Gastric acid inhibitor aggravates indomethacin-induced small intestinal injury via reducing Lactobacillus johnsonii

Abstract Proton pump inhibitors (PPIs) alter the composition of the intestinal microbiome, exacerbating indomethacin (IND)-induced small intestinal damage. Vonoprazan fumarate inhibits gastric acid secretion using a different mechanism from PPIs. We investigated the effects of both drugs on the intestinal microbiome and IND-induced small intestinal damage. We sought to clarify whether PPI-induced dysbiosis and worsening of the damage were due to a specific drug class effect of PPIs. Rabeprazole administration increased operational taxonomic unit numbers in the small intestines of C57BL/6 J mice, whereas the difference was not significant in the vonoprazan-treated group but exhibited a trend. Permutational multivariate analysis of variance of the unweighted UniFrac distances showed significant differences between vehicle- and vonoprazan- or rabeprazole-treated groups. L. johnsonii was the predominant microbial species, and the population ratio decreased after vonoprazan and rabeprazole administration. The vonoprazan- and rabeprazole-treated groups showed increased IND-induced damage. This high sensitivity to IND-induced damage was evaluated by transplantation with contents from the small intestine of mice treated with either vonoprazan or rabeprazole. Supplementation of L. johnsonii orally in mice treated with rabeprazole and vonoprazan prevented the increase in IND-induced small intestinal damage. In conclusion, both rabeprazole and vonoprazan aggravated NSAID-induced small intestinal injury by reducing the population of L. johnsonii in the small intestine via suppressing gastric acid secretion.