Effects of montelukast combined with inhaled corticosteroids on the airway–gut microbiome and immune regulation in children with asthma

To evaluate the effect of montelukast combined with inhaled corticosteroids (ICS) on the microbiome-metabolism-immunity axis in children with asthma and to quantify the mediating role of short-chain fatty acids, this single-center, randomized controlled trial enrolled 100 asthmatic children (aged 6-11) who received inhaled corticosteroids with or without montelukast for 12 weeks (n = 50 in the combination group and n = 50 in the ICS-alone group). Microbiome profiles from nasal and fecal samples were assessed via 16S sequencing, and short-chain fatty acids (SCFAs) were quantified by LC-MS/MS. Immune markers (Tregs, cytokines) were measured by flow cytometry and Bio-Plex. Efficacy analyses employed linear mixed-effects models, and SCFA mediation was tested using bootstrap analysis. The combination group demonstrated significantly greater improvements in clinical outcomes including fractional exhaled nitric oxide (FeNO) (β_int = -10.24 ppb, 95% CI -16.37 to -4.11, P = 0.001), Childhood Asthma Control Test (C-ACT) score (β_int = +1.83, P < 0.05) and FEV1% (β_int = +1.87, P < 0.05) compared to ICS alone. Microbiome analysis revealed enhanced α-diversity in both nasal and fecal samples (interaction P < 0.01) with significant community structure changes (PERMANOVA interaction P_perm < 0.01). Specific genus-level alterations included reduced nasal Moraxella and Haemophilus (logFC < 0, q < 0.10) and increased fecal SCFA-producing taxa including Faecalibacterium, Roseburia, Subdoligranulum, Agathobacter, and Eubacterium hallii group (logFC > 0, q < 0.10). The combination therapy also led to elevated fecal and serum SCFA levels (β_int > 0, P < 0.01), enhanced regulatory T cell (Treg) and IL-10 responses, and suppressed Th2 cytokines (IL-4/IL-5/IL-13). Mediation analysis confirmed SCFAs partially mediated FeNO improvement, with proportions of 30.0% for total SCFAs and 37.5% for butyrate (ACME and ADE both negative, P < 0.01). The combination of montelukast and inhaled corticosteroids was superior to inhaled corticosteroids alone, providing clinical benefits that were linked to favorable remodeling of the airway-gut microbiome and enhanced Treg/IL-10 immunity. This improvement was partially mediated by short-chain fatty acids, with a comparable safety profile.