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

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 ?F508-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. Overall design: 4x Colon WT, 4x Colon HO, 5x Lung WT, 3x Lung HO WT: Collaborative Cross with wt-Cftr HO: Collaborative Cross with F508-Cftr mutation