Paroxetine Administration Affects Microbiota and Bile Acid Levels in Mice

Frederik Dethloff, Fernando Vargas, Emmanuel Elijah, Robert Quinn, Dong Ik Park, David P Herzog, Marianne B Müller, Emily C Gentry, Rob Knight, Antonio Gonzalez, Pieter C Dorrestein, Christoph W Turck, Frederik Dethloff, Fernando Vargas, Emmanuel Elijah, Robert Quinn, Dong Ik Park, David P Herzog, Marianne B Müller, Emily C Gentry, Rob Knight, Antonio Gonzalez, Pieter C Dorrestein, Christoph W Turck

Abstract

Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder. Several antidepressant drugs that belong to the class of selective serotonin reuptake inhibitors have been found to display antimicrobial activities. In fact, one of the first antidepressants discovered serendipitously in the 1950s, the monoamine-oxidase inhibitor Iproniazid, was a drug used for the treatment of tuberculosis. In the current study we chronically treated DBA/2J mice for 2 weeks with paroxetine, a selective serotonin reuptake inhibitor, and collected fecal pellets as a proxy for the gut microbiota from the animals after 7 and 14 days. Behavioral testing with the forced swim test revealed significant differences between paroxetine- and vehicle-treated mice. Untargeted mass spectrometry and 16S rRNA profiling of fecal pellet extracts showed several primary and secondary bile acid level, and microbiota alpha diversity differences, respectively between paroxetine- and vehicle-treated mice, suggesting that microbiota functions are altered by the drug. In addition to their lipid absorbing activities bile acids have important signaling activities and have been associated with gastrointestinal diseases and colorectal cancer. Antidepressant drugs like paroxetine should therefore be used with caution to prevent undesirable side effects.

Keywords: antidepressant; bile acids; metabolomics; microbiome; paroxetine.

Copyright © 2020 Dethloff, Vargas, Elijah, Quinn, Park, Herzog, Müller, Gentry, Knight, Gonzalez, Dorrestein and Turck.

Figures

Figure 1
Figure 1
Paroxetine treatment revealed antidepressant-like and anxiolytic effects in DBA/2J mice. Chronic paroxetine (PARO) treatment for 14 days increased time of active coping (p = 1.5 E-7) in the Forced Swim Test (FST). Sample size was n = 10 for PARO group and n = 10 for Vehicle group. Bars represent mean ± SD, ***p

Figure 2

Fecal pellet alpha diversity is…

Figure 2

Fecal pellet alpha diversity is significantly different (p-value = 0.011402, q-value = 0.034207)…

Figure 2
Fecal pellet alpha diversity is significantly different (p-value = 0.011402, q-value = 0.034207) in paroxetine- compared to vehicle-treated mice. Alpha-diversity was compared between treatment and control groups using Faith's Phylogenetic Diversity (PMID: 19455206). Sample sizes were n=8 for Paroxetine 1 week group, n = 12 for Paroxetine 2 week group and n = 20 for Vehicle group.

Figure 3

(A) Fecal pellet bile acid…

Figure 3

(A) Fecal pellet bile acid level ratios following 1 week (1w) and (B)…
Figure 3
(A) Fecal pellet bile acid level ratios following 1 week (1w) and (B) 2 weeks of paroxetine (PARO) treatment, sample size n = 10 each. Bars represent mean log2 fold changes PARO *Vehicle-1. Significance was tested using Student's t-test; significance is indicated (p < 0.05 = *; p < 0.01= **). Several fecal pellet bile acid levels are increased following PARO treatment. (C) Several fecal bile acid levels correlate significantly with behavior, body weight gain, PARO metabolites, and other bile acid levels (indicated with white asterisk, p < 0.1). Correlogram displays the Pearson correlation coefficient values of treatment with PARO. Lower left represents the correlations after 1 week (1w) of treatment und upper right the correlations after 2 weeks (2w) of treatment. Size and color intensity reflect the absolute value as indicated by the color bar. Abbreviations in order of appearance: BWgain, body weight gain; FST, forced swim test; paroxetine, PARO; paroxetine metabolite I, PARO M I; paroxetine metabolite III, PARO M III; F-DCA, phenylalanodeoxycholic acid; F-CA, phenylalanocholic acid; GLCA, glycolithocholic acid; GDCA, glycodeoxycholic acid; DCA, deoxycholic acid.
Figure 2
Figure 2
Fecal pellet alpha diversity is significantly different (p-value = 0.011402, q-value = 0.034207) in paroxetine- compared to vehicle-treated mice. Alpha-diversity was compared between treatment and control groups using Faith's Phylogenetic Diversity (PMID: 19455206). Sample sizes were n=8 for Paroxetine 1 week group, n = 12 for Paroxetine 2 week group and n = 20 for Vehicle group.
Figure 3
Figure 3
(A) Fecal pellet bile acid level ratios following 1 week (1w) and (B) 2 weeks of paroxetine (PARO) treatment, sample size n = 10 each. Bars represent mean log2 fold changes PARO *Vehicle-1. Significance was tested using Student's t-test; significance is indicated (p < 0.05 = *; p < 0.01= **). Several fecal pellet bile acid levels are increased following PARO treatment. (C) Several fecal bile acid levels correlate significantly with behavior, body weight gain, PARO metabolites, and other bile acid levels (indicated with white asterisk, p < 0.1). Correlogram displays the Pearson correlation coefficient values of treatment with PARO. Lower left represents the correlations after 1 week (1w) of treatment und upper right the correlations after 2 weeks (2w) of treatment. Size and color intensity reflect the absolute value as indicated by the color bar. Abbreviations in order of appearance: BWgain, body weight gain; FST, forced swim test; paroxetine, PARO; paroxetine metabolite I, PARO M I; paroxetine metabolite III, PARO M III; F-DCA, phenylalanodeoxycholic acid; F-CA, phenylalanocholic acid; GLCA, glycolithocholic acid; GDCA, glycodeoxycholic acid; DCA, deoxycholic acid.

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