Therapeutic effect of fecal microbiota transplantation on chronic unpredictable mild stress-induced depression - PubMed (original) (raw)
Therapeutic effect of fecal microbiota transplantation on chronic unpredictable mild stress-induced depression
Ting Cai et al. Front Cell Infect Microbiol. 2022.
Abstract
Background and objective: Depression is a complex neuropsychiatric disease with extensive morbidity. Its pathogenesis remains unclear, and it is associated with extremely low rates of cure and complete remission. It is vital to study the pathogenesis of depression to develop effective treatments. This study aimed to explore the therapeutic effects and mechanisms of fecal microbiota transplantation (FMT) for the treatment of depression in rats.
Methods: Thirty Sprague-Dawley (SD) rats were randomly divided into three groups: control, chronic unpredictable mild stress (CUMS) to model depression, and CUMS+FMT. For the CUMS and CUMS+FMT groups, after CUMS intervention (four weeks), the rats were given normal saline or FMT (once/week for three weeks), respectively. Behavior, colonic motility, 16S rDNA amplicon sequencing, and untargeted metabolomics on fecal samples were compared between the three rat groups. The following markers were analyzed: 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), glutamate (Glu), and brain-derived neurotrophic factor (BDNF) levels in the hippocampus; glucagon-like peptide 1 (GLP-1), lipopolysaccharide (LPS), and interleukin (IL)-6 levels in the serum; and GLP-1, GLP-1 receptor (GLP-1R), and serotonin 4 receptor (5-HT4R) levels in colonic tissues.
Results: FMT improved symptoms of depression and colonic motility in rats exposed to CUMS. The expression levels of 5-HT, GABA, BDNF, and other biochemical indices, significantly differed among the three groups. Meanwhile, the intestinal microbiota in the CUMS+FMT group was more similar to that of the control group with a total of 13 different fecal metabolites.
Conclusion: FMT exerted antidepressant effects on CUMS-induced depression in rats, and the mechanism involved various neurotransmitters, inflammatory factors, neurotrophic factors, and glucagon-like peptides.
Keywords: depression; fecal microbiota transplantation; gastrointestinal mobility; intestinal microflora; metabolites.
Copyright © 2022 Cai, Zheng, Shi, Yuan, Hu, Zhou, Xiao and Wang.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Figures
Figure 1
Mean weight of each experimental group throughout the study period. # p < 0.05 compared to CUMS group. CUMS, chronic unpredictable mild stress; FMT, fecal microbiota transplantation.
Figure 2
Results of behavioral experiments and glass bead discharge test. (A) Changes in the food intake in each group; (B) changes in the sucrose preference test in each group. C–E, Open-field test: (C) total distance; (D) immobility time; (E) Number of upright times. (F) Forced swimming test; (G) glass bead discharge test. *p < 0.05, **p < 0.01, ***p < 0.001 compared with the control group; #p < 0.05 compared with the CUMS group; and &p < 0.05, &&&p < 0.001 represent statistically significant differences between the values before and after FMT. Abbreviations: CUMS, chronic unpredictable mild stress; FMT, fecal microbiota transplantation.
Figure 3
Changes in biochemical indices of each group. (A–D), Expression of 5-HT, GABA, Glu, and BDNF in hippocampal tissues from each group; (E–G), Expression of serum GLP-1, LPS, and IL-6 levels in each group; (H–I), Expression of GLP-1 and GLP-1R in colonic tissue; (J), Expression of 5-HT4R and GLP-1R. *p < 0.05, **p < 0.01 compared to the control group;#p < 0.05 compared to the CUMS group. 5-HT, 5-hydroxytryptamine; 5-HT4R, 5-hydroxytryptamine 4-receptor; GABA, gamma-aminobutyric acid; Glu, glutamate; BDNF, brain derived neurotrophic factor; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; LPS, lipopolysaccharide; IL-6, interleukin-6; CUMS, chronic unpredictable mild stress; FMT, fecal microbiota transplantation.
Figure 4
Levels of 5-HT, GABA, Glu, and BDNF in the hippocampus detected by immunohistochemistry (400× magnification). 5-HT, 5-hydroxytryptamine; GABA, gamma-aminobutyric acid; Glu, glutamate; BDNF, brain derived neurotrophic factor; CUMS, chronic unpredictable mild stress; FMT, fecal microbiota transplantation.
Figure 5
Results of 16s rDNA amplicon sequencing. (A), Distribution of population composition by phylum rank; (B), Pie chart of dominant populations by phylum rank; (C), Distribution of population composition by genus rank; (D), Pie chart of dominant populations by genus rank; (E), Differences in selected populations of interest. N, Normal group; C, CUMS group; F, CUMS+ FMT group.
Figure 6
Results of untargeted metabolomics analysis. (A), OPLS-DA analysis of fecal samples from the CUMS+FMT and CUMS groups before/after CUMS (Fa/Fb); (B), OPLS-DA analysis of fecal samples from the CUMS+FMT group before/after FMT (Fb/Fc); (C, D) Volcano plot; (C), Anion mode analysis of fecal samples from the CUMS+FMT group before/after CUMS (Fa/Fb); (D), Anion mode analysis of fecal samples from the CUMS+FMT group before/after FMT(Fb/Fc). Red represents differentially expressed metabolites; (E), Heat map analysis of fecal samples from CUMS+FMT group before/after CUMS (Fa/Fb); (F), Heat map analysis of fecal samples from CUMS+FMT group before/after FMT (Fb/Fc); purple represents downregulation and red represents upregulation. OPLS-DA, Orthogonal Partial Least Square-Discriminate Analysis; Fa, fecal samples from the CUMS+FMT group before CUMS; Fb, fecal samples from the CUMS+FMT group after CUMS; Fc, fecal samples from the CUMS+FMT group after FMT; VIP, variable importance in projection; FC, fold change; CUMS, chronic unpredictable mild stress; FMT, fecal microbiota transplantation.
References
- Cao J. (2010). Clinical analysis of paroxetine in treatment of depression with irritable bowel syndrome. Asia-Pacific Tradit. Med. 6 (07), 61–62. [In Chinese]
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