Alteration of the gut mycobiome in individuals with metabolically unhealthy obesity

Background: Obesity is a heterogeneous condition, with some individuals remaining metabolically healthy (MHO) while others develop metabolically unhealthy obesity (MUO) characterized by metabolic syndrome and related complications. Although the gut microbiome has been implicated in this heterogeneity, the role of the gut mycobiome remains poorly defined. Methods: We reanalyzed metagenomic data from 171 MUO patients and 212 MHO controls. A curated fungal genome catalog was used to construct gut mycobiome profiles. Taxonomic composition, diversity, and cross-kingdom microbial networks were evaluated. Associations with host metabolic parameters were examined, and random forest models were applied to assess the diagnostic potential of key markers. Results: While fungal α-diversity did not differ significantly between MUO and MHO, compositional and ecological shifts were evident. A total of 14 fungal species, including Kazachstania c80, Pichia kudriavzevii c98, and Wickerhamiella c156, were enriched in MUO patients and showed significant correlations with host metabolic parameters such as uric acid, triglycerides, and LDL cholesterol. Cross-kingdom network analysis revealed fungus-centered interaction patterns in MUO, with Pichia kudriavzevii c98 and Wickerhamiella c156 acting as hub species. Importantly, random forest models demonstrated that integrating fungal with bacterial features enhanced predictive accuracy compared to single-kingdom models, emphasizing the diagnostic value of the mycobiome. Conclusions: MUO is associated with distinct alterations in the gut mycobiome, characterized by specific fungal enrichments and fungus-driven microbial networks linked to host metabolic dysregulation. Incorporating fungal features enhances microbiome-based classification, highlighting the potential of the mycobiome as a complementary biomarker for distinguishing MUO from MHO