Original Article | Published:

Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism

Molecular Psychiatry volume 21, pages 786796 (2016) | Download Citation

Abstract

Major depressive disorder (MDD) is the result of complex gene–environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiology of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clinical sampling, the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with ‘depression microbiota’ derived from MDD patients resulted in depression-like behaviors compared with colonization with ‘healthy microbiota’ derived from healthy control individuals. Mice harboring ‘depression microbiota’ primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host’s metabolism.

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Acknowledgements

This work was supported by the National Basic Research Program of China (973 Program, grant no. 2009CB918300 and 2013CB532406) and the National Natural Science Foundation of China (Grant nos. 81401140 and 30900456).

Author contributions

Designed the experiments: PX, HW and JY. Performed the metagenomic analysis: PZ, MLL, ZF and LZ. Performed the metabolomic analysis: CJZ, XJX, BHZ and PZ. Performed the fecal microbiotic transplantation: ZF, BHZ, MLL, XTZ, XYD and WXL. Analyzed the metagenomic and metabolomic data: JJC, SHF and XJX. Collected the clinical samples: DYY, YTY, XYD, XTZ and HQM. Drafted the manuscript: PX, HW and PZ. Revised the manuscript for intellectual content: JY, PX and NDM.

Author information

Author notes

    • P Zheng
    • , B Zeng
    •  & C Zhou

    These authors contributed equally to this work.

    • J Licinio
    • , H Wei
    •  & P Xie

    These authors are co-senior authors.

Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    • P Zheng
    • , C Zhou
    • , M Liu
    • , Z Fang
    • , X Xu
    • , L Zeng
    • , J Chen
    • , S Fan
    • , X Du
    • , X Zhang
    • , Y Yang
    • , N D Melgiri
    •  & P Xie
  2. Chongqing Key Laboratory of Neurobiology, Chongqing, China

    • P Zheng
    • , C Zhou
    • , M Liu
    • , Z Fang
    • , X Xu
    • , L Zeng
    • , J Chen
    • , S Fan
    • , X Du
    • , X Zhang
    • , Y Yang
    • , N D Melgiri
    •  & P Xie
  3. Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China

    • P Zheng
    • , C Zhou
    • , M Liu
    • , Z Fang
    • , X Xu
    • , L Zeng
    • , J Chen
    • , S Fan
    • , X Du
    • , X Zhang
    • , Y Yang
    • , N D Melgiri
    •  & P Xie
  4. Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China

    • B Zeng
    • , W Li
    •  & H Wei
  5. Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing, China

    • D Yang
  6. Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    • H Meng
  7. Mind & Brain Theme, South Australian Health and Medical Research Institute and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia

    • J Licinio

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to J Licinio or H Wei or P Xie.

Supplementary information

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DOI

https://doi.org/10.1038/mp.2016.44

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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