B33-23 Gut Epithelial Aryl Hydrocarbon Receptor Deficiency Aggravates Fungal Dysbiosis-mediated Neutrophilic Allergic Airway Disease

Rationale

The intestinal microbiota involves a dynamic community of bacteria, viruses, and fungi. Intestinal colonization with Candida albicans has been shown to drive systemic expansion of fungal-specific Th17 CD4+ T cells and IL-17 responsiveness by circulating neutrophils and promote lung inflammation in allergic airway disease (AAD). The gut epithelial barrier is integral for maintaining mucosal immunity and regulating intestinal microbes. Intestinal epithelial cell (IEC) aryl hydrocarbon receptor (AhR) is important for maintaining intestinal homeostasis through regulation of mucosal immunity and gut barrier integrity. However, it is unclear whether enteric AhR affects immunity in the lung, and whether intestinal AhR could have beneficial or detrimental effects on fungi-mediated AAD development via gut-lung axis.

Methods

Germ-free (GF) mice and gut epithelial AhR-deficient mice were used to test the effects of C. albicans colonization on allergic airway disease (AAD) in a house dust mite (HDM) challenge model. Isolation of lung structural cells, BALF collection, and HE staining were performed to evaluate lung inflammation. Mitochondrial dysfunction was assessed through quantitative Real-Time PCR and flow cytometry. UEA-1 staining for fucosylation and imaging mass cytometry (IMC) for lung cellular interactions were conducted. Microbiome sequencing was also performed to analyze the community structure of the gut microbiota.

Results

In this study, we demonstrated that enteric AhR deficiency exacerbates development of AAD induced by house dust mite (HDM) challenge and C. albicans colonization due to excessive fucosylation in lung structural cells. Enteric AhR deficiency drives the IL-17 responsiveness and neutrophil accumulation, disrupts the community structure of gut microbiota, particularly decreasing the abundance of Akkermansia muciniphila, all of which leads to increases in mitochondrial dysfunction, superoxide production, and fucosylation in lung structural cells in C. albicans-mediated AAD. The administration of A. muciniphila or deletion of Fut2 reduces lung fucosylation, which abrogates the exacerbating effects of C. albicans on AAD. We further discovered fucosylation controls neutrophil adhesion through L-selectin glycan ligand biosynthesis in lung structural cells.

Conclusions

Our studies indicate that enteric AhR signal can remotely influence the interplay of lung fucosylation and neutrophil adhesion and enhance Candida albicans-mediated neutrophilic AAD.

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