Liraglutide alleviates depression in mice via gut microbiota-endocannabinoid pathway, independent of GLP-1R activation

Glucagon-like peptide-1 receptor (GLP-1R) agonists are widely prescribed for metabolic diseases like type 2 diabetes and obesity. However, their neuropsychiatric effects, particularly on depressive symptoms, remain poorly understood and controversial. While GLP-1R activation is central to their metabolic actions, it's unclear if this mechanism extends to their potential mood-modulating effects, leaving a significant gap in understanding their broader therapeutic potential beyond direct receptor engagement.

Researchers investigated liraglutide's antidepressant effects in mice using both pharmacological (e.g., GLP-1R antagonist Exn9 treatment) and genetic (Glp1r-/- mice) approaches. They assessed depression-like behaviors and then explored underlying mechanisms by depleting gut microbiota. Multi-omics analyses were employed to identify specific microbial and metabolic changes. Finally, fecal microbiota transplantation (FMT) from liraglutide-treated mice and colonization with specific bacterial strains were performed to confirm causality.

Liraglutide consistently demonstrated antidepressant efficacy in mice. Crucially, this effect persisted even when GLP-1R was pharmacologically blocked with Exn9 or genetically absent in Glp1r-/- mice, indicating a GLP-1R-independent mechanism. Conversely, gut microbiota depletion completely abolished liraglutide's antidepressant effects, highlighting the microbiota's essential role. Multi-omics analyses revealed that liraglutide significantly increased the abundance of Lactobacillus delbrueckii. This increase, in turn, restored levels of the endocannabinoid 2-arachidonoylglycerol (2-AG). The elevation of 2-AG was found to mediate the antidepressant effects by normalizing excessive neuronal activity in brain regions critical for emotional processing.

Importantly, fecal microbiota transplantation from liraglutide-treated mice or direct colonization with Lactobacillus delbrueckii alone successfully replicated the antidepressant effects.