Minocycline alters depression, microglia and microbiome in a sex- and trait anxiety-dependent manner

The main cause of disability worldwide is major depressive disorder with limited treatment options. However a number of novel approaches are being assessed, from augmentation strategy to novel approaches like manipulation of the immune system or the microbiome-gut-brain axis. Thus, we examined the potential beneficial effects of minocycline alone or as augmentation of escitalopram on behavior, microglia and microbiome in rats selectively bred for high anxiety-like behavior (HAB), a model of high innate depression and anxiety. We could show that depressive-like, but not anxiety-like behavior, was alleviated by 3 weeks of minocycline treatment exclusively in male HAB rats with a concomitant reduction in microglial numbers in the infralimbic and prelimbic prefrontal cortex. Interestingly, these effects were all blunted when minocycline was administered together with escitalopram. However, female HAB rats did not respond to any treatment provided. Further, minocycline lead to a robust shift in cecal microbial composition in both HAB and rats not selected for anxiety-like behavior. The initial differences between both breeding lines were almost completely balanced after minocycline and correlated with behavioral outcome, suggesting a normalization of the microbiome in HAB rats. Interestingly, minocycline markedly increased abundance of Lachnospiraceae, a family of bacteria known for its butyrate production. Thus, our data suggests a sex- and trait-dependent effect of minocycline on depressive-like behavior that is potentially mediated by a reduced microglial number in the prefrontal cortex and changes in microbial diversity, supporting the microbiota-gut-brain axis as potential target in the treatment of psychiatric disorders.