without evidence of independent clinical utility for IL-23 in the present dataset. These findings are exploratory and require validation in larger prospective cohorts.