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

, 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.