Background: The gut microbiome has been implicated in the onset and progression of depression. Yet, the role of the gut virome in depression remains unexplored, and a diagnostic model has not been satisfactorily constructed.Methods: Herein, we analysed the gut virome profiles of 29 patients with depression and 33 healthy controls using bulk metagenome sequencing.Results: A total of 45 differentially abundant viral taxa were identified, among which four, s_Stenotrophomonas_virus_Pokken, g_Pokkenvirus, s_Dickeya_virus_AD1, and g_Alexandravirus, demonstrated strong diagnostic potential (AUCs > 0.8). These four viruses also exhibited strong correlations, suggesting they may constitute a synergistic ecological cluster. Function annotation revealed seven metabolic pathways with significant differences, including alanine, aspartate, and glutamate metabolism, branched-chain amino acid (BCAA) biosynthesis, and energy metabolism in patients with depression.Conclusion: This study identified four distinct viral signatures for depression and proposes novel viral biomarkers for the diagnosis of depression, offering a robust diagnostic approach and new insights into the pathological mechanisms of depression.

The escalating comorbidity between depression and metabolic syndromes induced by a high-fat diet (HFD) poses a substantial social and economic burden on society. However, the precise molecular mechanisms by which a HFD qualitatively alters the basal pathophysiology of chronic unpredictable mild stress (CUMS) remain unclear. In this study, the differential roles of microbial and metabolic pathways in the onset and exacerbation of depression were investigated using CUMS rat models fed a normal diet (ND-CUMS) or HFD (HFD-CUMS). Our findings indicated that HFD intervention showed a trend toward aggravating depressive behaviors and resulted in significantly more severe neuronal injury in the hippocampus relative to the ND-CUMS group. Notably, integrated multi-omics (metagenome and metabolome) analysis revealed a crucial pathway divergence: basal CUMS depression was strongly associated with the dysregulation of glycerophospholipid metabolism, linked to microbiota such as Bacteroides thetaiotaomicron and Terrisporobacter glycolicus , while HFD triggered a predominant disruption of the sphingolipid metabolism pathway. Exploratory mediation analysis suggested that a sphingolipid-related signature that may statistically connect HFD-associated microbial shifts with neural injury and behavioral readouts. Therefore, our findings reveal a distinct mechanistic shift underpinning metabolic-comorbid depression. HFD does not merely exacerbate stress-induced depression but fundamentally transitions the underlying pathology from glycerophospholipid to sphingolipid signaling, highlighting the potential of targeting specific lipid metabolic reprogramming as a promising therapeutic strategy for combating metabolic-comorbid depression.