Effects of azithromycin on alleviating airway inflammation in asthmatic mice by regulating airway microbiota and metabolites

Asthma is a chronic respiratory disease with increasing global prevalence, often linked to disrupted airway microbiota. Azithromycin has shown promise in asthma treatment, but whether its effect is owing to its antimicrobial capacity remains largely unknown. A house dust mite (HDM)-induced asthmatic mouse model was used to evaluate the effects of azithromycin on airway inflammation and microbiota. Mice were divided into control, HDM-induced asthma, HDM + azithromycin, and azithromycin-alone groups. Airway microbiota was analyzed using 16S rRNA sequencing, and metabolomic profiles were assessed via liquid chromatography-tandem mass spectrometry. Azithromycin alleviated type 2 airway inflammation in HDM-induced asthma, restoring microbiota diversity by modulating specific genera, including <i>Streptococcus</i>, <i>Staphylococcus</i>, <i>Ruminococcus</i>, <i>Coprococcus</i>, <i>Bifidobacterium,</i> etc. Combination analysis with metabolomics revealed that azithromycin significantly regulated airway microbiota-associated sphingomyelin metabolism. Azithromycin's therapeutic effects in asthma are associated with its ability to regulate airway microbiota and its associated sphingomyelin metabolism, highlighting the potential for microbiota-targeted therapies in asthma.IMPORTANCEAsthma, a prevalent chronic respiratory condition, poses a significant global health challenge due to its increasing prevalence and associated morbidity. The role of airway microbiota in asthma pathogenesis is gaining attention, with evidence suggesting that disruptions in this microbial community contribute to disease severity. Our study investigates the impact of azithromycin, a macrolide antibiotic, on airway inflammation and microbiota in a mouse model of asthma. The findings reveal that azithromycin not only alleviates airway inflammation but also restores microbiota diversity and modulates microbiota-associated sphingomyelin metabolism. This research underscores the potential of microbiota-targeted therapies in asthma management, offering a novel therapeutic strategy that could improve patient outcomes and reduce the healthcare burden associated with asthma.