Liver health may influence mental health via inflammation and glutamate levels

A study in China found that feeding mice a high-fat diet combined with fructose syrup induces neuroinflammation and anxiety-like behaviors. It also damaged their livers in ways similar to what is seen in non-alcoholic fatty liver disease (NAFLD). However, injections of a natural compound called corilagin protected against these adverse changes. The paper was published in Psychopharmacology.

Non-alcoholic fatty liver disease is a condition in which excess fat builds up in the liver of individuals who drink little or no alcohol. It is the most common liver disorder in industrialized countries and is often linked to obesity, insulin resistance, and type 2 diabetes. NAFLD ranges from simple fatty liver (steatosis) to a more severe form called non-alcoholic steatohepatitis, which involves inflammation and liver cell damage.

Over time, non-alcoholic steatohepatitis can progress to fibrosis, cirrhosis, or even liver cancer. Most people with NAFLD have no symptoms, but some may experience fatigue or discomfort in the upper right abdomen. Diagnosis is typically made through imaging tests or liver biopsy. There is currently no specific medication approved for NAFLD, so treatment focuses on weight loss, a healthy diet, and physical activity.

Study author Hongmei Du and her colleagues aimed to explore the relationship between liver injury caused by a high-fat, high-fructose diet and the development of anxiety-like behaviors in mice. In rodent models, anxiety-like behaviors include actions such as avoiding open areas or remaining motionless, which may indicate heightened fear or stress.

The study used 26 male, 8-week-old C57BL/6J mice — a commonly used inbred laboratory strain known for its genetic consistency and predictable behavior in biomedical experiments.

The mice were randomly assigned to three groups. One group was fed a normal diet. The second group received a high-fat diet and had free access to water containing 12.5% fructose syrup. The third group received the same high-fat, high-fructose diet, but also received intraperitoneal injections of corilagin (2.5 mg/kg) every other day.

Corilagin is a natural polyphenol found in several medicinal plants. It has demonstrated anti-inflammatory, antioxidant, and potential anticancer effects in earlier research. In this study, its role was to test whether it could counteract the harmful effects of the high-fat, high-fructose diet.

In addition to these three diet-based groups, the researchers used a second model to test anxiety-like behavior. This involved four more groups of mice, where anxiety was induced using chronic social defeat stress — a method that repeatedly exposes mice to larger, aggressive counterparts over several days. This stress protocol reliably produces behaviors in mice that resemble human depression and anxiety. Of these four groups, two were subjected to chronic social defeat stress, but only one received corilagin. The other two groups served as controls — one with corilagin and one without.

Following the four-week treatments, the mice underwent a battery of behavioral tests designed to assess anxiety-related behaviors. After behavioral testing, the researchers euthanized the mice and analyzed tissue samples from the liver and brain.

Mice that received the high-fat, high-fructose diet developed anxiety-like behaviors. They also showed clear signs of liver damage, including fat accumulation and elevated levels of enzymes indicating liver cell injury. In the brain, signs of inflammation were observed in the cortex and hippocampus — regions associated with emotion and memory.

Mice treated with corilagin showed reduced liver damage, lower inflammation in both the liver and brain, decreased levels of glutamate (a neurotransmitter that can be toxic at high levels), and fewer anxiety-like behaviors. However, corilagin did not alleviate anxiety behaviors in the mice subjected to chronic social defeat stress, suggesting that its behavioral benefits depend on improving liver health, not direct action on the brain.

“This study demonstrated that HFFD [high-fat fructose diet], continued for four weeks, induced anxiety-like behavior, liver damage, and higher levels of transaminases, glutamate, and inflammation in the liver and brain, which were partially reversed by corilagin, a liver protector. These results suggest a potential therapeutic target for patients with NAFLD-induced anxiety disorders to effectively alleviate their symptoms and improve the quality of life,” the study authors concluded.

The study highlights a potentially important link between liver function and mental health — and suggests that dietary interventions or liver-targeted therapies could help address mood disturbances tied to metabolic diseases. However, it is important to note that the research was conducted in mice, not humans. While mouse models offer valuable insights, they do not perfectly replicate human physiology or behavior. Also, corilagin is not currently approved as a medication for use in humans.

The paper, “High-fat Fructose diet induces neuroinflammation and anxiety-like behaviors by modulating liver-brain axis communication,” was authored by Hongmei Du, Yuan Zhou, Jia Wang, Xianbing Bai, Borui Tao, and Ming Chen.