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Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE129359 | GEO | 2019/04/05

REPOSITORIES: GEO

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Project description:To identify gene expression changes associated with Crtc1 deficiency, we performed genome-wide transcriptome profile analyses by using mouse cDNA microarrays in the cortex of Crtc1â/â and WT female mice BACKGROUND: Recent studies involve the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brain of mood disorders patients. We showed that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate neurobehavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. METHODS: The molecular basis of the behavioral phenotype of Crtc1â/â mice was further examined using microarray analysis. We characterized Agmat expression in the prefrontal cortex (PFC) and hippocampus (HIP) by quantitative polymerase chain reaction (qPCR), Western blot (WB) analysis, and confocal immunofluorescence microscopy. The antidepressant effect of agmatine was assessed by the forced swim test (FST). Brain-derived neurotrophic factor (BDNF) levels and eukaryotic elongation factor 2 (eEF2) phosphorylation were measured by WB. RESULTS: Microarray, qPCR and WB analyses revealed an upregulation of Agmat in Crtc1â/â PFC and HIP, where immunofluorescence microscopy showed more Agmat-expressing cells, notably parvalbumin- and somatostatin-interneurons. Acute agmatine treatment efficiently improved depressive-like behavior of Crtc1â/â mice in the FST, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit induced by upregulated Agmat. In WT mice, agmatine rapidly increased BDNF levels and eEF2 dephosphorylation, indicating that it might be a fastâacting antidepressant with NMDA receptor antagonist properties. CONCLUSIONS: Collectively, these findings support the involvement of the agmatinergic system in the depressive-like phenotype of Crtc1â/â mice, and allow a better understanding of the agmatinergic system and its putative role in major depression. RNA from cortex of 5 WT and 5 KO mice was used

Project description:To identify gene expression changes associated with Crtc1 deficiency, we performed genome-wide transcriptome profile analyses by using mouse cDNA microarrays in the cortex of Crtc1‒/‒ and WT female mice BACKGROUND: Recent studies involve the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brain of mood disorders patients. We showed that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate neurobehavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. METHODS: The molecular basis of the behavioral phenotype of Crtc1‒/‒ mice was further examined using microarray analysis. We characterized Agmat expression in the prefrontal cortex (PFC) and hippocampus (HIP) by quantitative polymerase chain reaction (qPCR), Western blot (WB) analysis, and confocal immunofluorescence microscopy. The antidepressant effect of agmatine was assessed by the forced swim test (FST). Brain-derived neurotrophic factor (BDNF) levels and eukaryotic elongation factor 2 (eEF2) phosphorylation were measured by WB. RESULTS: Microarray, qPCR and WB analyses revealed an upregulation of Agmat in Crtc1‒/‒ PFC and HIP, where immunofluorescence microscopy showed more Agmat-expressing cells, notably parvalbumin- and somatostatin-interneurons. Acute agmatine treatment efficiently improved depressive-like behavior of Crtc1‒/‒ mice in the FST, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit induced by upregulated Agmat. In WT mice, agmatine rapidly increased BDNF levels and eEF2 dephosphorylation, indicating that it might be a fast–acting antidepressant with NMDA receptor antagonist properties. CONCLUSIONS: Collectively, these findings support the involvement of the agmatinergic system in the depressive-like phenotype of Crtc1‒/‒ mice, and allow a better understanding of the agmatinergic system and its putative role in major depression.

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Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior

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