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: 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/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.

Introduction: Histological remission is the most predictive endpoint in inflammatory bowel disease (IBD), yet repeated biopsies are invasive. Interleukins (ILs) are emerging biomarkers that may capture histology-aligned activity. We systematically evaluated IL-6, IL-23, IL-17A, IL-1β, IL-8, and IL-10 as diagnostic and prognostic biomarkers in ulcerative colitis (UC) and Crohn’s disease (CD). Methods: MEDLINE, EMBASE, and Web of Science were searched (January 1995–March 2025). Eligible studies quantified ILs in serum, plasma, stool, or tissue and reported diagnostic/prognostic outcomes against validated histology indices. Risk of bias was assessed with QUADAS-2 (diagnostic) and QUIPS (prognostic). Certainty was graded using GRADE. Due to assay heterogeneity, narrative synthesis was performed. Results: Sixty-four adult cohorts were included. Serum IL-6 (AUC 0.82–0.85; sensitivity/specificity ≈75–80%) and IL-23 (AUC 0.84–0.86; specificity up to 92%) consistently discriminated histological activity. Tissue IL-23/IL-17A aligned with neutrophils, crypt injury, and apoptosis, detecting subclinical inflammation and forecasting relapse (notably in ileal CD). IL-1β/IL-8 modestly reflected neutrophil-rich lesions. IL-10 inversely correlated with activity and higher remission levels predicted longer flare-free survival. Conclusion: IL-6 and IL-23 are the strongest serum biomarkers for histology-aligned activity; tissue IL-17A adds lesion-level resolution, while IL-10 provides prognostic value. Interleukin profiling complements CRP and fecal calprotectin, with its immediate role in precision-medicine stratification rather than replacement of current standards. Key Messages:Histological remission is the most reliable endpoint in inflammatory bowel disease but requires invasive biopsies. Interleukin profiling offers a biologically specific, noninvasive alternative that aligns with histological activity. Among candidate cytokines, serum IL-6 and IL-23 consistently show the strongest diagnostic performance, while tissue IL-17A enhances lesion-level resolution and IL-10 provides prognostic value for remission stability. Interleukin signatures therefore complement C-reactive protein and fecal calprotectin, supporting precision-medicine strategies for individualized monitoring and therapy optimization in IBD.