AbstractBackgroundEar, nose and throat involvement in granulomatosis with polyangiitis (GPA) is frequently the initial disease manifestation. Previous investigations have observed a higher prevalence ofStaphylococcus aureusin patients with GPA, and chronic nasal carriage has been linked with an increased risk of disease relapse. In this cross-sectional study, we investigated changes in the nasal microbiota including a detailed analysis ofStaphylococcusspp. by shotgun metagenomics in patients with active and inactive granulomatosis with polyangiitis (GPA). Shotgun metagenomic sequence data were also used to identify protein-encoding genes within the SEED database, and the abundance of proteins then correlated with the presence of bacterial species on an annotated heatmap.ResultsThe presence ofS. aureusin the nose as assessed by culture was more frequently detected in patients with active GPA (66.7%) compared with inactive GPA (34.1%). Beta diversity analysis of nasal microbiota by bacterial 16S rRNA profiling revealed a different composition between GPA patients and healthy controls (P = 0.039). Beta diversity analysis of shotgun metagenomic sequence data forStaphylococcusspp. revealed a different composition between active GPA patients and healthy controls and disease controls (P = 0.0007 andP = 0.0023, respectively), and between healthy controls and inactive GPA patients and household controls (P = 0.0168 andP = 0.0168, respectively). Patients with active GPA had a higher abundance ofS. aureus, mirroring the culture data, while healthy controls had a higher abundance ofS. epidermidis.Staphylococcus pseudintermedius, generally assumed to be a pathogen of cats and dogs, showed an abundance of 13% among theStaphylococcusspp. in our cohort. During long-term follow-up of patients with inactive GPA at baseline, a higherS. aureusabundance was not associated with an increased relapse risk. Functional analyses identified ten SEED protein subsystems that differed between the groups. Most significant associations were related to chorismate synthesis and involved in the vitamin B₁₂pathway.ConclusionOur data revealed a distinct dysbiosis of the nasal microbiota in GPA patients compared with disease and healthy controls. Metagenomic sequencing demonstrated that this dysbiosis in active GPA patients is manifested by increased abundance ofS. aureusand a depletion ofS. epidermidis, further demonstrating the antagonist relationships between these species. SEED functional protein subsystem analysis identified an association between the unique bacterial nasal microbiota clusters seen mainly in GPA patients and an elevated abundance of genes associated with chorismate synthesis and vitamin B₁₂pathways. Further studies are required to further elucidate the relationship between the biosynthesis genes and the associated bacterial species.