Exercise and Intestinal Barrier Integrity: Molecular Mechanisms and Therapeutic Potential in Gut Health and Disease

The intestinal barrier (IB) is a critical interface that maintains internal homeostasis. Its functional compromise-termed intestinal hyperpermeability-permits luminal antigens such as lipopolysaccharide to enter the circulation, triggering metabolic endotoxemia and low-grade systemic inflammation that underpin both intestinal and extra-intestinal diseases. This narrative review was based on a comprehensive literature search of PubMed, Web of Science, and Scopus databases up to July 2026, using keywords related to exercise, intestinal barrier, tight junction proteins, inflammation, oxidative stress, gut microbiota, and short-chain fatty acids. The synthesis indicates that regular moderate-intensity continuous training (30-60 min/session, 3-5 sessions/week) enhances barrier integrity through upregulation of tight junction proteins, suppression of TLR4/NF-κB-driven inflammation, activation of Nrf2-mediated antioxidant defenses, and beneficial remodeling of gut microbiota composition and short-chain fatty acid production. Exercise also induces peripheral-gut crosstalk mediated by myokines and vagal cholinergic signaling. The relationship between exercise volume and barrier function follows a J-shaped dose-response curve, with moderate exercise conferring protection while excessive high-intensity or prolonged exercise transiently increases permeability via splanchnic hypoperfusion and hypoxia-induced epithelial stress. Exercise shows preliminary therapeutic potential as an adjunctive intervention in inflammatory bowel disease, irritable bowel syndrome, and metabolic-associated fatty liver disease, with systemic benefits extending through the gut-liver and gut-brain axes. However, clinical translation remains limited by small sample sizes, short follow-up periods, and heterogeneous protocols. Future research should prioritize large-scale randomized controlled trials, precision exercise prescriptions, and synergistic exercise-probiotic co-interventions to establish definitive clinical guidelines.