Paracellular permeability and tight junction regulation in gut health and disease

Abstract

Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention.

Hyaluronic Acid-Conjugated Thermoresponsive Polymer-Based Bioformulation Enhanced Wound Healing and Gut Barrier Repair of a TNBS-Induced Colitis Injury Ex Vivo Model in a Dynamic Perfusion Device

“…Moreover, TNF-α is a key proinflammatory cytokine that plays a central role in the initiation and propagation of inflammatory responses. Regeneration of the gut mucosa after TNBS treatment involves the repair of these key components, making them relevant targets for our study. , According to the qPCR data, as shown in Figure B, after TNBS treatment, Muc-2 mRNA expression was significantly ( p ≤ 0.001) diminished as compared to healthy controls. However, treatment with P­(NIPAM- co -NTBAM)-HA or P­(NIPAM- co -NTBAM)-HA-ePRDL significantly ( p ≤ 0.01 and p ≤ 0.001, respectively) enhanced the Muc-2 expression in colon tissues in comparison to TNBS-damaged colon tissues.…”

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling

“…S5I, S5J). These data suggest that PGE2 is critical for the IAF-induced barrier disruption phenotype, but additional factors may also be involved ( 54 ).…”

Ethanol‐exposed lung fibroblasts cause airway epithelial barrier dysfunction

“…The differences in the findings in the current study and previous studies could be due to the differences in experimental design (direct exposure to ethanol by epithelial cells in the previous study), TGFβ1 level, and other factors produced by LF. Additionally, given that paracellular permeability in the epithelial monolayer depends not only on tight junction protein expression but also their correct localization within the plasma membrane (Horowitz et al, 2023), we speculate that the effect of ethanol‐exposed fibroblasts on ZO‐1 membrane localization is sufficient to significantly alter tight junction function by disrupting ZO‐1/claudins/occludin interaction (Lynn et al, 2020).…”