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 language | English (US) |
|---|---|
| Article number | e0152044 |
| Journal | PLoS One |
| Volume | 11 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2016 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Reduced epithelial Na+/H+exchange drives gut microbial dysbiosis and promotes inflammatory response in T cell-mediated murine colitis
AU - Laubitz, Daniel
AU - Harrison, Christy A.
AU - Midura-Kiela, Monica T.
AU - Ramalingam, Rajalakshmy
AU - Larmonier, Claire B.
AU - Chase, John H.
AU - Caporaso, James G
AU - Besselsen, David G.
AU - Ghishan, Fayez K.
AU - Kiela, Pawel R.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84963638664&partnerID=8YFLogxK
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U2 - 10.1371/journal.pone.0152044
DO - 10.1371/journal.pone.0152044
M3 - Article
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 4
M1 - e0152044
ER -