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Background The diagnosis, treatment, and prevention of atherosclerosis co-depression are poor, so it is urgent to explore new targets. Based on the "microbiota-gut-brain axis," this study aimed to investigate the changes of lipid metabolites in the prefrontal cortex and hippocampus regions and the characteristics of the gut microbiota in ApoE-/- mice with atherosclerosis co-depression. Methods ApoE-/- mice (hyperlipid feeding combined with binding, HFB group, n = 14, male) fed a high-fat diet for 16 weeks with binding stimulation were u