Regulation of intestinal epithelial permeability by tight junctions Original paper

What was reviewed?

This paper reviewed how intestinal epithelial tight junctions (TJs) create and dynamically regulate the gut’s selective paracellular barrier, and how inflammation, pathogens, and diet-derived factors remodel TJ structure to shift permeability and disease risk. It synthesizes molecular details of key TJ components (occludin, claudins, JAM family proteins, tricellulin, and ZO scaffolds) and the signaling pathways that control their localization, phosphorylation, endocytosis, and cytoskeletal coupling. Because TJ dysfunction is frequently clinically framed as “leaky gut,” the review focuses mechanistically, connecting specific TJ protein changes and upstream mediators (notably cytokines and microbial toxins) to barrier defects that amplify mucosal immune activation and systemic consequences.

Who was reviewed?

Rather than a single population, the review integrates evidence from multiple experimental and clinical contexts: human mucosal biopsy observations (especially inflammatory bowel disease and celiac disease), animal models of colitis, stress, and autoimmune disease, and widely used intestinal epithelial cell lines (e.g., Caco-2, T84, HT29/B6). It also covers pathogen exposure models (e.g., Vibrio cholerae, EPEC/EHEC, Clostridium perfringens) and nutritional/probiotic interventions. The “who” is therefore best understood as intestinal epithelial barriers across species and model systems, with clinical anchoring in diseases where permeability is measurably increased and TJ protein patterns are altered.

Most important findings

A central theme is that intestinal TJ permeability is not a monolithic phenomenon: it can increase via cytoskeletal contraction (MLCK–MLC phosphorylation), via selective induction of pore-forming claudins (notably claudin-2), or via TJ protein internalization/disassembly driven by inflammatory signaling. Key inflammatory mediators—including TNF-α, IFN-γ, IL-1β, IL-4, IL-6, and IL-13—impair barrier function through distinct, sometimes synergistic pathways, frequently converging on MLCK activation and/or claudin-2 upregulation. Conversely, protective signals such as TGF-β and EGF can restore TJ organization and resist oxidative or cytokine-mediated disruption. From a microbiome-signature perspective, the review highlights how bacterial toxins and pathogen adhesion mechanisms directly target TJ complexes (e.g., V. cholerae ZOT/HA-P, CPE binding to claudin-3/-4, EPEC/EHEC effects involving MLCK and TJ protein redistribution), and how microbially produced short-chain fatty acids (especially butyrate) strengthen barrier integrity via AMPK and accelerated TJ assembly. It also emphasizes probiotics and their secreted factors (e.g., E. coli Nissle 1917, Lactobacillus rhamnosus GG, Bifidobacterium infantis–conditioned media) as modulators that normalize TJ protein localization/expression and counter cytokine or pathogen insults.

Key implications

Clinically, this review supports using “barrier phenotype” thinking: increased permeability can reflect specific TJ protein shifts (loss/redistribution of occludin/ZO proteins; rise of claudin-2 pores) and upstream immune–microbial triggers, not merely nonspecific inflammation. It also frames actionable therapeutic directions: targeting TNF-α–MLCK pathways (already indirectly validated by anti-TNF improving permeability in IBD), leveraging diet-derived or microbe-derived metabolites (butyrate, acetate/propionate), and selecting probiotic strains or postbiotic products with demonstrated TJ-protective signaling. For microbiome databases, it provides a mechanistic map linking pathogens and commensal-derived metabolites to barrier outcomes that plausibly mediate downstream immune activation in IBD, celiac disease, T1D, ALD, and IBS.

Citation

Suzuki T. Regulation of intestinal epithelial permeability by tight junctions.Cellular and Molecular Life Sciences. 2013;70(4):631-659. doi:10.1007/s00018-012-1070-x