A new study published in the journal Cell Host & Microbe has completely transformed the scientific community’s understanding of how popular weight-loss and diabetes medications (GLP-1 receptor agonists) affect mental health. Scientists from Southeast University (China) have discovered an alternative biological pathway that explains the antidepressant effects of these drugs.
Until now, it was believed that the drug crosses the blood-brain barrier and acts directly on the receptors of the central nervous system. However, experiments conducted on chronic stress models refuted this principle. It turned out that following administration, the medication primarily accumulates in gut tissues rather than the brain. Moreover, in genetically modified models where GLP-1 receptors were completely knocked out, the drug still fully retained its antidepressant and anti-anxiety effects.
The researchers proved that the improvement in mental state depends entirely on live gut microorganisms—when the microbiome was wiped out using broad-spectrum antibiotics, the drug’s antidepressant effect disappeared as well. Fecal metagenomic sequencing revealed that the treatment leads to a sharp increase in the population of a specific bacterium in the gut: Lactobacillus delbrueckii.
This microbe produces large amounts of a lipid precursor (diacylglycerol), which the host organism converts into the endocannabinoid 2-AG. In turn, the elevated 2-AG acts as a “metabolic brake,” calming the hyperactive, stress-induced brain neural circuits that drive depressive behavior.
According to the scientists, the study showed promising results for the development of personalized medicine, as the use of specific probiotic strains of Lactobacillus delbrueckii could become effective in treating depressed patients who are simultaneously battling obesity or type 2 diabetes. However, the authors note that since the mechanistic testing was conducted only on male models, it is essential to extend future research to female subjects to confirm whether the microbiome-endocannabinoid pathway operates similarly in both sexes.
