Changes in Gut Microbiota by Chronic Stress Affect the Efficacy of Fluoxetine

Major depressive disorders (MDD) constitute a leading cause of disability worldwide and current pharmacological treatments are partially effective with high relapse rates. The gut microbiota has recently emerged as a potential target of therapeutic interest for MDD, yet the precise mechanisms remain unknown. In the present study, we transferred fecal microbiota from chronically stressed mice to non-stressed recipient mice. We found that chronic stress resulted in gut dysbiosis that was transferable to the recipient mice. The transmitted dysbiosis induced despair-like behavior, decreased hippocampal neurogenesis and weakened the antidepressant and neurogenic effects of a standard selective serotonin reuptake inhibitor, fluoxetine (FLX). These effects were paralleled by a substantial perturbation of key metabolic processes, namely tryptophan metabolism. Supplementation with 5-hydroxytryptophan, the immediate serotonin precursor, restored FLX efficacy and exerted antidepressant effects. Our results reveal that stress-induced changes in gut microbiota are involved in the pathogenesis of depressive disorders and minimize FLX efficacy via perturbations in tryptophan catabolism.