Reduced epithelial Na+/H+exchange drives gut microbial dysbiosis and promotes inflammatory response in T cell-mediated murine colitis

Daniel Laubitz, Christy A. Harrison, Monica T. Midura-Kiela, Rajalakshmy Ramalingam, Claire B. Larmonier, John H. Chase, James G Caporaso, David G. Besselsen, Fayez K. Ghishan, Pawel R. Kiela

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Inflammatory bowel diseases (IBD) are associated with functional inhibition of epithelial Na+/H+exchange. In mice, a selective disruption of NHE3 (Slc9a3), a major apical Na+/H+exchanger, also promotes IBD-like symptoms and gut microbial dysbiosis. We hypothesized that disruption of Na+/H+exchange is necessary for the development of dysbiosis, which promotes an exacerbated mucosal inflammatory response. Therefore, we performed a temporal analysis of gut microbiota composition, and mucosal immune response to adoptive T cell transfer was evaluated in Rag2-/-and NHE3-/-/Rag2-/-(DKO) mice with and without broad-spectrum antibiotics. Microbiome (16S profiling), colonic histology, T cell and neutrophil infiltration, mucosal inflammatory tone, and epithelial permeability were analyzed. In adoptive T cell transfer colitis model, Slc9a3 status was the most significant determinant of gut microbial community. In DKO mice, NHE3-deficiency and dysbiosis were associated with dramatically accelerated and exacerbated disease, with rapid body weight loss, increased mucosal T cell and neutrophil influx, increased mucosal cytokine expression, increased permeability, and expansion of CD25-FoxP3+Tregs; this enhanced susceptibility was alleviated by oral broad-spectrum antibiotics. Based on these results and our previous work, we postulate that epithelial electrolyte homeostasis is an important modulator in the progression of colitis, acting through remodeling of the gut microbial community.

Original languageEnglish (US)
Article numbere0152044
JournalPLoS One
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2016

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Dysbiosis
T-cells
colitis
Colitis
intestinal microorganisms
T-lymphocytes
inflammation
T-Lymphocytes
Adoptive Transfer
inflammatory bowel disease
mice
Inflammatory Bowel Diseases
microbial communities
neutrophils
Permeability
permeability
antibiotics
Anti-Bacterial Agents
mucosal immunity
Mucosal Immunity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Laubitz, D., Harrison, C. A., Midura-Kiela, M. T., Ramalingam, R., Larmonier, C. B., Chase, J. H., ... Kiela, P. R. (2016). Reduced epithelial Na+/H+exchange drives gut microbial dysbiosis and promotes inflammatory response in T cell-mediated murine colitis. PLoS One, 11(4), [e0152044]. https://doi.org/10.1371/journal.pone.0152044

Reduced epithelial Na+/H+exchange drives gut microbial dysbiosis and promotes inflammatory response in T cell-mediated murine colitis. / Laubitz, Daniel; Harrison, Christy A.; Midura-Kiela, Monica T.; Ramalingam, Rajalakshmy; Larmonier, Claire B.; Chase, John H.; Caporaso, James G; Besselsen, David G.; Ghishan, Fayez K.; Kiela, Pawel R.

In: PLoS One, Vol. 11, No. 4, e0152044, 01.04.2016.

Research output: Contribution to journalArticle

Laubitz, D, Harrison, CA, Midura-Kiela, MT, Ramalingam, R, Larmonier, CB, Chase, JH, Caporaso, JG, Besselsen, DG, Ghishan, FK & Kiela, PR 2016, 'Reduced epithelial Na+/H+exchange drives gut microbial dysbiosis and promotes inflammatory response in T cell-mediated murine colitis', PLoS One, vol. 11, no. 4, e0152044. https://doi.org/10.1371/journal.pone.0152044
Laubitz, Daniel ; Harrison, Christy A. ; Midura-Kiela, Monica T. ; Ramalingam, Rajalakshmy ; Larmonier, Claire B. ; Chase, John H. ; Caporaso, James G ; Besselsen, David G. ; Ghishan, Fayez K. ; Kiela, Pawel R. / Reduced epithelial Na+/H+exchange drives gut microbial dysbiosis and promotes inflammatory response in T cell-mediated murine colitis. In: PLoS One. 2016 ; Vol. 11, No. 4.
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