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Digestive Diseases and Sciences

, Volume 63, Issue 4, pp 881–889 | Cite as

Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria

  • Eiichiro Yasutomi
  • Namiko Hoshi
  • Soichiro Adachi
  • Takafumi Otsuka
  • Lingling Kong
  • Yuna Ku
  • Haruka Yamairi
  • Jun Inoue
  • Tsukasa Ishida
  • Daisuke Watanabe
  • Makoto Ooi
  • Masaru Yoshida
  • Tomoya Tsukimi
  • Shinji Fukuda
  • Takeshi Azuma
Original Article

Abstract

Background and Aims

Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Side effects including an increased risk of intestinal infections have been reported. It is assumed that PPIs can increase susceptibility to enteropathogens; however, the underlying mechanisms are unknown. Here in this study, we explored whether Lansoprazole (Laz), one of the PPIs, increases the susceptibility to enteropathogens, and further investigated the mechanism of it.

Methods

Mice were administered Laz intraperitoneally once daily and orally infected with Citrobacter rodentium (C. rodentium). The establishment of intestinal infection was assessed by histology and inflammatory cytokine expression levels measured by quantitative PCR. To test whether Laz changes the intestinal environment to influence the susceptibility, intestinal pH, microbiota, metabolites and immune cell distributions were evaluated via pH measurement, 16S rRNA gene sequencing, metabolome, and flow cytometry analyses after Laz administration.

Results

Colitis was induced with less C. rodentium in Laz-treated mice as compared with the controls. We found that increased numbers of C. rodentium could reach the cecum following Laz administration. Laz increased pH in the stomach but not in the intestines. It induced dysbiosis and changed the metabolite content of the small intestine. However, these changes did not lead to alterations of immune cell distribution.

Conclusions

Laz raised susceptibility to C. rodentium as increased numbers of the pathogen reach the site of infection. Our results suggest that it was due to increased stomach pH which allowed more peroral enteropathogens to pass the stomach, but not because of changes of intestinal environment.

Keywords

Proton pump inhibitors Gastrointestinal microbiome Immunity Intestinal diseases 

Notes

Acknowledgments

This study was supported in part by grants from the Hyogo Science and Technology Association to N.H.; the Yakult Bio-Science Foundation to N.H.; JST PRESTO (JPMJPR1537) to S.F.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10620_2017_4905_MOESM1_ESM.docx (4.5 mb)
Supplementary material 1 (DOCX 4565 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Eiichiro Yasutomi
    • 1
  • Namiko Hoshi
    • 1
  • Soichiro Adachi
    • 1
  • Takafumi Otsuka
    • 1
  • Lingling Kong
    • 1
  • Yuna Ku
    • 1
  • Haruka Yamairi
    • 1
  • Jun Inoue
    • 1
  • Tsukasa Ishida
    • 1
  • Daisuke Watanabe
    • 1
  • Makoto Ooi
    • 1
  • Masaru Yoshida
    • 1
    • 2
    • 3
  • Tomoya Tsukimi
    • 4
  • Shinji Fukuda
    • 4
    • 5
    • 6
    • 7
  • Takeshi Azuma
    • 1
  1. 1.Division of Gastroenterology, Department of Internal MedicineKobe University Graduate School of MedicineKobeJapan
  2. 2.Division of Metabolomics Research, Department of Internal RelatedKobe University Graduate School of MedicineKobeJapan
  3. 3.AMED-CREST, AMEDKobeJapan
  4. 4.Institute for Advanced BiosciencesKeio UniversityYamagataJapan
  5. 5.Intestinal Microbiota ProjectKanagawa Institute of Industrial Science and TechnologyKanagawaJapan
  6. 6.Transborder Medical Research CenterUniversity of TsukubaIbarakiJapan
  7. 7.PRESTOJapan Science and Technology AgencySaitamaJapan

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