High-fat Fructose diet induces neuroinflammation and anxiety-like behaviors by modulating liver-brain axis communication.

Rationale: Patients with non-alcoholic fatty liver disease (NAFLD) may experience non-cognitive impairments such as anxiety and depression. However, the specific mechanism of the association between liver injury and neurological disorders is unclear.

Objectives: In this study, we aimed to explore the relationship and underlying mechanism between high-fat fructose diet (HFFD)-induced liver injury and anxiety-like behavior in mice.

Methods: A mouse model of NAFLD was established using an HFFD, and behavioral tests were performed to detect anxiety-like behaviors in mice; moreover, we used enzyme linked immunosorbent assay (ELISA) to detect glutamate levels in treated and normal diet (ND) mice, as well as to explore inflammation levels in mice using immunofluorescence and other methods.

Results: Mice in the HFFD-treated group exhibited anxiety-like behaviors, as well as elevated serum lipid and glutamate levels, increased liver injury, and hepatic tissue fat accumulation. Additionally, HFFD-fed mice exhibited elevated levels of IL-6, IL-1β, and TNF-α in the liver, hippocampus, and cortex compared with the ND counterparts; HFFD-induced astrocyte and microglial activation was detected in the cortical and hippocampal regions. However, corilagin treatment alleviated these HFFD-associated pathological changes. Corilagin did not ameliorate anxiety behaviors in mice in the absence of liver injury.

Conclusion: Our results indicated that the HFFD-induced NAFLD and mild hepatic fibrosis led to elevated levels of glutamate and aminotransferases, which infiltrated the brain, causing inflammation, and subsequently induced anxiety-like behaviors in mice. These pathological and behavioral manifestations were ameliorated through corilagin intervention. This study provides a possible underlying mechanism between HFFD and neurological disorders.