AbstractThe pathogenesis of asthma has been partially linked to lung and gut microbiome. We utilized a steroid‐resistant chronic model of cockroach antigen‐induced (CRA) asthma with corticosteroid (fluticasone) treatment to examine lung and gut microbiome during disease. The pathophysiology assessment demonstrated that mucus and airway hyperresponsiveness were increased in the chronic CRA with no alteration in the fluticasone (Flut)‐treated group, demonstrating steroid resistance. Analysis of mRNA from lungs showed no decrease of MUC5AC or Gob5 in the Flut‐treated group. Furthermore, flow‐cytometry in lung tissue showed eosinophils and neutrophils were not significantly reduced in the Flut‐treated group compared to the chronic CRA group. When the microbiome profiles were assessed, data showed that only the Flut‐treated animals were significantly different in the gut microbiome. Finally, a functional analysis of cecal microbiome metabolites using PiCRUSt showed several biosynthetic pathways were significantly enriched in the Flut‐treated group, with tryptophan pathway verified by ELISA with increased kynurenine in homogenized cecum samples. While the implications of these data are unclear, they may suggest a significant impact of steroid treatment on future disease pathogenesis through microbiome and associated metabolite pathway changes.