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

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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.

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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.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chu-o-ku, Kobe, Hyogo, 650-0017, Japan

    Eiichiro Yasutomi, Namiko Hoshi, Soichiro Adachi, Takafumi Otsuka, Lingling Kong, Yuna Ku, Haruka Yamairi, Jun Inoue, Tsukasa Ishida, Daisuke Watanabe, Makoto Ooi, Masaru Yoshida & Takeshi Azuma

  2. Division of Metabolomics Research, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan

    Masaru Yoshida

  3. AMED-CREST, AMED, Kobe, Hyogo, 650-0017, Japan

    Masaru Yoshida

  4. Institute for Advanced Biosciences, Keio University, Yamagata, 997-0052, Japan

    Tomoya Tsukimi & Shinji Fukuda

  5. Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology, Kanagawa, 210-0821, Japan

    Shinji Fukuda

  6. Transborder Medical Research Center, University of Tsukuba, Ibaraki, 305-8577, Japan

    Shinji Fukuda

  7. PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan

    Shinji Fukuda

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  1. Eiichiro Yasutomi
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Correspondence to Namiko Hoshi.

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Yasutomi, E., Hoshi, N., Adachi, S. et al. Proton Pump Inhibitors Increase the Susceptibility of Mice to Oral Infection with Enteropathogenic Bacteria. Dig Dis Sci 63, 881–889 (2018). https://doi.org/10.1007/s10620-017-4905-3

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  • DOI: https://doi.org/10.1007/s10620-017-4905-3

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