Abstract
Emerging evidence suggests that fatigue caused by accumulated stress may serve as a prodromal symptom of psychiatric disorders, and gut microbiome dysbiosis has been reported in many such conditions. However, little is known about microbial and metabolic signatures associated with fatigue in otherwise healthy individuals. This study aimed to investigate associations between fatigue, the gut microbiome, and fecal metabolites in healthy Japanese adults. We identified characteristic microbial and metabolic differences specific to fatigued healthy individuals. Taxonomic analysis revealed a reduction in potentially beneficial bacteria and an enrichment of Escherichia coli in their gut microbiome. Functional profiling demonstrated enrichment of KEGG orthologs related to oxidative stress and depletion of energy-producing pathways. Correspondingly, key energy metabolites such as citrate were decreased. Notably, some fatigue-associated bacterial alterations overlapped with findings from external datasets on psychiatric disorders and myalgic encephalomyelitis/chronic fatigue syndrome, suggesting associative overlap in gut microbial alterations. These findings suggest associations between host fatigue and gut microbiome alterations involving oxidative stress and impaired energy metabolism. The consistent overlap of fatigue-associated microbial changes with those observed in psychiatric disorders highlights the potential relevance of gut microbial signatures in fatigue-related biological states. This study provides a foundation for future studies on gut microbial and metabolic pathways.