The unique role of fluoxetine in alleviating depression and anxiety by regulating gut microbiota and the expression of vagus nerve-mediated serotonin and melanocortin-4 receptors

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used for depression, but its potential effects on gut microbiota regulation and vagus nerve-mediated serotonin receptor expression have not been well studied. We investigated changes in the gut microbiome regulated by fluoxetine and vagus nerve-mediated expression of several serotonin (5-HT) receptor types associated with anxiety and depression. Oral administration of fluoxetine alleviated lipopolysaccharide (LPS)-induced depressive and anxiety behaviors, increased 5-HT1A, 2 C, and melanocortin 4 (MC4) receptor expression, and the composition of Lactobacillus in mice's gut microbiome. In contrast, in the vagotomized group, fluoxetine did not modulate behaviors and receptor expression. Increased Lactobacillus composition was found to correlate significantly with behavioral test results. The importance of Lactobacillus growth to the efficacy of fluoxetine was confirmed by the effectiveness of fluoxetine, which was reduced by co-administering antibiotics. To determine the additional impact of the gut microbiome, we isolated Limosilactobacillus reuteri and Ligilactobacillus murinus, which were increased in the fluoxetine-treated group and administrated. The results showed that administration of each strain improved anxious or depressive behavior, as did fluoxetine, and vagotomy eliminated these effects. These results suggest that fluoxetine administration increases the proportion of Lactobacillus in the gut, which modulates 5-HT1A, 2 C, and MC4 receptor expression through the enteric nervous system and improves depression.