Gut epithelial aryl hydrocarbon receptor deficiency aggravates fungal dysbiosis-mediated neutrophilic allergic airway disease in mice

Fungal and bacterial dysbiosis are linked to asthma disease severity, yet how overgrowth of the commensal fungus Candida albicans contributes to disease progression is not fully understood. Here, we show that intestinal aryl hydrocarbon receptor (AhR) deficiency exacerbates house dust mite (HDM)-induced allergic airway disease (AAD) during oral Candida albicans colonization through enhanced IL-17 responsiveness and lung structural cell fucosylation. Intestinal AhR deficiency promotes exaggerated IL-17 responses that promotes neutrophil migration and accumulation in the lung and reshapes the gut microbiota, particularly reducing the abundance of Akkermansia muciniphila. Concurrently, increased fucosylation of lung structural cells enhances L-selectin glycan ligand biosynthesis, thereby promoting neutrophil adhesion and retention within inflamed lung tissue. These adherent neutrophils lead to mitochondrial dysfunction, oxidative stress, and tissue injury in epithelial and endothelial compartments. Administration of A. muciniphila or its derived outer membrane vesicles (OMVs), as well as genetic deletion of Fut2, reduces lung fucosylation, suppresses neutrophil adhesion and NET formation, and attenuates Candida albicans–exacerbated AAD. Together, these findings show that intestinal AhR signaling remotely regulates an IL-17- gut microbiota-fucosylation axis that promotes neutrophil adhesion, mitochondrial dysfunction of lung structure cell, and neutrophilic airway inflammation during Candida albicans–associated asthma. Fungal and bacterial dysbiosis are linked to asthma severity. Here the authors use mice deficient in intestinal epithelial cell AhR to show that in the absence of AhR, house dust mite-induced allergic airway disease is heightened in the presence of Candida albicans and fucosylation of lung structural cells affects neutrophil adhesion and retention in inflamed lung tissue involving inhibition of the mucus-utilising bacterium Akkermansia muciniphila.