Abstract
Chronic stress causes maladaptive changes in the brain that lead to depressive behavior. In the present study, we investigate whether chronic stress alters gut microbiota compositions that are related to stress-induced maladaptive changes in the brain. Mice treated with daily 2-h restraint for 14 days (CRST) exhibit depressive-like behavior. Sequence readings of 16S rRNA genes prepared from fecal samples taken from CRST-treated mice suggest that chronic stress induces gut microbiota changes that are pronounced in the post-stress period, relative to those that occur in the 14-day stress phase. The genus Lactobacillus is one such microbiota substantially changed following chronic stress. In contrast, intraperitoneal injection of extracellular vesicles (EVs) isolated from culture media of the Gram-positive probiotic Lactobacillus plantarum is sufficient to ameliorate stress-induced depressive-like behavior. Interestingly, EVs from the Gram-positive probiotic Bacillus subtilis and EVs from the Gram-negative probiotic Akkermansia muciniphila also produce anti-depressive-like effects. While chronic stress decreases the expression of MeCP2, Sirt1, and/or neurotrophic factors in the hippocampus, EVs from the three selected probiotics differentially restore stress-induced changes of these factors. These results suggest that chronic stress produces persistent changes in gut microbiota composition, whereas purified EVs of certain probiotics can be used for treatment of stress-induced depressive-like behavior.
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Data and materials will be made available on reasonable request.
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Abbreviations
- Bdnf:
-
Brain-derived neurotrophic factor
- CREB:
-
cAMP response element binding protein
- CRST:
-
Chronic restraint stress
- EVs:
-
Extracellular vesicles
- GC:
-
Glucocorticoid
- HDAC2:
-
Histone Deacetylase 2
- IMI:
-
Imipramine
- MeCP2:
-
Methyl CpG binding protein 2
- Ngf:
-
Nerve growth factor
- NT3:
-
Neurotrophin 3
- NT4/5:
-
Neurotrophin 4/5
- OTUs :
-
Operational taxonomic units
- rRNA :
-
Ribosomal RNA
- Sirt1:
-
Sirtuin 1
- TrkB:
-
Tropomyosin receptor kinase B
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Funding
This research was supported by a grant (2021R1A2B5B02002245) from the Ministry of Science, ICT and Future Planning, Republic of Korea.
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JC and HK carried out the experiments; YKK provided EVs; JC, HK, and PLH designed the experiments, performed the statistical analysis, and wrote the manuscript.
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All animals were handled in accordance with the animal care guidelines of Ewha Womans University (IACUC 15–012).
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JC, HK, and PLH have no competing financial interests; YKK belongs to MD Healthcare Inc.
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Choi, J., Kwon, H., Kim, YK. et al. Extracellular Vesicles from Gram-positive and Gram-negative Probiotics Remediate Stress-Induced Depressive Behavior in Mice. Mol Neurobiol 59, 2715–2728 (2022). https://doi.org/10.1007/s12035-021-02655-9
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DOI: https://doi.org/10.1007/s12035-021-02655-9