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A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress–induced depressive-like behavior in mice by regulating gut microbiota and metabolites

  • Applied Microbial and Cell Physiology
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Abstract

Major depressive disorder (MDD) is a neurasthenic disease, which is the second-largest burden of disease globally. Increasing studies have revealed that depression is associated with abnormalities in gut microbiota and metabolites. Several species of bacteria have been classified as psychobiotics, which confer mental health benefits through interactions with commensal gut microbiota. Therefore, it is essential to identify new psychobiotics and elucidate their mechanisms in the treatment of depression. This study aims to evaluate the antidepressant effect of Akkermansia muciniphila (AKK) in a mouse model of depression induced by chronic restraint stress (CRS). C57BL/6 male mice were divided into three groups: mice subjected to CRS, mice not subjected to CRS, and mice treated with AKK for 3 weeks. Behavioral tests were performed, and hormone, neurotransmitter, and brain-derived neurotrophic factor (BDNF) levels were measured. Cecal microbiota was analyzed using 16S rRNA gene sequencing, and serum metabolites were detected using untargeted metabolomics. In addition, correlations between altered gut microbiota and metabolites with significant variations in serum associated with AKK ameliorating depression were analyzed using Pearson’s correlation coefficient. The results revealed that AKK significantly ameliorated depressive-like behavior and restored abnormal variations in depression-related molecular (corticosterone, dopamine, and BDNF). Moreover, AKK altered chronic stress–induced gut microbial abnormalities. Untargeted metabolomics analysis revealed 23 potential biomarkers in serum that could be associated with the mechanisms underlying CRS-induced depression and the therapeutic effects of AKK. Pearson’s correlation coefficient analysis revealed that AKK predominantly upregulated β-alanyl-3-methyl-l-histidine and edaravone to relieve depression. Furthermore, β-alanyl-3-methyl-l-histidine and edaravone exhibited the antidepressant phenotype in mice subjected to CRS. In conclusion, the study demonstrated that AKK ameliorates chronic stress–induced depressive symptoms in mice by regulating gut microbiota and metabolites.

Key points

• AKK reduces depressive-like behaviors induced by chronic stress.

• AKK regulates the gut microbial structure and metabolomics of serum under the chronic stress.

• Antidepressant effect of AKK correlates with the increase of β-alanyl-3-methyl-l-histidine and edaravone.

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Funding

This work was financially supported by the Natural Science Foundation of Jiangsu Province (No. 81873309).

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Authors and Affiliations

  1. The Affiliated Hospital of Nan**g University of Chinese Medicine, Nan**g, Jiangsu, China

    Yang Ding, Guo** Shi, Qiong Wang, **yong Zhou & Yugen Chen

  2. First Clinical Medical College, Nan**g University of Chinese Medicine, Nan**g, Jiangsu, China

    Yang Ding, Fan Bu, Tuo Chen, **aomin Yuan, Zeyu Feng, Zhenglan Duan & Rong Wang

  3. Nan**g Hospital of Chinese Medicine Affiliated to Nan**g University of Chinese Medicine, Nan**g, Jiangsu, China

    Sumin Zhang

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  1. Yang Ding
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Contributions

Y. D. designed the study, performed the experiments, analyzed the data, and wrote the manuscript. F. B., T. C., G. P. S., Z. Y. F., Z. L. D., and R. W. helped with performed experiments and analyzed data. Y. G. C. and X. M. Y. helped with design and review of the manuscript. S. M. Z., Q. W., and J. Y. Z contributed analytical tools. All authors read and approved the manuscript.

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Ding, Y., Bu, F., Chen, T. et al. A next-generation probiotic: Akkermansia muciniphila ameliorates chronic stress–induced depressive-like behavior in mice by regulating gut microbiota and metabolites. Appl Microbiol Biotechnol 105, 8411–8426 (2021). https://doi.org/10.1007/s00253-021-11622-2

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