Intestinal permeability and the zonulin pathway: tight junctions, mucosal immunity, dietary modulators and clinical relevance.
- 1Department of Real Madrid Graduate School, Faculty of Medicine, Health and Sports, Universidad Europea de Madrid, Campus de Villaviciosa, Madrid, Spain.
Abstract
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.
Related
- From the Gut to the Brain: Modeling Intestinal Absorption and Assessing Blood–Brain-Barrier Permeability of Small-Molecule Drugs by IAM Chromatography
- A Retrospective Analysis of the Association Between Prediabetes and Biomarkers of Intestinal Permeability in Patients with Prediabetes from Durban, South Africa.
- From Gut to Brain: A Longitudinal Assessment of Intestinal Permeability and Immune Activation Markers in Early-Stage Schizophrenia Spectrum Disorders
- Intestinal Permeability in Irritable Bowel Syndrome With and Without Comorbid Conditions: Results From the European DISCOvERIE Cohort.
- The Gut–Muscle Axis in Polycystic Ovary Syndrome: Proposed Mechanistic Roles of Intestinal Permeability, Bile Acid Signalling, and Skeletal Muscle Dysfunction
BibTeX
@article{bermejo2026intestinal,
title = {{Intestinal permeability and the zonulin pathway: tight junctions, mucosal immunity, dietary modulators and clinical relevance.}},
author = {David Granizo Bermejo and Guillermo García-Pérez-de-Sevilla and Antonio Molina-López},
journal = {Frontiers in nutrition},
year = {2026},
month = oct,
doi = {10.3389/fnut.2026.1938370},
url = {https://europepmc.org/article/MED/42903485},
note = {CC BY},
}
RIS
TY - JOUR
TI - Intestinal permeability and the zonulin pathway: tight junctions, mucosal immunity, dietary modulators and clinical relevance.
AU - David Granizo Bermejo
AU - Guillermo García-Pérez-de-Sevilla
AU - Antonio Molina-López
PY - 2026
DA - 2026/10/06
JO - Frontiers in nutrition
DO - 10.3389/fnut.2026.1938370
UR - https://europepmc.org/article/MED/42903485
AB - 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.
SN - 2296-861X
ER -