High-fat diet-driven gut microbial sphingolipid metabolic reprogramming is associated with stress susceptibility in...

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.