High-cholesterol diet promotes depression- and anxiety-like behaviors in mice by impact gut microbe and neuroinflammation

Neuropsychiatric disorders, including anxiety and depression, are one of the most common mental illnesses worldwide. A growing body of evidence shows that there is a complex relationship between dietary patterns and mental health. In our study, C57BL/6J mice were divided into three groups: control diet group (CON, 10 % kcal fat), high-cholesterol diet model group (HCD, 42.0 % kcal fat + 1.25 % kcal Cholesterol), and chronic restraint stress group (CRS, 10 % kcal fat) which as a positive control group for the depression model. Six weeks later, depressive- and anxiety-like behavior were evaluated for using the OFT, SPT and TST. Glucose intolerance and liver fat were detected by IGTT and liver lipid kit. The expression of peripheral and central inflammation was detected by LEGEND plex kits. 5-HT (also named 5-hydroxytryptamine, 5-HT) and related receptors expression were monitored by ELISA, RT-PCR and Western blot. Meantime, gut microbe of stool samples was performed by 16S rRNA gene sequencing. Similar to CRS model, short-term HCD intervention induced anxiety and depression-like behavior behavioral abnormalities in mice. HCD consumption resulted in significantly increased body weight, liver fat (LDL-C, TC, TG), peripheral inflammation (IL-1β, MCP-1, IL-17A) and neuroinflammation (MCP-1). The concentration of 5-HT increased in the hippocampus, meanwhile, the expression of 5-HT receptor HTR2A was distinct in different regions of the brain tissue. More importantly, we found that compared with the CON diet, HCD induced the decrease of intestinal flora diversity, especially the decrease the relative abundance of Akkermansia_muciniphila, which was statistically significant. Further, Pearson correlation analysis showed that Akkermansia_muciniphila was significantly negatively correlated with the concentration of MCP-1, IL-17A in serum and 5-HT in hippocampus. Therefore, we speculated that the disorder of neuroinflammation induced by HCD consumption promotes depression- and anxiety-like behaviors in mice through the gut microbe.