Urinary metabolites and fatigue in a population-based metabolomics study: an exploratory analysis

Abstract Introduction Nearly every fifth adult person suffers from chronic fatigue, but its etiology and related mechanisms are poorly understood. Metabolomics data offer new possibilities for identifying metabolites related to disease etiology. Objectives This study aimed to investigate the association between urinary metabolites and fatigue in the general population. Methods Fatigue severity was assessed using the Fatigue Assessment Scale (FAS). 51 urinary metabolites were quantified via ¹H nuclear magnetic resonance (¹H-NMR). Multivariable linear regression models adjusted for possible confounders were performed on data of 570 participants of the Metabolism , Nutrition and Immune System in Augsburg (MEIA) study to explore the associations between urinary metabolites and fatigue. Results Four urinary metabolites showed significant associations with fatigue, namely hypoxanthine (β = 0.932, 95% CI 0.168–1.697, p = 0.017), 3-hydroxyhippurate (β = 0.213, 95% CI 0.003–0.424, p = 0.047), dimethylamine (β = 0.756, 95% CI 0.255–1.257, p = 0.003), and trimethylamine-N-oxide (β = 0.088, 95% CI 0.002–0.174, p = 0.045). Stratified analyses showed that the association of hypoxanthine was limited to individuals with obesity (BMI ≥ 30 kg/m 2 ; β = 3.186, 95% CI 1.742–4.629, p < 0.001). After correction for multiple testing (false discovery rate), none of these associations remained statistically significant. Conclusion Urinary metabolites related to purine degradation and gut microbial metabolism may reflect fatigue-related biological processes, demonstrating the potential of urinary metabolomics to identify biochemical alterations and possible mechanisms of fatigue pathophysiology.