Proton pump inhibitor increases intestinal epithelial paracellular permeability via the p38-MAPK/NF-κB signaling...

Proton pump inhibitors (PPIs), among the most widely administered medications globally, are correlated with adverse effects including fracture, enteric infections, gastroenteric tumors, and increased paracellular permeability of upper gastrointestinal tract. However, previous studies have primarily focused on PPI-induced intestinal microbiota dysbiosis or pH-dependent effects, the mechanisms underlying the association between PPI use and intestinal barrier dysfunction remain poorly understood. Therefore, this study aimed to investigate the relationship between PPI use and intestinal epithelial paracellular permeability both in vitro and in vivo, and to explore the potential signaling pathway mechanisms involved. These efforts seek to broaden the current understanding of the influence of PPIs therapy on intestinal barrier function.

Different concentrations of pantoprazole sodium were administered intraperitoneally once a day for seven consecutive days in male C57BL/6J mice and were applied to Caco-2BBe cell monolayers accordingly. H&E was used to evaluate the epithelial morphology of jejunum and ileum. The permeability of FITC-dextran 4000 (FD4) and transepithelial electrical resistance (TEER) value were measured. The expression and distribution of occludin were assessed by quantitative real-time PCR, western blotting, and immunofluorescence analysis. The potential signaling pathways were also examined. PPI did not induce macroscopic lesions in the jejunum and ileum. However, PPI significantly decreased the mRNA and protein expression levels of occludin, reduced TEER values, and increased intestinal epithelial paracellular permeability of FD4 in the jejunum, ileum, and Caco-2BBe cell monolayers. In Caco-2BBe cell monolayers, the phosphorylation levels of p38-MAPK and NF-κB were higher in PPI-treated group than the control group. Pretreatment of Caco-2BBe cell monolayers with a p38-MAPK inhibitor (10 µM) prior to PPI exposure (100 µM) downregulated the activation of p38-MAPK and NF-κB, accompanied by increased occludin expression, elevated TEER value, and decreased FD4 permeability.

Although the absence of macroscopic intestinal lesions, PPI directly enhances intestinal epithelial paracellular permeability by decreasing the expression of the tight junction protein occludin, mediated by the p38-MAPK/NF-κB signaling pathway. These findings highlight that the potential and insidious side effects of PPI on the intestinal epithelial barrier warrant increased attention and caution from clinicians when prescribing PPIs for various gastrointestinal diseases.