Abstract
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.
Highlights
Introduction According to the World HealthOrganization, depression has become the leading cause of disability worldwide affecting approximately 300 million people with a lifetime prevalence of 10.7% in men and 18.1% in women in the US1
Male and female high anxiety-like behavior (HAB) and NAB rats were treated with either minocycline (40 mg/kg), escitalopram or a combination of both via the drinking water for 22 days, and fluid intake was monitored daily
(see figure on previous page) Fig. 1 Experimental design and behavioral outcome after treatment of male and female NAB and HAB rats with either vehicle (Veh), minocycline (Min), escitalopram (Esc), or a combination of both (Min+Esc) for 22 days. a After 15 days of treatment, social preference behavior was tested in the social preference test (SPT), followed by evaluation of anxiety-like behavior in the light–dark box (LDB; day 17) and the elevated plus-maze (EPM; day 19), and of depressive-like behavior in the pre-swim and forced swim test (FST; day 22)
Summary
Organization, depression has become the leading cause of disability worldwide affecting approximately 300 million people with a lifetime prevalence of 10.7% in men and 18.1% in women in the US1. Numerous treatment options for major depressive disorder (MDD) are available such as the frequently prescribed and highly efficacious selective serotonin reuptake inhibitor (SSRI) escitalopram[2,3]. To achieve therapies with faster onset, two major approaches can be utilized, i.e. optimization of existing options or the discovery of agents with novel mechanisms of action. Treatment regimens move towards augmentation strategies, a combination of conventional antidepressants with non-antidepressant substances to increase efficacy and overcome treatment resistance[5]. Central inflammation and the microbiome-gut–brain axis are two areas receiving growing traction[6,7]
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