Altered gut mycobiome and cross-kingdom microbial interactions in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder shaped by host genetics and environmental exposures, including the gut microbiota. While bacterial dysbiosis in SLE is well characterized, the role of the gut mycobiome and its cross-kingdom interactions remains largely unexplored. Using fecal metagenomic sequencing from 117 SLE patients and 115 healthy controls (HCs), we established a non-redundant fungal genome catalog and revealed significant alterations in fungal composition, function, and cross-kingdom ecology. Fungal diversity was increased in SLE, with enrichment of potentially pathogenic taxa such as Candida, Malassezia, and Trichophyton, and depletion of commensal genera such as Pichia. Functional analysis showed expanded biosynthetic and redox capacities in SLE-associated fungi, including enrichment of RiPP- and terpene-related biosynthetic gene clusters and oxidative stress–related Pfam domains. Several predicted metabolites—such as kynurenine, phenylacetic acid, secondary bile acids, and acylcarnitines—were linked to immune activation and inflammation, suggesting that fungal metabolism may contribute to immune dysregulation. Network analysis revealed sparser and less centralized fungal–bacterial interactions in SLE, indicating disrupted ecological stability and the emergence of fungal taxa as key structural drivers. Integrating fungal and bacterial profiles markedly improved diagnostic performance (AUC = 0.934), underscoring the complementary predictive value of the gut mycobiome. In contrast, post-treatment samples showed reduced fungal richness but no major compositional shifts. This study provides a comprehensive, multi-dimensional view of the gut mycobiome in SLE, demonstrating its taxonomic, functional, and ecological remodeling. Our findings highlight the potential contribution of fungal metabolic and redox activities to SLE pathogenesis and support the inclusion of fungi in multi-kingdom microbiome frameworks for disease diagnosis and therapeutic development.