BioTechniques News
Beatrice Bowlby
Emerging evidence has hinted that glucagon-like peptide-1 receptor (GLP-1R) weight loss drugs may be associated with mental health benefits. Now, researchers report that these unexpected side effects could stem from changes in the gut microbiome.
The GLP-1R agonist liraglutide may alleviate depression through an independent gut–brain pathway, scientists from Southeast University (Nanjing, China) have revealed. Using a combination of pharmacological and genetic approaches in mouse models, they highlighted a novel mechanism of action for GLP-1R analogs, which represents a potential therapeutic target for depression.
Despite their widespread use for the treatment of metabolic disease, the neuropsychiatric effects of GLP-1Rs remain poorly understood. “Previous clinical and preclinical studies have been contradictory,” explained co-corresponding author Yonggui Yuan. “Some studies reported antidepressant effects of GLP-1 agonists, while others suggested increased risk of depression or anxiety.”
The conflicting findings underscore an urgent need for further research on the relationship between GLP-1 analogs and depression – which is what Yuan and colleagues set out to provide.
“The prevailing model held that these drugs act directly on GLP-1 receptors in the brain,” Yuan continued, “while our study provides evidence for an alternative pathway.”
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To reach this conclusion, the team used a chronic unpredictable stress (CUS) mouse model and co-administered liraglutide with the specific GLP-1R antagonist exendin 9–39 (Exn9). Liraglutide significantly increased sucrose preference in a sucrose preference test and reduced immobility time in a forced swimming test and tail suspension test – antidepressant-like effects that were not reversed by Exn9.
In CUS-exposed Glp1r−/− knockout mice, the weight- and food-intake-suppressing effects of liraglutide were abolished, but the drug retained antidepressant efficacy, demonstrating that GLP-1R activation is not required for the antidepressant effects of liraglutide.
To identify the mechanism of action, the researchers injected mice with Cy5-labeled liraglutide before in vivo imaging to measure whole-body fluorescence. The fluorescently labeled GLP-1R drug accumulated predominantly in the abdominal region and was enriched in the intestine. Furthermore, depleting the gut microbiota in CUS mice using a cocktail of broad-spectrum antibiotics overturned liraglutide’s antidepressant effects, highlighting the essential role of the microbiome in mediating this pathway.
Multi-omics analysis of fecal samples from the mice enabled the team to identify the specific microbial taxa involved. Specifically, liraglutide increased the abundance of Lactobacillus delbrueckii, which supplies diacylglycerol, a precursor of the endocannabinoid 2-arachidonoylglycerol (2-AG). Using whole-brain c-Fos mapping in CUS mice following fecal microbiota transplants, the researchers realized that 2-AG regulates antidepressant effects by inhibiting neuronal activation in emotion- and stress-related regions of the brain.
Together, the findings showcase how liraglutide ameliorates depressive symptoms via the gut microbiota–endocannabinoid-brain axis.
“The demonstration that a clinically approved metabolic drug can exert neuropsychiatric effects through microbiota-dependent mechanisms opens new avenues for drug repurposing and suggests that the therapeutic potential of existing pharmacological agents may extend far beyond their originally intended targets,” the researchers write in their conclusion.
The post Gut feelings: antidepressant effects of GLP-1s may be explained by the microbiome appeared first on BioTechniques.
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