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Extracellular Vesicles from Gram-positive and Gram-negative Probiotics Remediate Stress-Induced Depressive Behavior in Mice

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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 Availability

Data and materials will be made available on reasonable request.

Code Availability

Not applicable.

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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Author notes

  1. Juli Choi and Hyejin Kwon contributed equally to this file.

Authors and Affiliations

  1. Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul, 03760, Republic of Korea

    Juli Choi, Hyejin Kwon & Pyung-Lim Han

  2. MD Healthcare Inc, Rm 1303 Woori Technology Bldg, World Cup Buk-ro 56-gil, Mapo-Gu Seoul, Republic of Korea

    Yoon-Keun Kim

  3. Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul, 03760, Republic of Korea

    Pyung-Lim Han

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  1. Juli Choi
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Contributions

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.

Corresponding author

Correspondence to Pyung-Lim Han.

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All authors consent to the publication of the manuscript in Mol Neurobiol, should the article be accepted by the Editor-in-chief.

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All animals were handled in accordance with the animal care guidelines of Ewha Womans University (IACUC 15–012).

Conflict of Interest

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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