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This study demonstrates that dysfunction of the CFTR protein specifically in intestinal epithelial cells is sufficient to cause the gut microbiome changes observed in cystic fibrosis, particularly the overgrowth of E. coli bacteria. Using mouse models, researchers showed that CFTR mutations in the gut lining alone lead to increased E. coli levels, enhanced intestinal barrier permeability, and elevated immune responses. The findings indicate that E. coli overgrowth resulting from these epithelial changes is pathogenic and contributes to disease progression in cystic fibrosis.
Why it matters
These results establish a direct mechanistic link between CFTR dysfunction in the gut and harmful microbiome changes in cystic fibrosis, suggesting that targeting intestinal E. coli overgrowth or restoring epithelial barrier function could be therapeutic strategies. The research may explain why CF patients experience gastrointestinal complications and inflammation beyond the well-known lung problems.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Changes in the gut microbiome in cystic fibrosis (CF) are well characterized, yet their causes and downstream effects remain largely unknown. Well-documented alterations include reduced overall complexity (i.e. alpha diversity) of the gut microbiota and increased relative abundance of E. coli, which are associated with greater inflammation and shorter stature in infants. Previous results from our laboratory using a germ-free cystic fibrosis transmembrane conductance regulator (Cftr) mutant mouse model (CF mouse) demonstrated that the observed fecal microbiome dysbiosis is driven by mutated Cftr independent of factors such as diet or antibiotic treatment. We expand on these results in this report by using the defined 8-member community Altered Schaedler Flora (ASF) with and without E. coli, to show that E. coli is pathogenic in the context of the CF gut microbiome, resulting in increased intestinal permeability. We also show that Cftr deletion in intestinal epithelial cells alone, using a Villin-Cre targeted model, is sufficient to raise E. coli abundance in the fecal microbiome, increase intestinal permeability, and amplify the number of TH17 cells in the mesenteric lymph nodes. Together, our results demonstrate that the intestinal epithelium plays a dominant role in fecal microbiome alterations in CF and that the resultant dysbiosis contributes to CF pathogenesis.