Potassium-Competitive Acid Blocker Increases Ileal Permeability and Exacerbates Ileal Inflammation under Stress Conditions in a Mouse Model of Eosinophilic Enteritis.
This mouse study investigated whether potassium-competitive acid blockers (P-CABs), sometimes empirically used for eosinophilic gastrointestinal diseases, might worsen eosinophilic enteritis (EoN) under psychological stress conditions. Researchers established an EoN model in BALB/c mice using ovalbumin sensitization and challenge, then exposed animals to water avoidance stress (WAS) or sham stress, with or without P-CAB administration. Compared to the WAS-only group, WAS combined with P-CAB significantly worsened multiple disease markers, including diarrhea incidence, villus/crypt ratio, eosinophil and mast cell counts, Th2 cytokine expression (mRNA and protein), OVA-specific IgE levels, and ileal permeability measured via Ussing chamber. The study further found that larazotide acetate, a zonulin inhibitor targeting gut tight junctions, reduced ileal inflammation and permeability in WAS + P-CAB-treated EoN mice, suggesting a permeability-mediated mechanism. Key limitations include exclusive use of a mouse model, which may not fully replicate human eosinophilic gastrointestinal disease, and the artificial nature of the stress and sensitization protocols. These findings raise important cautions about P-CAB use in patients with EoN who may be under psychological stress, though human clinical evidence is still lacking.
Why this grade: All experimental work was conducted exclusively in BALB/c mice using an ovalbumin-sensitization model, with no human subjects or clinical data included.
Introduction Potassium-competitive acid blockers (P-CABs) have been empirically administered to treat non-esophageal eosinophilic gastrointestinal diseases, although their efficacy remains unproven. Our previous findings demonstrated that psychological stress impairs the intestinal barrier and exacerbates eosinophilic enteritis (EoN) in a mouse model. Moreover, we demonstrated that P-CAB increased intestinal permeability under psychological stress. The aim of this study is to clarify the hypothesis that P-CAB exacerbate EoN by increasing intestinal permeability under stressful conditions. Methods An EoN model was established in BALB/c mice using ovalbumin (OVA) sensitization and challenge. Mice were subjected to water avoidance stress (WAS) or sham stress (SS) and were administered P-CAB or saline as a vehicle. The ileum was collected for the analysis of ileal microscopic inflammation, mRNA and protein expression levels of T helper type 2 (Th2) cytokines, and ex vivo ileal permeability using a Ussing chamber. Results Compared with the WAS + Vehicle group, WAS + P-CAB significantly exacerbated the incidence of diarrhea, villus/crypt ratio, eosinophil and mast cell counts, mRNA and protein levels of Th2 cytokines, OVA-specific immunoglobulin E protein levels, and ileal permeability. Larazotide acetate, a zonulin inhibitor, significantly improved ileal inflammation and decreased ileal permeability in the WAS + P-CAB-treated EoN mice. Conclusions P-CAB increased ileal permeability and exacerbated EoN under stressful conditions. Furthermore, a zonulin inhibitor demonstrated therapeutic effects in EoN with P-CAB under stressful conditions.
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