Association of plasma n-3 polyunsaturated fatty acid with gut mycobiome and implications for glucose homeostasis.

The pivotal role of gut fungi (i.e., mycobiome) in host health is increasingly recognized. Diet is a critical determinant factor for both gut fungi and host metabolic health. This study aimed to investigate the associations of plasma n-3 polyunsaturated fatty acids (PUFAs), an important dietary lipid component, with gut mycobiome and explore the relationship of n-3 PUFA-related gut fungi with type 2 diabetes (T2D) and glycemic phenotypes. Here, we identified four fungal genera that were inversely associated with plasma total n-3 PUFA in the discovery cohort. Among these, Debaryomyces, Kodamaea, and Wickerhamomyces were consistently associated with total n-3 PUFA in the metaanalysis of 4 human cohorts (FDR-meta<0.1). We also found that Wickerhamomyces was positively associated with host fasting blood glucose and glycated hemoglobin (FDR<0.05). Moreover, we observed an interaction between n-3 PUFA and Kodamaea on T2D (P-interaction=0.02), which was confirmed in the mice study. In human and mice studies, the inverse associations between n-3 PUFA and glycemic phenotypes were only observed in the Kodamaea-free population. Additionally, the enrichment of specific primary bile acids, namely cholic acid and its conjugated forms, was associated with Kodamaea colonization. Our results indicate that n-3 PUFA is associated with specific gut fungal genera, which may, in turn, affect host glucose homeostasis.