Crypt-Level Tight Junction Remodeling Is Associated with Disease Course and Clinical Outcomes in Inflammatory Bowel Disease

Background: Intestinal barrier dysfunction is a hallmark of inflammatory bowel disease (IBD), yet the clinical significance of tight junction (TJ) remodeling remains unclear. We investigated whether alterations in the expression and localization of key TJ proteins are associated with disease activity and clinical outcomes in IBD. Methods: This retrospective, single-center study included patients with Crohn’s disease (CD; n = 100), ulcerative colitis (UC; n = 120), and healthy controls (n = 80). Immunohistochemistry was used to assess the expression and subcellular localization of occludin and claudin-1 separately in surface (SE) and crypt epithelium (CR), with staining classified as predominantly membranous (regular) or cytoplasmic (irregular). The primary endpoint was IBD-related hospitalization. Secondary endpoints included surgery, initiation of biologic therapy, and clinical relapse. Logistic and Cox regression models were applied, and longitudinal changes were assessed in paired biopsies. Results: Both occludin and claudin-1 were dysregulated in active disease, showing increased expression and cytoplasmic redistribution compared with remission and controls. TJ alterations were more pronounced in the CR and correlated with clinical, endoscopic, and histological activity. In CD, occludin CR overexpression was independently associated with hospitalization (aOR 1.010; p = 0.05) and surgery (aHR 1.013; p = 0.005), while irregular occludin CR staining was associated with initiation of biologic therapy (aOR 3.48; p = 0.03). In UC, increased occludin CR levels and irregular CR staining were associated with IBD-related hospitalization in multivariable analyses (aOR 1.014; p = 0.035 and aOR 2.78; p = 0.032, respectively). Higher occludin CR levels identified UC patients at increased risk of clinical relapse (aHR 1.012; p = 0.002). In paired biopsies (n = 127), TJ architecture—particularly in the CR—improved over time, with reduced expression and a shift toward membranous localization, most prominently in bio-experienced patients. Conclusions: TJ remodeling, particularly crypt-level occludin dysregulation, is associated with disease activity and clinical outcomes, capturing a clinically relevant dimension of epithelial barrier dysfunction in IBD.