Sex-specific microbial and tryptophan signatures of depression implicate archaeal methanogens and indole-3-acetic acid only in women.

Sex differences in mental health are often overlooked, yet gut microbiota-host metabolite interactions may contribute to sexual dimorphism in depression. In a population-based cohort, we investigated sex-specific links among plasma tryptophan metabolites, depressive symptoms (PHQ-9), and the gut microbiome, controlling for smoking, diet, alcohol, and physical activity. Women (N = 419) exhibited higher plasma indole-3-acetic acid (IAA) and picolinic acid (PA) concentrations, but lower trigonelline (TRIG) than men (N = 383). Machine learning models with SHAP explanations revealed that IAA and TRIG were positively associated, whereas PA was negatively associated with depression severity in women, whereas only kynurenic acid (KA) was inversely associated in men. In women, depression severity strongly correlated with methanogenic archaea, including Methanobrevibacter smithii, and microbial methane-production pathways. Methanobrevibacter and specifically M. smithii were negatively linked to genes for tryptophan, PA, and KA biosynthesis, but positively to genes for IAA and nicotinate/nicotinamide metabolism. Most microbial species associated with depression severity in women were predicted to produce IAA. These findings reveal pronounced sex-specific microbiome-metabolite interactions, highlighting potentially distinct microbial mechanisms shaping depression in men and women.