Abstract Asthma is a lung disease characterized by recurrent airway hyper-responsiveness, which is often triggered by type 2 inflammatory cytokines produced by Th2 helper cells or type 2 innate lymphoid cells. The direction and severity of inflammation is often determined by the pro-inflammatory or anti-inflammatory cytokines produced by myeloid cells upon sensing of commensal microbiota or microbial pathogens through pattern recognition receptors. The link between asthma and airway bacterial communities has been well documented owing to culture-free next generation sequencing technology. The use of 16s rRNA sequencing methods reveals the dysregulated airway microbiome in asthmatic patients. However, it lacks insights into how the airway microbiota manipulate mucosal immune regulations and alter inflammatory status during steady state or asthma onset. In vivo systems are indispensable to the study of the cross talk between microbiota and tissue inflammation. Traditional mouse models of asthma are not well-suited to the study of dysbiotic airway microbiota in asthmatic patients because humans and mice present major differences in their microbiota, as well as in their immune responses to microorganisms. The rapid development of studies on asthma and airway microbiome urgently needs novel murine models to deciphering the underlying interplays between commensal bacteria and mucosal immune responses and, therefore, to explain the epidemiological findings and translate them into clinical interventions. We have developed a unique humanized mouse model named MISTRG, in which several human cytokine coding genes were knocked into their respective mouse loci. MISTRG mice develop functional human lymphoid and myeloid lineage cells. More importantly, over 90% of immune cells in the lung of MISTRG mice were human immune cells. In this proposed work, we will deploy this novel humanized mouse model to investigate the interplay between dysbiotic airway microbiota and airway inflammation. Upon completion of our proposed work, we will obtain a comprehensive evaluation on airway microbiota composition and its corresponding inflammatory signature in this novel humanized mouse model of airway inflammation. Our study will provide direct evidence on how dysbiotic microbiota can induce or alter airway inflammatory response to trigger asthma onset. This study will be a breakthrough for current research on asthma and airway microbiota to help elucidate the complex pathogenesis underlying this disorder and provide more evidence for microbiota-based asthma prevention and control.