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

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Abstract

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 Cftrtm1Unc 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.

Authors

Xiaomeng You, Jisun Paik, Stacey Meeker, Kevin S. Mears, Christopher E. Pope, Hillary S. Hayden, Kelsi Penewit, Adam Waalkes, Sruthi Sridevan, Stephen J. Salipante, Lucas R. Hoffman, Julia F. Charles