Major depressive disorder is the main cause of disability worldwide with imperfect treatment options. However, novel therapeutic approaches are currently discussed, from augmentation strategies to novel treatments targeting the immune system or the microbiome-gut-brain axis. Therefore, we examined the potential beneficial effects of minocycline, a tetracycline antibiotic with pleiotropic, immunomodulatory action, alone or as augmentation of escitalopram on behavior, prefrontal microglial density, and the gut microbiome in rats selectively bred for high anxiety-like behavior (HAB). We show that concomitant with their high innate anxiety and depression, HABs have lower microglial numbers in the infralimbic and prelimbic prefrontal cortex and an altered gut microbiota composition compared with controls. Three weeks of minocycline treatment alleviated the depressive-like phenotype, further reduced microglial density, exclusively in male HAB rats, and reduced plasma concentrations of pro-inflammatory cytokines. However, coadministration of escitalopram, which had no effect alone, prevented these minocycline-induced effects. Moreover, minocycline led to a robust shift in cecal microbial composition in both HABs and rats non-selected for anxiety-like behavior. Minocycline markedly increased relative abundance of Lachnospiraceae and Clostridiales Family XIII, families known for their butyrate production, with a corresponding increase and positive correlation in plasma 3-OH-butyrate levels in a trait-dependent manner. Thus, our data suggest that the antidepressant effect of minocycline is sex- and trait-dependent, associated with a reduced microglial number in the prefrontal cortex, and with changes in microbial composition and their metabolites. These results further support the microbiome-gut–brain axis as potential target in the treatment of depression.

严重的抑郁症是世界范围内残疾的主要原因，治疗选择不完善。然而，目前正在讨论新的治疗方法，从增强策略到针对免疫系统或微生物组-肠道-脑轴的新方法。因此，我们研究了米诺环素，一种具有多效性，免疫调节作用的四环素抗生素，单独或作为依他普仑对行为，前额叶小胶质细胞密度和肠道微生物组的选择性增育对高焦虑样行为（HAB）的潜在影响。 。我们显示，伴随其高高的先天性焦虑和抑郁，HABs在下肢和前肢前额叶皮层中的小胶质细胞数量较低，并且肠道菌群组成与对照组相比发生了变化。米诺环素治疗三周缓解了抑郁样表型，仅在雄性HAB大鼠中进一步降低了小胶质细胞密度，并降低了促炎细胞因子的血浆浓度。但是，依他普仑单独给药不能单独发挥作用，但可以预防这些由米诺环素引起的作用。此外，米诺环素导致未选择焦虑样行为的HAB和大鼠的盲肠微生物组成发生强烈变化。米诺环素显着增加了Lachnospiraceae和Clostridiales家族XIII的相对丰度，这些家族以其丁酸盐的产生而闻名，并且血浆中3-OH-丁酸盐的水平以特征依赖的方式相应增加并呈正相关。因此，我们的数据表明，美满霉素的抗抑郁作用与性别和性状有关，与额叶前额叶皮层中的小胶质细胞数量减少，微生物组成及其代谢物的变化有关。这些结果进一步支持了微生物组-肠-脑轴作为抑郁症治疗的潜在靶标。