The Intestinal Microbiome Influences Airway Hyperresponsiveness in a Cystic Fibrosis Mouse Model
1. Meakins-Christie Laboratories and the Department of Human Genetics, McGill University, Montreal, Quebec, Canada; 2. Meakins-Christie Laboratories and the Departments of Medicine, McGill University, Montreal, Quebec, Canada
Background: Cystic fibrosis (CF) is a systemic disease that includes both intestinal and respiratory disease phenotypes. Cystic fibrosis transmembrane conductance regulator deficient mouse models develop components of the CF clinical disease including airway hyperresponsiveness, small intestinal bacterial overgrowth and an altered intestinal microbiome. Dysbiosis of the intestinal microbiota has been recognized as an important contributor to many systemic diseases; therefore, we investigated whether altering the murine intestinal microbiome would affect the CF lung and intestinal disease.
Methods: BALB/c Cftrtm1UNC (CF) mice and wild-type littermates were treated with streptomycin from in utero until sacrifice at 12 weeks of age and were compared to untreated mice. At sacrifice, airway mechanics were measured by FlexiVent, intestinal disease by histological and imaging examination, and immune cell profiles by flow cytometry. Intestinal bacterial load was measured using real-time PCR and the intestinal microbiome was characterized by pyrosequencing of the 16S rRNA gene.
Results: Streptomycin treatment caused a reduction in the intestinal bacterial overgrowth in CF mice and altered the intestinal microbiome. The CF intestinal disease phenotypes of crypt to villus axis distension, goblet cell hyperplasia and muscle thickness increase were not affected by streptomycin treatment in CF mice. However, the CF phenotype of airway hyperresponsiveness was ameliorated with streptomycin treatment, and this correlated to total Lactobacillus levels. Streptomycin treatment also increased the levels of TH17 lymphocytes in the lungs and mesenteric lymph nodes, while reducing the CF specific increase in respiratory IL-17+ γδ T cells.
Conclusions: These data suggest that components of the intestinal microbiome that are susceptible to streptomycin treatment are able to influence the lung environment in in BALB/c Cftrtm1UNC mice, but were insufficient to alter the CF intestinal disease. Additionally, intestinal Lactobacillus overgrowth and altered T lymphocyte subsets were identified as potentially contributing to the airway hyperresponsiveness phenotype in this model.