title: Rebamipide inhibits indomethacin-induced small intestinal injury: possible involvement of intestinal microbiota modulation by upregulation of α-defensin 5.
abstract: Enterobacteria play important roles in the pathophysiology of small intestinal injuries induced by nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the effects of rebamipide, a gastrointestinal mucoprotective drug, on indomethacin-induced small intestinal injuries, intestinal microbiota, and expression levels of α-defensin 5, which is a Paneth cell-specific antimicrobial peptide and is important for the regulation of intestinal microbiota. Indomethacin (10mg/kg) was orally administered to mice after oral administration of rebamipide (100 or 300 mg/kg) or vehicle for 1 week, and the small intestinal injuries were assessed. After oral administration of rebamipide, the small intestinal contents were subjected to terminal restriction fragment length polymorphism (T-RFLP) analysis to assess the intestinal microbiota composition. Further, the expression levels of mRNA and protein for α-defensin 5 in the ileal tissue were determined by real-time reverse transcription-polymerase chain reaction and western blotting analysis, respectively. Rebamipide inhibited indomethacin-induced small intestinal injuries and T-RFLP analysis showed that rebamipide increased the percentage of Lactobacillales and decreased the percentage of Bacteroides and Clostridium than that in vehicle-treated controls. The mice that were treated with rebamipide showed an increase in α-defensin 5 mRNA expression and protein levels in the ileal tissue compared to vehicle-treated control mice. Indomethacin reduced expression of α-defensin 5 mRNA in ileal tissue, while rebamipide reversed expression of α-defensin 5 mRNA. In conclusion, our study results suggest that rebamipide inhibits indomethacin-induced small intestinal injuries, possibly by modulating microbiota in the small intestine by upregulation of α-defensin 5.
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka City, Osaka 545-8585, Japan. ttanigawa@med.osaka-cu.ac.jp
authors: Tetsuya
authors: T
authors: Tanigawa
authors: Toshio
authors: T
authors: Watanabe
authors: Koji
authors: K
authors: Otani
authors: Yuji
authors: Y
authors: Nadatani
authors: Fumikazu
authors: F
authors: Ohkawa
authors: Mitsue
authors: M
authors: Sogawa
authors: Hirokazu
authors: H
authors: Yamagami
authors: Masatsugu
authors: M
authors: Shiba
authors: Kenji
authors: K
authors: Watanabe
authors: Kazunari
authors: K
authors: Tominaga
authors: Yasuhiro
authors: Y
authors: Fujiwara
authors: Koji
authors: K
authors: Takeuchi
authors: Tetsuo
authors: T
authors: Arakawa
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004269:DNA, Bacterial / Q000235:genetics; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007213:Indomethacin / Q000009:adverse effects; D007421:Intestine, Small / Q000187:drug effects* / Q000293:injuries / Q000382:microbiology / Q000473:pathology; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation; D023084:alpha-Defensins / Q000096:biosynthesis*
chemical_list: D004269:DNA, Bacterial; D005765:Gastrointestinal Agents; D015363:Quinolones; D023084:alpha-Defensins; C052785:rebamipide; D000409:Alanine; D007213:Indomethacin