Preventive Intrapulmonary Treatment with Ligilactobacillus Murinus Reduces Airway Inflammation and Mucus Plugging in Mice with Cystic Fibrosis-Like Lung Disease.

Background:Chronic airway dysbiosis plays an important role in the pathogenesis of cystic fibrosis (CF) lung disease and may serve as a therapeutic target. However, studies investigating the effects of direct therapeutic targeting of the airway microbiome are lacking. In this study, we therefore used βENaC-overexpressing (βENaC-Tg) mice and determined the evolution of abnormal lung microbiota and effects of re-balancing bacterial communities on chronic airway inflammation and mucus plugging in this model of CF lung disease. Methods:The development of the respiratory microbiome was determined by 16S rRNA gene sequencing and the effects of preventive intranasal instillation of endogenous probiotic bacteria on the lung phenotype were determined in βENaC-Tg mice and wild-type littermates. Results:Neonatal βENaC-Tg mice developed severe respiratory dysbiosis characterised by an increase in the relative abundance of Streptococcus and a decrease in Ligilactobacillus compared to wild-type littermates. Ligilactobacillus murinus SMH17 was identified as the dominant Ligilactobacillus species in the lungs of neonatal wild-type mice. Preventive treatment by intranasal instillation of L. murinus SMH17 was well tolerated and reduced age-specific markers of airway inflammation including inflammatory cell counts and proinflammatory cytokines in neonatal and juvenile βENaC-Tg mice. In addition, preventive treatment with L. murinus SMH17 reduced airway mucus plugging in βENaC-Tg mice by ∼40%. Conclusion:Preventive intrapulmonary application of the endogenous probiotic L. murinus SMH17 reduces airway inflammation and mucus plugging in mice with CF-like lung disease. These data support further elucidation of inhaled probiotics as a strategy to treat chronic airway dysbiosis in patients with CF.