Accumulating evidence demonstrates that the gut microbiota affects brain function and behavior, including depressive behavior. Antidepressants are the main drugs used for treatment of depression. We hypothesized that antidepressant treatment could modify gut microbiota which can partially mediate their antidepressant effects. Mice were chronically treated with one of five antidepressants (fluoxetine, escitalopram, venlafaxine, duloxetine or desipramine), and gut microbiota was analyzed, using 16s rRNA gene sequencing. After characterization of differences in the microbiota, chosen bacterial species were supplemented to vehicle and antidepressant-treated mice, and depressive-like behavior was assessed to determine bacterial effects. RNA-seq analysis was performed to determine effects of bacterial treatment in the brain. Antidepressants reduced richness and increased beta diversity of gut bacteria, compared to controls. At the genus level, antidepressants reduced abundances of Ruminococcus , Adlercreutzia , and an unclassified Alphaproteobacteria. To examine implications of the dysregulated bacteria, we chose one of antidepressants (duloxetine) and investigated if its antidepressive effects can be attenuated by simultaneous treatment with Ruminococcus flavefaciens or Adlercreutzia equolifaciens . Supplementation with R. flavefaciens diminished duloxetine-induced decrease in depressive-like behavior, while A. equolifaciens had no such effect. R. flavefaciens treatment induced changes in cortical gene expression, up-regulating genes involved in mitochondrial oxidative phosphorylation, while down-regulating genes involved in neuronal plasticity. Our results demonstrate that various types of antidepressants alter gut microbiota composition, and further implicate a role for R. flavefaciens in alleviating depressive-like behavior. Moreover, R. flavefaciens affects gene networks in the brain, suggesting a mechanism for microbial regulation of antidepressant treatment efficiency.

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During the past decade, there has been a substantial rise in the knowledge about the effects of gut microbiota on host physiology and behavior, including depressive behavior. Initial studies determined that gut microbiota can regulate host tryptophan levels, which is a main serotonin precursor. A dysfunctional serotonergic system is considered to be one of the main factors contributing to the development of depression. Therefore, we hypothesized that regulation of brain tryptophan and serotonin can explain, at least partly, the effects of microbiota on depressive behavior. To test this hypothesis, we examined depressive-like behavior and brain levels of serotonin and tryptophan, of germ free (GF) and specific-pathogen free (SPF) mice under basal conditions, or after acute tryptophan depletion (ATD) procedure, which is a method to decrease tryptophan and serotonin levels in the brain. In basal conditions, GF mice exhibited less depressive-like behavior in sucrose preference, tail-suspension and forced swim tests, compared to SPF mice. In addition, in mice that were not subjected to ATD, GF mice displayed higher levels of tryptophan, serotonin and 5-hydroxyindoleacetic acid (the main degradation product of serotonin) in medial prefrontal cortex (mPFC) and hippocampus (HIPPO), compared to SPF mice. Interestingly, ATD increased depressive-like behavior of GF, but not of SPF mice. These behavioral changes were accompanied by a stronger reduction of tryptophan, serotonin and 5-hydroxyindoleacetic acid in mPFC and HIPPO in GF mice after ATD, when compared to SPF mice. Therefore, the serotonergic system of GF mice is more vulnerable to the acute challenge of tryptophan reduction, and GF mice after tryptophan reduction behave more similarly to SPF mice. These data provide functional evidence that microbiota affects depression-like behavior through influencing brain tryptophan accessibility and the serotonergic system.

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Background: Oxidative stress is reliably observed in major depressive disorder (MDD). However, molecular data on the principal cellular redox-sensitive transcriptional factors and the levels of their downstream-regulated antioxidant enzymes in MDD are scarce. Methods: In the peripheral blood mononuclear cells (PBMC) of subjects with a current episode of MDD (n = 30) and healthy controls (n = 35), we investigated alterations in the levels of redox-sensing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, its inhibitor Keap1, and nuclear factor-κB (NF-κB), along with their cognate downstream effectors, the antioxidant enzymes (AOEs): manganese and copper zinc superoxide dismutase (MnSOD and CuZnSOD, respectively), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR). Results: MDD subjects exhibited higher levels of Nrf2 and its regulator Keap1, as well as NF-κB in the cytoplasm of PBMC compared to controls. This state was further reflected by increased levels of MnSOD, CuZnSOD and CAT proteins and by the lack of correlation between MnSOD and CAT, which could indicate impaired oxidative detoxification capacity in MDD patients. Moreover, increased levels of MnSOD, CuZnSOD and CAT in MDD patients positively correlated with levels of Nrf2, while increased levels of SODs were also positively related to NF-κB. There were no differences regarding the levels of GPx and GLR proteins, but the ratio of GLR/GPx was reduced, suggesting diminished capacity of GPx in antioxidative defence in PBMC of MDD subjects. Conclusion: These data provide evidence that MDD is characterized by up-regulation of redox-sensitive transcriptional factors (Nrf2 and NF-κB) and AOEs (MnSOD, CuZnSOD and CAT), indicating pro-oxidative state in the PBMC of MDD patients.

Autism spectrum disorder (ASD) presents a wide, and often varied, behavioral phenotype. Improper assessment of risks has been reported among individuals diagnosed with ASD. Improper assessment of risks may lead to increased accidents and self-injury, also reported among individuals diagnosed with ASD. However, there is little knowledge of the molecular underpinnings of the impaired risk-assessment phenotype. In this study, we have identified impaired risk-assessment activity in multiple male ASD mouse models. By performing network-based analysis of striatal whole transcriptome data from each of these ASD models, we have identified a cluster of glutamate receptor-associated genes that correlate with the risk-assessment phenotype. Furthermore, pharmacological inhibition of striatal glutamatergic receptors was able to mimic the dysregulation in risk-assessment. Therefore, this study has identified a molecular mechanism that may underlie risk-assessment dysregulation in ASD.