Microbiota-driven gut-brain signaling underlies antidepressant effects of a GLP-1 analog

Jun 10, 2026Cell host & microbe

Gut bacteria signals may explain antidepressant effects of a GLP-1 drug

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Abstract

Liraglutide increased the abundance of Lactobacillus delbrueckii, which is associated with antidepressant effects.

Liraglutide alleviates depression through a gut-brain pathway that does not rely on the GLP-1 receptor.
Antidepressant effects of liraglutide are maintained even in the absence of GLP-1 receptors in mice.
Depletion of gut microbiota negates the antidepressant effects of liraglutide.
Increased levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are linked to the antidepressant effects of liraglutide.
Fecal microbiota transplantation from liraglutide-treated mice replicates the observed antidepressant effects.

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Despite widespread clinical use of glucagon-like peptide-1 receptor (GLP-1R) agonists for metabolic disease, their neuropsychiatric effects remain poorly understood and controversial. Here, we demonstrate that liraglutide alleviates depression through a gut-brain pathway that operates independently of GLP-1R. Using both pharmacological and genetic approaches, we demonstrated that liraglutide retained antidepressant efficacy in GLP-1R antagonist-Exn9-treated mice or in Glp1rmice, whereas gut microbiota depletion abolished its effects. Multi-omics analyses revealed that liraglutide increased the abundance of Lactobacillus delbrueckii, which in turn restored the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG). The elevation of 2-AG mediated the antidepressant effects by normalizing excessive neuronal activity in emotional processing brain regions. Importantly, fecal microbiota transplantation from liraglutide-treated mice or Lactobacillus delbrueckii colonization replicated the antidepressant effects. These findings uncover a non-canonical mechanism of action for GLP-1 analogs, highlighting a specific microbiota-endocannabinoid metabolic pathway as a potential therapeutic target for depression. -/-

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Microbiota-driven gut-brain signaling underlies antidepressant effects of a GLP-1 analog

Abstract

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