Multiniche mycobiome profiling identifies distinctive fungal dysbiosis in Common Variable Immunodeficiency Metagenome

Common variable immunodeficiency is associated with bacterial dysbiosis, particularly in patients with immune dysregulation, but the contribution of the fungal microbiome remains poorly understood. We conducted a cross-sectional, multi-compartment study in 41 adults with CVID (24 with immune dysregulation, dCVID, 17 with infectious-only manifestations, iCVID) and 15 matched healthy controls. Saliva, sputum and stool were profiled using ITS1 amplicon sequencing with ASV-based taxonomic assignment, followed by diversity analyses, canonical correspondence analysis with ADONIS, differential abundance testing with ANCOM-BC and random forest models with Boruta selection. Across all three niches, mycobiome composition differed significantly between CVID and controls, whereas dCVID and iCVID did not separate. Fungal richness and evenness were reduced in CVID, most prominently in respiratory and oral samples. ANCOM-BC revealed a reproducible Candida-skewed configuration in both phenotypes, with marked enrichment of Candida albicans in sputum, stool and saliva, accompanied by increased abundance of other opportunistic yeasts such as Nakaseomyces glabratus. In contrast, environmental or putatively commensal taxa were consistently depleted. Random forest models based on fungal profiles accurately discriminated CVID from controls, with AUC up to 0.92 in saliva and 0.90 in stool, whereas classification of dCVID versus iCVID was modest. Together, these findings provide the first integrated view of mycobiome alterations across multiple ecological niches in CVID, highlighting cross-compartment expansion of opportunistic yeasts over commensals. The enrichment of C. albicans supports a potential pathobiont role, and the strong discriminatory performance of fungal signatures underscores their promise as non-invasive biomarkers in this immunodeficiency.