Some people taking GLP-1 drugs for diabetes and obesity experience mental health benefits—particularly, a decrease in symptoms of depression. In a mouse model study in the Cell Press journal Cell Host & Microbe publishing on June 10, researchers report that these mental health improvements appear to result from changes in the gut microbiome that lead to an abundance of a microbe strain known to have a favorable effect on neurons related to stress.
"Previous clinical and preclinical studies have been contradictory," says co-corresponding author Yonggui Yuan of Southeast University in Jiangsu, China. "Some studies reported antidepressant effects of GLP-1 agonists, while others suggested increased risk of depression or anxiety. The prevailing model held that these drugs act directly on GLP-1 receptors in the brain, while our study provides evidence for an alternative pathway."
For this study, the researchers used the weight-loss drug liraglutide, marketed under the brand names Victoza and Saxenda. To determine the drug's effect on the brain, the team mimicked stress in mouse models. "We observed that when we systemically administered liraglutide to the mice, it accumulated predominantly in the intestine rather than the brain," says co-corresponding author Bing Han, also of Southeast University.
Using standard behavioral tests, the researchers showed that liraglutide retained its antidepressant activity even in mice with GLP-1 receptors knocked out. This suggested the effects came about through another pathway.
The team then showed that mice whose gut microbiota had been depleted using broad-spectrum antibiotics did not experience liraglutide's antidepressant effects, pointing to a key role for the microorganisms in the gut.
To identify specific microbial taxa involved, the team studied fecal samples from the mice. Among the microorganisms altered by liraglutide, Lactobacillus delbrueckii was the most significantly increased species. L. delbrueckii produces diacylglycerol—a precursor that is converted into the endocannabinoid 2-arachidonoylglycerol (2-AG). Elevated 2-AG is known to normalize hyperactivation in stress-related brain regions.
"We found that the abundance of L. delbrueckii correlated with behavioral improvements," says co-corresponding author Honghong Yao, also of Southeast University.
This finding revealed a brain-gut microbiota connection that directly links metabolic drugs such as liraglutide to mood regulation.
The researchers say the finding suggests several potential clinical applications, including treating patients with metabolic conditions such as diabetes and obesity who are also experiencing depression and targeting depression through probiotic intervention.
They also note several limitations to the work, including the fact that it was done in mouse models, not humans, and that the mice were all male. Because depression is different in males and females, it's important to determine whether the mechanisms are the same in both sexes, says the team.
