Gut microbiota are required for reduced IGF-1 and bone growth in postnatal cystic fibrosis mice

Children with cystic fibrosis (CwCF) have impaired linear growth that correlates with poor clinical outcomes. Growth-stunted CwCF also exhibit a marked fecal dysbiosis, and lower serum levels of the gut microbiome-regulated growth factor IGF-1, relative to those without stunting. We hypothesized that the CF gut microbiome negatively impacts IGF-1 and skeletal growth in CwCF. To test this hypothesis, we compared bone phenotypes, IGF-1 and linear growth trajectories of C57BL/6 Cftr tm1Unc mutant mice (CF) to their wild-type littermates (WT) either colonized with (specific pathogen free, SPF) or without (germ-free, GF) normal microbiota. At 4 weeks of age, CF mice had reduced femur length and diminished serum IGF-1 compared to WT mice under SPF, but not GF, conditions. In contrast, by 14 weeks femur lengths and IGF-1 were similar in CF mice raised under both SPF and GF conditions. Accordingly, we observed significantly slower growth in CF mice under SPF, but not GF, conditions only from 1 to 4 weeks. CF mice also exhibited more pronounced relative taxonomic and functional dysbiosis at 4 compared with 14 weeks. These results suggest that gut microbiota play a critical role in early postnatal CF skeletal growth impairment, while microbe-independent mechanisms likely predominate in later life.