Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used but frequently cause gastrointestinal (GI) side effects, including ulcers and mucosal erosion. Proton pump inhibitors (PPIs), while effective in preventing NSAID-induced upper GI injury, can worsen small intestinal damage. Potassium-competitive acid blockers (P-CABs), such as fexuprazan, offer potential advantages over PPIs, but their effects on NSAID-induced enteropathy remain unclear. This study aimed to evaluate the protective effects of fexuprazan on NSAID-induced small intestinal injury and elucidate the underlying mechanism.

A mouse model of small intestinal injury was established using indomethacin. Mice were pre-treated with fexuprazan or esomeprazole before indomethacin administration. Small intestinal damage was assessed by gross examination, Evans blue staining, histological analysis, and inflammatory cytokine measurements. Additional evaluations included immune cell infiltration, mucin production, tight junction protein expression, bacterial translocation, autophagy-related protein levels, and gut microbiota composition using 16S rDNA sequencing.

Fexuprazan significantly alleviated intestinal shortening, mucosal erosion, and elevated inflammatory cytokine (TNF-α, IL-6, IL-1β) levels compared to esomeprazole. It restored mucosal barrier integrity by preserving mucin production and tight junction protein (ZO-1 and claudin-1) expression, reduced immune cell infiltration, and mitigated bacterial translocation. Fexuprazan also normalized autophagy-related protein expression (Beclin-1, ATG5-ATG12, LC3-I/II) and reshaped the gut microbiota, favoring a reduction in inflammation.

Fexuprazan demonstrated protective effects against NSAID-induced small intestinal injury, while esomeprazole did not. Its ability to preserve intestinal barrier integrity, modulate inflammatory responses, and restore gut microbiota composition highlights its therapeutic potential in NSAID-induced enteropathy.