Intestinal permeability and the zonulin pathway: tight junctions, mucosal immunity, dietary modulators and clinical relevance

The intestinal barrier separates the luminal content, including the gut microbiota, dietary antigens and toxins, from the mucosal immune system, and its integrity is essential for immune homeostasis. Loss of barrier control, commonly termed increased intestinal permeability or leaky gut, has been implicated in a broad spectrum of gastrointestinal, metabolic, autoimmune, neuropsychiatric, hepatic and cardiovascular conditions. Paracellular transport across the epithelium is governed by apical junctional complexes, of which tight junctions are the principal regulators, while the overlying mucus layer, antimicrobial peptides, secretory immunoglobulin A and the gut-associated lymphoid tissue together constitute a multi-layered defensive interface. Among the physiological modulators of tight junctions, zonulin, identified as pre-haptoglobin-2, is the only endogenous protein currently known to reversibly regulate paracellular permeability, and its release is triggered chiefly by gliadin and by the gut microbiota. This narrative review summarizes the molecular architecture of the intestinal epithelial junctions, the immunological organization of the mucosal barrier, the zonulin signaling pathway, the principal dietary factors that compromise barrier integrity (excess glucose, fructose, fat, omega-6 fatty acids, salt, alcohol and food additives), and the clinical conditions and laboratory tests associated with intestinal permeability. A clearer understanding of the diet-microbiota-barrier-immunity axis may support nutritional strategies aimed at preserving intestinal barrier function and modulating mucosal immune activation.