Sex differences in fecal metabolic profiles of major depressive disorder: unveiling sex-specific metabolomic panel

Abstract

Background: Major depressive disorder (MDD) disproportionately affects women, who exhibit a higher prevalence and greater symptom severity than men. However, sex-specific pathophysiological mechanisms remain poorly understood. Emerging evidence implicates gut microbiota-derived metabolites in MDD, but many prior studies have failed to consider sex differences, potentially obscuring critical biomarkers. This study aims to address this gap by characterizing sex-specific fecal metabolite profiles in MDD. Methods: Untargeted metabolomics was used to examine fecal metabolic profiles in 279 participants (117 with MDD and 162 healthy controls). The cohort was stratified by biological sex to identify sex-specific metabolic alterations associated with depressive symptoms through statistical analyses. A machine learning approach incorporating feature selection was employed to identify potential discriminative biomarkers, with a particular focus on female metabolic characteristics. Results: Sex-stratified analysis revealed significant metabolic divergence in female MDD patients compared to healthy controls. Twenty-four differentially abundant metabolites were identified in females, with heptylamine and phenaceturic acid being unique to this group; no significant differences were observed in males. Correlation analyses showed that phenaceturic acid and 1-monoheptadecanoyl glyceride were significantly negatively correlated with depressive symptom severity in females. Besides, a sex-specific diagnostic panel based on five key fecal metabolites demonstrated promising performance in distinguishing female MDD patients from healthy controls. Conclusion: By systematically revealing sex-dependent metabolic alterations, this study identified potential biomarkers for sex-specific diagnostic and therapeutic strategies. These findings highlight the importance of integrating sex-specific perspectives in gut-brain axis research to advance precision medicine in MDD, rather than relying solely on generalized approaches. Trial registration: Human Research and Ethics Committee of Beijing Anding Hospital, Capital Medical University, China (Approval No. 2017-24), registered on 2018.07.24.