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Microbial dysbiosis associated with impaired intestinal Na+/H+ exchange accelerates and exacerbates colitis in ex-germ free mice

Mucosal Immunology (2018) | Download Citation

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Abstract

Intestinal epithelial Na+/H+ exchange facilitated by the apical NHE3 (Slc9a3) is a highly regulated process inhibited by intestinal pathogens and in inflammatory bowel diseases. NHE3−/− mice develop spontaneous, bacterially mediated colitis, and IBD-like dysbiosis. Disruption of epithelial Na+/H+ exchange in IBD may thus represent a host response contributing to the altered gut microbial ecology, and may play a pivotal role in modulating the severity of inflammation in a microbiome-dependent manner. To test whether microbiome fostered in an NHE3-deficient environment is able to drive mucosal immune responses affecting the onset or severity of colitis, we performed a series of cohousing experiments and fecal microbiome transplants into germ-free Rag-deficient or IL-10−/− mice. We determined that in the settings where the microbiome of NHE3-deficient mice was stably engrafted in the recipient host, it was able accelerate the onset and amplify severity of experimental colitis. NHE3-deficiency was characterized by the reduction in pH-sensitive butyrate-producing Firmicutes families Lachnospiraceae and Ruminococcaceae (Clostridia clusters IV and XIVa), with an expansion of inflammation-associated Bacteroidaceae. We conclude that the microbiome fostered by impaired epithelial Na+/H+ exchange enhances the onset and severity of colitis through disruption of the gut microbial ecology.

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grants 2R01DK041274 (to F.K.G. and P.K.R.) and 5R01DK073338 (to C.J.). The founders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Special thanks to Paula Campbell with the University of Arizona Flow Cytometry Core for her assistance flow sorting T cells for adoptive transfer.

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Author notes

  1. These authors contributed equally: Christian Jobin, Fayez K. Ghishan, Pawel R. Kiela

Affiliations

  1. Department of Pediatrics, Steele Children’s Research Center, Tucson, AZ, USA

    • Christy A. Harrison
    • , Daniel Laubitz
    • , Monica T. Midura-Kiela
    • , Deepa R. Jamwal
    • , Fayez K. Ghishan
    •  & Pawel R. Kiela
  2. Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA

    • Christy A. Harrison
    •  & Pawel R. Kiela
  3. University Animal Care, University of Arizona, Tucson, AZ, USA

    • Christina L. Ohland
    • , Karuna Patil
    •  & David G. Besselsen
  4. Division of Gastroenterology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA

    • Christian Jobin

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Contributions

C.A.H. designed and performed experiments, analyzed results, and wrote the paper; D.L. performed experiments, analyzed results, and edited the paper; C.L.O. designed and performed experiments with germ-free IL-10−/− mice; M.T.M-K., responsible for most experimental animals, performed experiments; K.P. designed and performed experiments with germ-free mice in Arizona; D.G.B. analyzed histology and scored samples; D.R.J. performed flow sorting of T cells; C.J. supervised experiments with germ-free IL-10−/− mice at the Univ. of Florida, provided funding, edited manuscript; F.K.G. supervised experiments at the University of Arizona, provided funding, edited manuscript; P.R.K. supervised experiments at the University of Arizona, designed the experiments, analyzed results provided funding, edited manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Pawel R. Kiela.

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https://doi.org/10.1038/s41385-018-0035-2