Rebamipide ameliorates indomethacin-induced small intestinal damage and proton pump inhibitor-induced exacerbation of this damage by modulation of small intestinal microbiota

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) induce small intestinal damage. It has been reported that rebamipide, a mucoprotective drug, exerts a protective effect against NSAID-induced small intestinal damage; however, the underlying mechanism remains unknown. In this study, we investigated the significance of the small intestinal microbiota in the protective effect of rebamipide against indomethacin-induced small intestinal damage in mice. A comprehensive analysis of the 16S rRNA gene sequencing revealed an alteration in the composition of the small intestinal microbiota at the species level, modulated by the administration of rebamipide and omeprazole. The transplantation of the small intestinal microbiota of the mice treated with rebamipide suppressed the indomethacin-induced small intestinal damage. Omeprazole, a proton pump inhibitor, exacerbated the indomethacin-induced small intestinal damage, which was accompanied by the alteration of the small intestinal microbiota. We found that the transplantation of the small intestinal microbiota of the rebamipide-treated mice ameliorated indomethacin-induced small intestinal damage and the omeprazole-induced exacerbation of the damage. These results suggest that rebamipide exerts a protective effect against NSAID-induced small intestinal damage via the modulation of the small intestinal microbiota, and that its ameliorating effect extends also to the exacerbation of NSAID-induced small intestinal damage by proton pump inhibitors.

Gut Microbiota in NSAID Enteropathy: New Insights From Inside

“…Interestingly, mice transplanted with feces from indomethacin-treated mice showed less intestinal injury and lower levels of proinflammatory cytokines when exposed to the NSAIDs, compared to the mice transplanted with feces from control groups (Xiao et al, 2017), and this result may be related to the adaptive beneficial changes in the gut microbiota. And Tanigawa et al reported that the transplantation of the small intestinal microbiota of the rebamipide-treated mice improved the small intestinal damage induced by indomethacin and omeprazole (Tanigawa et al, 2021). This observation suggested the potential role of FMT in the treatment of the NSAID enteropathy.…”

“…Tanigawa et al reported that in the rebamipide-treated mice, Lactobacillales increased while the abundance of Bacteroides and Clostridium subcluster XIVa decreased (Tanigawa et al, 2013). And it was reported that the administration of rebamipide decreased the concentration of Lactobacillus taiwanensis whereas increased the proportion of Lactobacillus murinus (Tanigawa et al, 2021). Meanwhile, increased expression of a-defensin 5, a critical anti-microbial peptide produced by Paneth cells was found in rebamipidetreated mice (Ouellette, 2004).…”

“…And Tanigawa et al. reported that the transplantation of the small intestinal microbiota of the rebamipide-treated mice improved the small intestinal damage induced by indomethacin and omeprazole ( Tanigawa et al., 2021 ). This observation suggested the potential role of FMT in the treatment of the NSAID enteropathy.…”

The influence of different proton pump inhibitors and potassium‐competitive acid blockers on indomethacin‐induced small intestinal injury

“…To induce small intestinal injury, we administered IND (10 mg/kg, Sigma) in a 0.5% CMC solution by oral gavage to nonfasting mice. Twenty‐four hours later, the mice were sacrificed, and small intestinal injury was observed 10 …”

“…Twenty-four hours later, the mice were sacrificed, and small intestinal injury was observed. 10 The study was performed after the mice were allowed to acclimate for 1 week. Then, the mice were randomly divided into six groups (n = 5): the control group, model group, and four intervention groups.…”