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

Iva Lukić, Dmitriy Getselter, Oren Ziv, Oded Oron, Eli Reuveni, Omry Koren, Evan Elliott

Research output: Contribution to journalArticlepeer-review

173 Scopus citations

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. Moreover, R. flavefaciens affects gene networks in the brain, suggesting a mechanism for microbial regulation of antidepressant treatment efficiency.

Original languageEnglish
Article number133
JournalTranslational Psychiatry
Volume9
Issue number1
DOIs
StatePublished - 9 Apr 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

We thank Dr. S. Morais from Ben-Gurion University for useful advice regarding culturing of R. flavefaciens. We thank N. Werbner from Faculty of medicine, Bar-Ilan University, for help during bioinformatic analyses of microbial sequencing. We thank Ilya Borovok for useful discussions regarding R. flavefaciens. We thank Marina Kurtz from Genomic Center at Bar-Ilan University, and Dr. Efrat Kligun from Genome Center at Technion, regarding bacterial and RNA sequencing. This work was funded by Teva Pharmaceuticals as part of their support of the Bar Ilan University Faculty of Medicine and by the Israel Science Foundation (Grant number 898/17). We thank to Miri Cohen-Zinder from the Institute of Animal Science at Newe Yaar Research Center, Israel, who provided us with rumen fluid for R. flavefaciens growth.

FundersFunder number
Bar Ilan University Faculty of Medicine
Teva Pharmaceuticals
Teva Pharmaceutical Industries
Israel Science Foundation898/17

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