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

Gut Microbial Signatures Can Discriminate Unipolar from Bipolar Depression

“…To identify the microbial biomarkers that most accurately reflect the underlying pathology of MDD and BD, and because emerging studies have shown that gut microbial composition may be influenced by antidepressants and antipsychotics, only well‐matched unmedicated subjects were recruited in the discovery set. In the validation set, to better confirm the diagnostic generalizability of our differential diagnostic assay in a closer‐to‐real‐world scenario, the samples were not matched on age and gender.…”

Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression

“…16,22,23 Moreover, recent experiments showed that FLX alters the gut microbiota in rats, 24,27 and in mice. 25,26,28,29 Interestingly, the specific bacteria underlying this difference do not match between studies (Table 1). Whereas we found significant increases in Prevotella and Ruminococcus relative abundance during pregnancy and lactation in FLX-treated rats, Cussotto et al report a complete depletion of some Prevotella OTUs in FLX-treated male rats, 24 and Lukić et al found many Ruminococcaceae OTUs to be lower in FLX-and escitalopram-treated mice relative to controls.…”

“…9 Several studies have found alterations in the gut microbiota composition of patients with major depression [10][11][12][13][14][15][16] and rodents with depressive-like symptoms. [17][18][19][20][21] Moreover, recent human population-based studies, 16,22,23 as well as rodent experiments, [24][25][26][27][28][29] showed that SSRIs modulate the gut microbiota composition, an effect that may be related to their in vitro antimicrobial properties. 24,30,31 The gut microbiota synthesizes a variety of metabolites that reach the systemic circulation, 32,33 which is of special relevance during pregnancy and lactation when there is a high metabolic demand.…”

Determining the association between fibromyalgia, the gut microbiome and its biomarkers: A systematic review

“…Minerbi's group [27] also collected information regarding drug use and smoking status, but little attention was given to these as confounders, nor was detail regarding the type, or extent of drug use or smoking provided. Drugs of many kinds may impact gut bacteria and their metabolism, and vice-versa: smoking is associated with an altered gut microbial profile [48] and the Ruminococcus genus (which was overexpressed in Clos-Garcia's patient group) can impact antidepressant metabolism, drugs which also alter the gut microbiota [49].…”