Fluoxetine ameliorates dysbiosis in a depression model induced by chronic unpredicted mild stress in mice - PubMed (original) (raw)

. 2019 Sep 7;16(9):1260-1270.

doi: 10.7150/ijms.37322. eCollection 2019.

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Fluoxetine ameliorates dysbiosis in a depression model induced by chronic unpredicted mild stress in mice

Lijuan Sun et al. Int J Med Sci. 2019.

Abstract

Background: Accumulating evidence has shown that neuropsychiatric disorders are associated with gut microbiota through the gut-brain axis. However, the effects of antidepressant treatment on gut microbiota are rarely studied. Here, we investigated whether stress led to gut microbiota changes and whether fluoxetine plays a role in microbiota alteration. Methods: We investigated changes in gut microbiota in a depression model induced by chronic unpredicted mild stress (CUMS) and a restoration model by applying the classic antidepressant drug fluoxetine. Results: We found that stress led to low bacterial diversity, simpler bacterial network, and increased abundance of pathogens, such as Escherichia/Shigella, and conditional pathogens, such as Enterococcus, Vagococcus, and Aerococcus. However, these changes were attenuated by fluoxetine directly and indirectly. Furthermore, the correlation analysis indicated strong correlations between gut microbiota and anxiety- and depression-like behaviors. Conclusions: This study revealed that fluoxetine led to restoration of dysbiosis induced by stress stimulation, which may imply a possible pathway through which one CNS target drug plays its role in reshaping the gut microbiota.

Keywords: depression; fluoxetine; gut-brain axis; microbiota; stress.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1

Figure 1

Fluoxetine showed a significant antidepressant and mild anti-anxiety effects in CUMS mice. (A) Experimental design of the study. (B) Body weight was measured weekly in all groups during the 6 weeks of CUMS.*P < 0.05, control+PBS_vs._ CUMS+PBS group; △P<0.05, control+PBS_vs._CUMS+fluoxetine, as measured by independent samples _t_-test. (C) SP at 1 h (_F_2,28=3.340, _P_=0.051), 4 h (_F_2,28=3.252, _P_=0.054), 16 h (_F_2,28=2.645, _P_=0.089), and 24 h (_F_2,28=4.928, _P_=0.015). (D) Time spent struggling and immobile in the TST (_F_2,28=8.572, _P_=0.001). (E) Time spent in all arms (_F_2,28=2.650, _P_=0.089) and in open arm in the EPM (_F_2,28=10.866, _P<_0.001). (F) Distance travelled (_F_2,28=1.299, _P_=0.289) and time spent in center in OFT (_F_2,28=0.768, _P_=0.523). Data are presented as mean ± S.E.M. Differences between the three groups were measured by one-way ANOVA. Time spent in arms and distance travelled are covariates for time spent in open arms and time in center respectively. *P < 0.05 **P < 0.01, between two groups, as measured by independent samples _t_-test. CUMS: chronic unpredictable mild stress; EPM: elevated plus maze; OFT: open-field test; SP: sucrose preference; TST: tail-suspension test.

Figure 2

Figure 2

Fluoxetine ameliorated the altered composition, low bacterial diversity and simple bacterial network induced by CUMS. (A) Shannon diversity scores. (B) PCoA analysis plots of Bray-Curtis dissimilarity between groups. (C) Network analysis at the genus level. Networks are randomly colored by modules. V: number of nodes. E: number of edges.

Figure 3

Figure 3

Fluoxetine remodeled stress-induced dysbiosis (directly and indirectly). (A) Lefse analysis of microbiomes between control+PBS and CUMS+PBS groups. (B) Lefse analysis of microbiomes and CUMS+PBS and CUMS+fluoxetine groups. (C) The bacterial network associated with depression and fluoxetine. Red dots: bacteria positively associated with depression-like behavior whose abundance was significantly increased in CUMS+PBS mice compared to Control+PBS; Blue dots: bacteria negatively associated with depression-like behavior whose abundance was significantly increased in CUMS+fluoxetine mice; Green dots: bacteria associated with depression and fluoxetine whose abundance was significantly increased in CUMS+PBS mice and decreased in CUMS+fluoxetine mice. Red line: positive correlation; grey line: negative correlation. (D) Heatmap of key OTUs. Red frame: OTUs affected by CUMS but not corrected by fluoxetine. Green frame: OTUs affected by CUMS and corrected by fluoxetine. Blue frame: OTUs not affected by CUMS but influenced by fluoxetine. CUMS: chronic unpredictable mild stress.

Figure 4

Figure 4

Fluoxetine recovered depression-specific bacteria at the OTUs level. Altered composition of gut bacteria with different abundance at the OTUs level.

Figure 5

Figure 5

Depression-specific bacterial genera were linked to anxiety- and depression-like behaviors. (A) Heatmap of Spearman's rank correlation coefficients between the behavioral indices and bacterial abundance between groups. (B) Correlation analysis between given bacteria and time course of SP. *P < 0.05, **P < 0.01, ***P < 0.001.

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