Integrated analysis of the gut mycobiota and plasma metabolome reveals mortality and age-specific characteristics in sepsis

Sepsis, a life-threatening syndrome with especially high incidence and mortality in older adults, imposes a major global health burden. Although the gut bacterial microbiota is known to influence sepsis pathogenesis, the role of the gut fungal community (mycobiota) and its functional metabolic output remains largely unknown. In this study, we characterized sepsis-associated alterations in the gut mycobiota and related plasma metabolic signatures, and explored their associations with age and survival outcomes. We conducted an integrated multi-omics analysis of fecal samples from patients with sepsis and matched healthy controls. Using internal transcribed spacer 1 (ITS1) sequencing and untargeted plasma metabolomics at admission, we compared the gut mycobiota composition and metabolic profiles between groups across age strata (non-older vs. older adults) and survival outcomes. Patients with sepsis exhibited significant gut mycobiota dysbiosis, characterized by a loss of diversity and marked overgrowth of opportunistic Candida. Metabolomics revealed distinct perturbations, particularly in the bile acid and inflammatory pathways. These alterations were profoundly exacerbated in non-survivors and elderly patients and were strongly correlated with higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, organ failure, and mortality. Our study identified a sepsis-specific gut mycobiota signature and associated plasma metabolomic disturbances that were associated with mortality and accentuated by aging. These findings reveal an association between the gut mycobiota, host metabolism, and clinical outcomes in sepsis, which merits further validation to assess its potential for prognostic or therapeutic applications. However, the causal relationship remains to be established, and future studies are needed to validate these associations and explore their translational potential.