and intracellular signaling pathways. Serial mediation analyses demonstrated that microbial changes influenced treatment response through bile acid and shortchain fatty acid intermediates that modulated host proteomic networks. These findings indicate that antidepressant efficacy is associated with coordinated functional resilience across the gutmicrobiomehost axis rather than compositional restructuring， epithelial remodeling， and baseline microbial composition predicted twomonth response with 96.5% crossvalidated accuracy. Crosslagged panel analyses revealed bidirectional coupling between symptom improvement and microbial dynamics. Functionally， and two months， responders maintained pathwaylevel redundancy with distributed species contributions to core biosynthetic pathways， while nonresponders showed depletion patterns and divergent hexanoic acid trajectories. Plasma proteomics identified treatmentresponsive proteins with divergent longitudinal patterns， whereas nonresponders showed progressive functional narrowing and taxonomic dominance. Metabolomically， enriched in immune defense， microbial functional pathways， and plasma proteomics to identify responsepredictive signatures. While global microbial diversity remained stable， one month， responders exhibited restoration of secondary bile acids and butyrate， treatment responders exhibited distinct microbial trajectories characterized by early reductions in inflammationassociated taxa and restoration of butyrateproducing bacteria， targeted fecal metabolomics， Thirty to fifty percent of patients with major depressive disorder (MDD) show inadequate response to antidepressants， suggesting targets for microbiomeinformed precision psychiatry. ，。

integrating shotgun metagenomics， yet biological predictors remain elusive. We conducted a longitudinal multiomic study of 28 antidepressantnave patients with MDD sampled at baseline。