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

Christy A. Harrison, Daniel Laubitz, Christina L. Ohland, Monica T. Midura-Kiela, Karuna Patil, David G. Besselsen, Deepa R. Jamwal, Christian Jobin, Fayez K Ghishan, Pawel R Kiela

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMucosal Immunology
DOIs
StateAccepted/In press - Jun 6 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Harrison, C. A., Laubitz, D., Ohland, C. L., Midura-Kiela, M. T., Patil, K., Besselsen, D. G., Jamwal, D. R., Jobin, C., Ghishan, F. K., & Kiela, P. R. (Accepted/In press). Microbial dysbiosis associated with impaired intestinal Na+/H+ exchange accelerates and exacerbates colitis in ex-germ free mice. Mucosal Immunology, 1-13. https://doi.org/10.1038/s41385-018-0035-2