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

Abstract

Summary: Major depressive disorders (MDDs) constitute a leading cause of disability worldwide and current pharmacological treatments are partially effective. The gut microbiota (GM) has recently emerged as a target of therapeutic interest for MDDs. In this study, we transfer GM from mice that sustained unpredictable chronic mild stress (UCMS) to healthy recipient mice. The fecal transfer induces despair-like behavior, decreases neurogenesis in the hippocampus (HpC), and impairs the antidepressant and neurogenic effects of a standard selective serotonin (5-HT) reuptake inhibitor, fluoxetine (FLX). These effects are paralleled by deficits in 5-HT bioavailability, biosynthesis, and reuptake in the HpC. Treatment with 5-hydroxytryptophan restores the levels of 5-HT and its precursors in the HpC, improves HpC neurogenesis, and alleviates despair-like symptoms. Our results reveal that stress-induced changes in GM are involved in the pathogenesis of depressive disorders and minimize FLX efficacy via alterations in the serotonergic pathway of Trp metabolism. : Siopi et al. demonstrate that perturbations in the gut microbiota by chronic stress induce resistance to serotonergic antidepressants via impairments in serotonin biosynthesis and bioavailability. Supplementation with the immediate serotonin precursor 5-hydroxytrytophan restores serotonin levels and neurogenesis in the hippocampus and confers resilience. Keywords: gut microbiota, chronic stress, depression, adult hippocampal neurogenesis, tryptophan, 5-hydroxytryptophan, serotonin, fluoxetine