Fluticasone Propionate Alters the Respiratory Tract Microbiota and Has Dose-Related Effects on Anti-Bacterial Host Defence

Background: Inhaled corticosteroids increase pneumonia frequency in COPD with lesser risk associated with lower drug doses. The aim of this study was to evaluate effects of fluticasone propionate(FP) on anti-bacterial host-defence. Methods: C57BL/6 mice were treated with intranasal FP or vehicle control. Lung tissue microbiota were assessed by 16S rRNA sequencing. In a mouse model of S.pneumoniae D39 infection, effects of FP on anti-bacterial responses and pathogen control were evaluated. Additionally, human peripheral blood mononuclear cells(PBMCs) were treated with clinically relevant concentrations of FP and stimulated with S.pneumoniaein vitro. Results: Mice treated with FP had increased lung bacterial loads at 8 hours post administration(p=0.015) and also showed a significant increase in bacterial diversity and expansion in Stenotrophomonas genera(p<0.001). Following challenge with S.pneumoniae, high dose FP(1mg/kg) suppressed a range of anti-bacterial responses and increased bacterial loads by quantitative culture in lung tissue (8 hours post-infection;p<0.001). Conversely lower dose FP(0.1mg/kg) had the opposite effect of reducing bacterial loads(p<0.01). The differential effects of FP related to dose were potentially mediated through effects on TNF-α induction and airway neutrophil recruitment which were suppressed by high dose but enhanced at lower dose FP. Similar dose-related effects of FP on TNF-α were observed in S.pneumoniae-stimulated PBMCs. Conclusion: FP alters respiratory microbiota and impairs anti-bacterial responses in a dose-dependent manner, effects that may provide mechanistic insight into the increased pneumonia signal observed clinically.