Fluoxetine-induced alteration of murine gut microbial community structure: evidence for a microbial endocrinology-based mechanism of action responsible for fluoxetine-induced side effects

Abstract

BackgroundDepression and major depressive disorder affect 25% of the population. First line treatment utilizing selective serotonin reuptake inhibitors (SSRIs) have met with limited success due to well-recognized negative side effects which include weight gain or loss. This inability to control unwanted side effects often result in patients stopping their antidepressant medications. The mechanisms underlying the failure of SSRIs are incompletely understood.MethodsMale CF-1 mice (5 weeks of age, N = 10 per group) were per orally administered fluoxetine (20 mg per kg body weight) or diluent daily for 29 days. During this time fecal specimens were collected at three defined time points (0, 15 and 29 days). At the conclusion of the 29-day dosing regimen, animals were subjected to two behavioral assessments. For bacterial identification of the microbiota, 16S rRNA gene sequencing was performed on 60 fecal specimens (three specimens per mouse time course, N = 20 mice) using Illumina MiSeq. Analysis of community sequence data was done using mothur and LEfSe bioinformatic software packages.ResultsDaily per oral administration of fluoxetine for 29 days to male mice resulted in a significant, time dependent, alteration in microbial communities accompanying changes in body weight. The calculated species richness and diversity indicators of the murine fecal microbial communities were inconsistent and not significantly different between the groups. Among the phylotypes decreased in abundance due to fluoxetine administration were Lactobacillus johnsonii and Bacteroidales S24-7 which belong to phyla associated with regulation of body mass. The observed changes in body weight due to fluoxetine administration mimicked the dramatic shifts in weight gain/loss that has been observed in humans. Further, at the conclusion of the 29-day dosing regimen fluoxetine-dosed animals evidenced a mild anxiogenic-like behavior.DiscussionWe report that the most widely used antidepressant, fluoxetine, which is an SSRI-type drug, results in the selective depletion of gut microbiota, specifically the Lactobacilli which are involved in the regulation of body weight. Concomitantly, fluoxetine administration increases the abundance of phylotypes related to dysbiosis. Since Lactobacilli have been previously shown to possess a known biogenic amine transporter that regulates the uptake of fluoxetine, it is proposed that a microbial endocrinology-based mechanistic pathway is responsible for the ability of SSRIs to selectively negatively impact beneficial microbiota. The results of this study therefore suggest that the negative clinical side effects due to fluoxetine administration may be due to alterations in gut microbiota. Further, the data also suggests that supplementation of bacterial genera directly affected by fluoxetine administration may prove useful in ameliorating some of the well-known side effects of chronic fluoxetine administration such as weight alterations.

The Effects of Gelatinized Wheat Starch and High Salt Diet on Gut Microbiota and Metabolic Disorder

“…This is consistent with the gut microbial composition in metabolic diseases revealed by many researchers [24]. The Muribaculum genus, previously classified as S24-7, is known to decrease in mice on high-fat diet and is associated with the regulation of body weight [25,26]. Moreover, Romboutsia, which is an obesity-related phylotype, is positively associated with lipid profile and lipogenesis in the liver [27].…”

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

“… Study Study design Highlighted findings FLX-treated vs vehicle-treated animals Corresponds to current results? Cussotto et al 2019 24 Male rats, 28 days of 10 mg/kg/day, in drinking water Alpha diversity: no significant difference Yes OTU abundance: depletion of Prevotella 7 and 9 No; we found increases in Prevotella Lyte et al 2019 25 Male mice, 29 days of 20 mg/kg/day, oral gavage Alpha diversity: no significant difference Yes OTU abundance: decrease in S24–7 ( Bacteroidales ) Potentially; we found decreases in several Bacteroidales OTUs Lukić et al 2019 26 Male mice, 21 days of 10 mg/kg/day, IP injections Alpha diversity: decrease No OTU abundance: decrease in Ruminococcus No Zhu et al 2019 27 Male rats, 21 days of 2 mg/kg/day, oral gavage, daily stress Alpha diversity: no significant difference Yes OTU abundance: Prevotellaceae Ga6A1 decreased, and Ruminoclostridium 6 and Ruminococcaceae NK4A214 increased Potentially; we found increases in Ruminococcus Fung et al 2019 28 Male and female mice, 7 days of 10 mg/kg/day, oral gavage OTU abundance: decrease in Turicibacter No (data not shown) Sun et al 2019 29 Male mice, 21 days of 12 mg/kg/day, oral gavage, daily stress Alpha diversity: no significant difference Yes …”

“… 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.…”

Unravelling the antimicrobial action of antidepressants on gut commensal microbes

“…Besides, other evidence gathered from animal studies suggested that the antidepressants modulate the composition of the intestinal microbiota 9,[16][17][18] . Administration of TCA desipramine causes important side effects and results in a higher incidence of infections generating gingivitis and dysbiosis of oral microbiota 19 .…”