Multi–omic Longitudinal Profiling Reveals Coordinated Gut Microbiota, Metabolomics, and Host Proteomics Signatures Predictive of Antidepressant Response in Drug–Naïve Depression

Thirty to fifty percent of patients with major depressive disorder (MDD) show inadequate response to antidepressants, yet biological predictors remain elusive. We conducted a longitudinal multi–omic study of 28 antidepressant–naïve patients with MDD sampled at baseline, one month, and two months, integrating shotgun metagenomics, microbial functional pathways, targeted fecal metabolomics, and plasma proteomics to identify response–predictive signatures. While global microbial diversity remained stable, treatment responders exhibited distinct microbial trajectories characterized by early reductions in inflammation–associated taxa and restoration of butyrate–producing bacteria, and baseline microbial composition predicted two–month response with 96.5% cross–validated accuracy. Cross–lagged panel analyses revealed bidirectional coupling between symptom improvement and microbial dynamics. Functionally, responders maintained pathway–level redundancy with distributed species contributions to core biosynthetic pathways, whereas non–responders showed progressive functional narrowing and taxonomic dominance. Metabolomically, responders exhibited restoration of secondary bile acids and butyrate, while non–responders showed depletion patterns and divergent hexanoic acid trajectories. Plasma proteomics identified treatment–responsive proteins with divergent longitudinal patterns, enriched in immune defense, epithelial remodeling, and intracellular signaling pathways. Serial mediation analyses demonstrated that microbial changes influenced treatment response through bile acid and short–chain fatty acid intermediates that modulated host proteomic networks. These findings indicate that antidepressant efficacy is associated with coordinated functional resilience across the gut–microbiome–host axis rather than compositional restructuring, suggesting targets for microbiome–informed precision psychiatry.