Together with diet, treatment with drugs is a major factor that influences gut microbiota composition. Indeed, the gut microbiota community may contribute to the therapeutic effects of certain drugs. For instance, metformin may act through a close interaction between Bacteroides fragilis, the bile acid glycoursodeoxycholic acid and intestinal farnesoid X receptor to improve metabolic dysfunction in individuals with type 2 diabetes. Although a range of non-antibiotic drugs can have an impact on the gut microbiome, information on the extent to which drug-induced changes in the gut microbiota may partly mediate their therapeutic effects remains elusive.
A new study, led by Dr. Evan Elliott from The Azrieli Faculty of Medicine at Bar-Ilan University (Israel), has found that human antidepressants affect gut microbiota in mice and Ruminococcus flavefaciens mediate the antidepressant effect of duloxetine.
The researchers studied the effects in mice of five commonly prescribed human antidepressants (fluoxetine, escitalopram, venlafaxine, duloxetine or desipramine) with different mechanisms of action on the gut microbiota, using 16S ribosomal ribonucleic acid sequencing.
After 21 days, all the antidepressants, except desipramine, had led to a reduction in microbial community richness. In contrast, all antidepressants led to a higher beta diversity when compared with controls.
When exploring which bacterial taxa differed in concentration in antidepressant-treated mice, Lukić and colleagues found that bacterial taxa abundance in stool samples varied depending on the antidepressant treated group. However, Ruminococcus, Adlercreutzia and an undefined genus belonging to the class Alphaproteobacteria were reduced in all antidepressant groups. Within them, Ruminococcus flavefaciens and Adlercreutzia equolifaciens were the most reduced gut bacteria secondary to antidepressant treatments.
The authors went a step further and examined whether a decrease in R. flavefaciens or A. equolifaciens in the antidepressant groups was causally related to their antidepressant effects. In mice treated with duloxetine that were simultaneously supplemented with R. flavefaciens, the antidepressant properties of the drug—measured through behavioral tests against different stimulus such as mobility and sucrose—were attenuated. However, A. equolifaciens failed to reduce the antidepressive effects of duloxetine. These data show that the role of gut microbiota in mediating the effect of antidepressants may rely specifically on certain gut bacteria.
By analyzing samples of mice’s medial prefrontal cortices, it was also found that the mechanisms behind R. flavefaciens’ effects on the brain function involved an increase of genes that take part in mitochondrial oxidative phosphorylation, which is a mechanism of action reported not only in the manifestation of depression, but also in the therapeutic effects of antidepressants such as fluoxetine. Furthermore, R. flavefaciens also decreased the expression of genes involved in synaptic signaling and neurogenesis, which has been reported as a common feature in patients with depression. The authors explained these findings through the reduced levels of serotonin and noradrenaline in brain regions due to the bacteria. Although R. flavefaciens‘ mechanism of action is not yet close to being elucidated, these results show the direct contribution of a gut bacterium sensitive to antidepressants, which may have an impact on depressive behaviors.
Antidepressants also led to effects on gene transcription of glucocorticoid receptor and protein ubiquitination in the brain that differed to those changes reported by R. flavefaciens.
On the whole, this study shows that the effects of antidepressants may be partly mediated by changes in gut microbiota composition and diversity in mice. Intriguingly, the role of R. flavefaciens in abolishing the effects of the antidepressant duloxetine on depressive-like behavior highlights the relevance of considering the gut microbiota as a new player in the management of behavior disorders.
Lukic I, Getselter D, Ziv O, et al. Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior. Transl Psychiatry. 2019; 9(1):133. doi:10.1038/s41398-019-0466-x.
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