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Genetic diversity in mouse models unlocks the gut-lung axis in Cystic Fibrosis

ABSTRACT: Despite Cystic Fibrosis Transmembrane conductance Regulator (CFTR) being identified as the gene responsible for cystic fibrosis (CF), there are multiple CF-causing genetic variants affecting phenotypes in people with CF (pwCF). Animal models generated so far have introduced various mutations in the Cftr gene, but none replicate the genetic diversity found in humans. Yet, CF mice exhibit variable degrees of extra-pulmonary phenotypes, lacking the lung dysfunction and susceptibility to infection that are primary manifestations in humans, thus limiting pathogenic studies. We opted for Collaborative Cross (CC) mice, a genetically diverse animal resource population, to identify a suitable genetic background for CF. Here, we show that ΔF508-Cftr homozygosity in CC037 mice produced a fully penetrant lethal phenotype within two months of age. Early in life, in the absence of mucus production, inflammatory and immune responses arise in the lungs and blood. The CF murine lung exhibits an activated immunoinflammatory and defense response to bacterial pathogens, sharing microbiology with the gut. Intestinal mucosal function shows impaired barrier integrity, provides an environmental niche for bacterial accumulation and triggers inflammation. Treating gut pathology protected CF mice from respiratory and systemic inflammation, establishing the groundwork for inter-organ communication, likely via the gut-lung axis. In sum, we report the first mouse model that reproduces human CF and provides a paradigm for mouse modeling relevant to multiple other genetic disorders. The significance of our findings is fundamental for CF, supporting the role of the gut in lung pathology and suggesting new diagnostic and therapeutic interventions beyond lung-related treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE273812 | GEO | 2025/07/30

REPOSITORIES: GEO

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Project description:Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) in cystic fibrosis (CF) results in exaggerated and chronic inflammation as well as increased susceptibility to chronic pulmonary infections, in particular with Pseudomonas aeruginosa. Based on the concept that host immune responses do not seem to be adequate to eradicate P.aeruginosa from the lungs of CF patients and that dendritic cells (DC) play an important role in initiating and shaping adaptive immune responses, this study analyzed the role of CFTR in bone marrow-derived murine DC from CFTR knockout (CF) mice with and without exposure to P.aeruginosa. DC expressed CFTR mRNA and protein, although at much lower levels compared to whole lung. Microarray analysis of gene expression levels in DC generated from CF and wild type (WT) mice revealed significantly different expression of 16 genes in CF DC compared to WT DC. Among the genes with lower expression in CF DC was Caveolin-1, a membrane lipid raft protein. Messenger RNA and protein levels of Caveolin-1 were decreased in the CF DC compared to WT DC. Consistently, the active form of sterol-responsive element binding protein (SREBP), a negative regulator of Caveolin-1 expression, was increased in CF DC. Following exposure to P.aeruginosa, gene expression levels in CF and WT DC changed for 912 genes involved in inflammation, chemotaxis, signaling, cell cycling and apoptosis more than 1.5-fold. Among the genes that showed a different response between WT and CF DC infected with P.aeruginosa, were 3Î²-hydroxysterol-Î7 reductase (Dhcr7) and stearoyl-CoA desaturase 2 (Scd2), two enzymes involved in the lipid metabolism that are also regulated by SREBP. These results suggest that CFTR dysfunction in non-epithelial cells results in changes in the expression of genes encoding factors involved in membrane structure and lipid-metabolism. These membrane alterations in immune cells may contribute to the abnormal inflammatory and immune response characteristic of CF. Experiment Overall Design: comparison of gene expression in dendritic cells of cystic fibrosis mice without or with Pseudosmonas aeruginosa infection vs wild type dendritic cell controls

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Genetic diversity in mouse models unlocks the gut-lung axis in Cystic Fibrosis

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