GLP-1 drugs could act on depression by improving the balance of microorganisms in the intestinal tract, preclinical research suggests.
The findings, in Cell Host & Microbe, suggest extra benefits from this new class of drugs, beyond their metabolic effects on diabetes and obesity.
The GLP-1 receptor agonist liraglutide appeared have mental health benefits on mice, influencing brain function and behavior and reducing symptoms of depression.
This related to an increase in the abundance in the microbe Lactobacillus delbrueckii, which is known to act positively on neurons relating to stress.
Researcher Yonggui Yuan, PhD, from Southeast University in Jiangsu, China, noted mixed results from previous studies into the antidepressant effects from GLP-1 agonists.
“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,” he said.
Emerging evidence suggests this drug class may exert biological effects beyond GLP receptors, such as reducing neuroinflammation after stroke or protecting against cisplatin-induced kidney injury.
The researchers therefore examined the neuropsychiatric effects of liraglutide and found that it had antidepressant effects that remained in mice deficient in the GLP-1 receptor.
The team identified a pathway independent of the GLP-1 receptor through which liraglutide could alleviate depressive-like behaviors in the animals.
Liraglutide encouraged the growth of L. delbrueckii by improving bacterial biosynthesis of serine and phosphoenolpyruvate (PEP), two metabolites that occupy pivotal roles in bacterial central metabolism.
PEP serves as a precursor for biosynthesis of amino acids, nucleotides, and cell wall components while the amino acid serine is a key node in one-carbon metabolism and a precursor for glycine, cysteine, and phospholipid synthesis, all essential for rapid bacterial proliferation.
Increasing levels of L. delbrueckii aided the production of diacylglycerol via triacylglycerol lipase.
This provided a precursor by which the animals could synthesize 2-arachidonoylglycerol (2-AG) levels, to normalize neuronal activity in emotional brain regions.
Gut-derived 2-AG inhibited stress-induced neuronal hyperactivity in the basolateral amygdala and dorsomedial hypothalamus, revealing a microbiota-endocannabinoid axis for potential use in depression therapy.
“Given the growing clinical use of GLP-1R agonists for metabolic disorders and the high comorbidity between metabolic and psychiatric conditions, understanding these pleiotropic, microbiota-mediated effects has important translational implications,” the authors noted.
“More broadly, 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 authors concluded.
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