Claudins in Gastrointestinal Disorders

Abstract

The gastrointestinal (GI) tract relies on a dynamic epithelial barrier, with claudins serving as pivotal determinants of paracellular permeability and cellular signaling. Dysregulation of claudins has been increasingly implicated in the pathogenesis of diverse GI disorders, including malignancies, inflammatory diseases, infections, and barrier dysfunction syndromes. This narrative review synthesizes current evidence on claudin biology in health and disease, highlighting how isoform-specific expression and localization shape barrier integrity and influence signaling pathways such as Wnt/β-catenin, Src kinase, and ERK. In cancer, aberrant claudin expression exhibits dual roles: tumor-suppressive when maintaining adhesion, yet oncogenic when mislocalized or overexpressed, driving epithelial-to-mesenchymal transition, stemness, and therapeutic resistance. Inflammatory and immune-mediated conditions such as inflammatory bowel disease, celiac disease, and eosinophilic esophagitis demonstrate characteristic shifts toward increased pore-forming claudins (e.g., claudin-2) and decreased sealing claudins (e.g., claudin-7, -8), thereby exacerbating barrier leakiness and immune activation. Infectious and metabolic disorders further exploit claudins, as exemplified by hepatitis C virus utilizing claudin-1 as a coreceptor. Beyond pathogenesis, claudins hold promise as diagnostic biomarkers and therapeutic targets: monoclonal antibodies against claudin-1, claudin-binding toxins, and anti-claudin-18.2 therapies are under investigation, with potential applications in gastroesophageal, gastric, pancreatic, and hepatic cancers. Emerging imaging tools leveraging claudin affinity further underscore their translational potential. By integrating findings from human studies, animal models, and mechanistic experiments, this review delineates the multifaceted roles of claudins in GI disorders and evaluates opportunities and challenges in harnessing these proteins for clinical intervention.

Keywords: claudins, gastrointestinal, cancer, inflammatory bowel disease, celiac disease