Reduced Epithelial Na+/H+ Exchange Drives Gut Microbial Dysbiosis and Promotes Inflammatory Response in T Cell-Mediated Murine Colitis

• Published in: PloS one 2016-04, Vol.11 (4), p.e0152044-e0152044
• Main Authors: Laubitz, Daniel, Harrison, Christy A, Midura-Kiela, Monica T, Ramalingam, Rajalakshmy, Larmonier, Claire B, Chase, John H, Caporaso, J Gregory, Besselsen, David G, Ghishan, Fayez K, Kiela, Pawel R
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics; Arthritis; Bacteria; Biology and Life Sciences; Body weight; Body weight loss; CD25 antigen; Colitis; Colitis - immunology; Colitis - metabolism; Colon; Communities; Crohn's disease; Crohns disease; Dysbacteriosis; Electrolytes; Exchanging; Foxp3 protein; Genomics; Histology; Homeostasis; Hydrogen; Immune response; Immune system; Immunology; Infiltration; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory response; Intestinal microflora; Intestine; Intestines - microbiology; Lupus; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Membrane permeability; Mice; Mice, Knockout; Microbiomes; Microbiota; Microorganisms; Mucosal immunity; Na+/H+-exchanging ATPase; Pathogenesis; Pediatrics; Permeability; RAG2 protein; Research and Analysis Methods; Rodents; Sodium-Hydrogen Exchangers - metabolism; T-Lymphocytes - immunology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152044

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.