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.
Highlights
It is well established that the vast assemblage of microbes harbored in the gastrointestinal tract exists in a mutualistic relationship with the host, which can become tenuous when disturbed [1,2,3]
We hypothesized that altered epithelial nutrient transport, especially the reduced Na+/H+ exchange activity, may be a significant contributor to inflammation-associated microbial dysbiosis which results in further disease exacerbation
We showed that NHE3 deficiency in mice is associated with a susceptibility to dextran sulfate
Summary
It is well established that the vast assemblage of microbes harbored in the gastrointestinal tract exists in a mutualistic relationship with the host, which can become tenuous when disturbed [1,2,3]. IBD is associated with a dysregulated immune response to commensal gut-resident bacteria, and is one of several disorders associated with altered gut microbial ecology [6, 7]. The microbiota of IBD patients show profound shifts in the relative abundance of major and minor taxonomic groups, reflective of altered intestinal ecology [1, 8,9,10]. One of the non-immune consequences of mucosal inflammation that may result in changes within the microbial habitat is altered epithelial nutrient and especially electrolyte transport [12, 13]. Epithelial electrolyte balance is critical in regulating nutrient uptake, intestinal, intracellular and systemic pH, maintaining stool consistency, and in promoting normal gut motility, all of which may contribute to the maintenance of microbial equilibrium in health
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