title: Reduced Epithelial Na+/H+ Exchange Drives Gut Microbial Dysbiosis and Promotes Inflammatory Response in T Cell-Mediated Murine Colitis.
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.
authors.affiliation: Department of Pediatrics-Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Laubitz
authors.affiliation: Department of Pediatrics-Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Christy A
authors.initials: CA
authors.lastname: Harrison
authors.affiliation: Department of Pediatrics-Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Monica T
authors.initials: MT
authors.lastname: Midura-Kiela
authors.affiliation: Department of Pediatrics-Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Rajalakshmy
authors.initials: R
authors.lastname: Ramalingam
authors.affiliation: Department of Pediatrics-Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Claire B
authors.initials: CB
authors.lastname: Larmonier
authors.affiliation: Department of Biological Sciences, Center for Microbial Genetics and Genomics at Northern Arizona University, Flagstaff, Arizona, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Chase
authors.affiliation: Department of Biological Sciences, Center for Microbial Genetics and Genomics at Northern Arizona University, Flagstaff, Arizona, United States of America.
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Caporaso
authors.affiliation: University Animal Care, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Besselsen
authors.affiliation: Department of Pediatrics-Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Fayez K
authors.initials: FK
authors.lastname: Ghishan
authors.affiliation: Department of Pediatrics-Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States of America.|Department of Immunobiology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Pawel R
authors.initials: PR
authors.lastname: Kiela
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017923:Sodium-Hydrogen Exchangers