Institut Pasteur, Perception and Memory Unit, 75015 Paris, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 3571, 75015 Paris, France.
Institut Pasteur, Microenvironment and Immunity Unit, 75724 Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1224, 75724 Paris, France.
Cell Rep. 2020 Mar 17;30(11):3682-3690.e6. doi: 10.1016/j.celrep.2020.02.099.
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.
重度抑郁症（MDDs）是全球致残的主要原因，目前的药物治疗部分有效。肠道微生物群（GM）最近成为 MDDs 的治疗靶点。在这项研究中，我们将经历不可预测的慢性轻度应激（UCMS）的小鼠的 GM 转移到健康的受体小鼠中。粪便转移会导致类似绝望的行为，减少海马（HpC）中的神经发生，并损害标准选择性 5-羟色胺（5-HT）再摄取抑制剂氟西汀（FLX）的抗抑郁和神经发生作用。这些影响与 HpC 中 5-HT 生物利用度、生物合成和再摄取的缺陷相平行。5-羟色氨酸治疗可恢复 HpC 中 5-HT 及其前体的水平，改善 HpC 神经发生，并缓解类似绝望的症状。我们的结果表明，GM 中应激诱导的变化参与了抑郁障碍的发病机制，并通过色氨酸代谢的 5-HT 途径的改变最小化了 FLX 的疗效。
