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Cystic fibrosis is a heritable disease that disrupts ion transport at mucosal surfaces, causing a buildup of mucus and dysregulation of microbial communities in both the lungs and the intestines. Persons with CF are known to have dysbiotic gut microbial communities, but the development of these communities over time beginning at birth has not been thoroughly studied. Here, we describe an observation study following the development of the gut microbiome of cwCF throughout the first 4 years of life, during the critical window of both gut microbiome and immune development. Our findings indicate the possibility of the gut microbiota as a reservoir of airway pathogens and a surprisingly early indication of a microbiota associated with inflammatory bowel disease. 

Persons with cystic fibrosis (CF), starting in early life, show intestinal microbiome dysbiosis characterized in part by a decreasedrelative abundance of the genus Bacteroides. Bacteroides is a major producer of the intestinal short chain fatty acid propionate. Wdemonstrate here that cystic fibrosis transmembrane conductance regulator-defective (CFTR−/−) Caco-2 intestinal epithelial cellsresponsive to the anti-inflammatory effects of propionate. Furthermore, Bacteroides isolates inhibit the IL-1β-induced inflammatorresponse of CFTR−/− Caco-2 intestinal epithelial cells and do so in a propionate-dependent manner. The introduction of Bacteroisupplemented stool from infants with cystic fibrosis into the gut of CftrF508del mice results in higher propionate in the stool as wethe reduction in several systemic pro-inflammatory cytokines. Bacteroides supplementation also reduced the fecal relativeabundance of Escherichia coli, indicating a potential interaction between these two microbes, consistent with previous clinicalstudies. For a Bacteroides propionate mutant in the mouse model, pro-inflammatory cytokine KC is higher in the airway and serucompared with the wild-type (WT) strain, with no significant difference in the absolute abundance of these two strains. Takentogether, our data indicate the potential multiple roles of Bacteroides-derived propionate in the modulation of systemic and airwayinflammation and mediating the intestinal ecology of infants and children with CF. The roles of Bacteroides and the propionate itproduces may help explain the observed gut-lung axis in CF and could guide the development of probiotics to mitigate systemic aairway inflammation for persons with CF.