Distinct effects of fish oil and olive oil on neurotransmitter metabolism, gut microbiota, and gut–brain axis dysfunction, depression-like behaviors in CUMS-induced rats

The pathogenesis of depression involves both physiological and psychological factors. Through the gut-brain axis, neurotransmitters, gut barrier function, and microbiota jointly regulate neuroinflammation, influencing brain function and emotional behaviors. Supplementation with omega-3 polyunsaturated and omega-9 monounsaturated fatty acids has been considered to alleviate emotional symptoms in epidemiologic aspects and clinical interventions, respectively. However, the mechanisms by which these lipids regulate neurotransmitter metabolism, neuroinflammation, and gut microbiota to influence mood and behavior remain unclear. Here, 25 Sprague Dawley rats were randomly divided into control (N), chronic unpredictable mild stress (C), drug (P), fish oil (F), and olive oil (O) groups. In behavior tests, all groups, except the F group, exhibited significant anhedonia week 6 onward, with more pronounced symptoms by week 8. The C group exhibited longer immobility in the forced swim test than did the other groups. Interventions with fish and olive oil reduced kynurenine-related metabolites in both the brain and gut. Correlation analyses revealed associations between serotonin, 3-hydroxykynurenine, and kynurenine and behavioral outcomes. The levels of serotonin and 3-hydroxykynurenine in the brain were correlated with corresponding levels in the gut, suggesting metabolic crosstalk. Claudin-1 expression was significantly upregulated in the P and F groups, whereas GPR43 expression was significantly upregulated in the F and O groups. Microbiota analysis revealed an abundance of Akkermansia in the O group and an abundance of Lactobacillus in the F and O groups. The levels of tryptophan- and tyrosine-related metabolites were correlated with the abundances of Lactobacillus , Akkermansia , Alistipes , Lachnoclostridium , and Turicibacter , suggesting that these microbes play a role in regulating the gut–brain axis. • Interventions with fish oil and olive oil reduced KYN-related metabolites in the brain and gut. • Serotonin and 3-HK in the brain were correlated with corresponding levels in the gut. • Claudin-1 and GPR43 expression were significantly upregulated in the fish oil group. • An abundance of Akkermansia in the O group and of Lactobacillus in the F and O groups was observed.