Microbiota-metabolome interplay in depression: Metabolic insights and diagnostic potential

Mounting evidence highlights the interplay between gut microbiota, metabolism, and depression. In this study, we analyze fecal and serum metabolomes in first-episode depression and matched controls (n = 186), with validation in three independent cohorts (n = 223, 85, 52) including drug intervention. Significant disruptions are noted in 53 gut microbial species, 12 microbiota-related metabolic pathways, and 34 metabolites in depressive individuals compared to controls. Sixteen metabolites exhibit reversal after drug administration. Partial Spearman analysis identifies 271 species-metabolite correlations, and mediation analysis unveils 61 metabolite-mediated species-depression correlations. Key features associated with depression, including Bifidobacterium longum, Parasutterella excrementihominis, tyrosine, serotonin, and homovanillic acid, are highlighted. A machine learning model with 34 metabolites achieves area under the receiver operating characteristic (ROC) curve values of 0.82 and 0.80 in discriminating depression from control in test and validation sets. Our findings highlight metabolites as key mediators linking microbiota to depression and as valuable indicators for its identification.