Aristeidis Kefas

The intestinal barrier is not a passive membrane but a layered and actively regulated interface. The epithelium and its tight junctions form the physical layer, which is complemented by a chemical layer of mucus and antimicrobial peptides, by the mucosal immune compartment, and by the resident microbiota. Together these layers separate a substantial microbial and dietary antigen load from the systemic circulation. Zonulin, identified as pre-haptoglobin-2, has been implicated in the reversible regulation of intestinal tight junctions while the broader concept of zonulin-related proteins (ZRP) encompasses proteins potentially associated with this regulatory system. Loss of barrier control has an established role in the pathogenesis of inflammatory bowel disease and has also been described in obesity, insulin resistance and atherosclerosis, with emerging evidence of an association with cardiovascular outcomes. Circulating ZRP have consequently attracted interest as potential biomarkers of intestinal barrier dysfunction and associated inflammatory and metabolic disturbances. However, uncertainty regarding the molecular specificity of commercial immunoassays complicates their biological interpretation and warrants further analytical and clinical validation. In this Review, we place zonulin within barrier physiology, appraise the clinical evidence in these disorders, and set out the analytical limitations that constrain its use as a biomarker.

Background and Aim: The therapeutic landscape for ulcerative colitis (UC) is rapidly evolving, with an increasing number of biologic agents available. This systematic review and meta-analysis synthesized randomized controlled trials (RCTs) data on biologic therapies for achieving key endoscopic and histologic endpoints in moderate to severe UC. Methods: A systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science and grey literature was conducted through November 2024. Separate meta-analyses were performed for induction and maintenance. A random-effects model was used to estimate relative risks (RR), with 95% confidence intervals (CI), and confidence in estimates was evaluated with the GRADE approach (Grading of Recommendation Assessment, Development and Evaluation). Results: We included 40 RCTs (13 therapies, 14,369 patients). Thirty-two trials provided data in induction and twenty-eight in maintenance. During induction, all biologic therapies, except mirikizumab and filgotinib 100 mg, demonstrated superiority over placebo (RR 2.02, 95% CI: 1.76–2.31, I² = 72%) for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 5.53, 95% CI: 3.78–8.09). For mucosal healing, all interventions were superior to placebo (RR 2.95, 95% CI: 2.11–4.13, I² = 61%), except filgotinib 100 mg. Risankizumab showed the highest efficacy (RR 10.25, 95% CI: 2.49–42.11). In maintenance, all therapies showed superiority over placebo for endoscopic improvement. For mucosal healing all therapies were superior to placebo, except risankizumab. Upadacitinib 30 mg showed the highest efficacy (RR 4.01, 95% CI: 1.81–8.87). Conclusions: Biologic and small-molecule therapies demonstrated substantial efficacy in achieving key endpoints. Standardized outcome definitions and further head-to-head RCTs are essential to strengthen confidence in our findings.