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Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice

Molecular Psychiatry volume 25, pages 2905–2918 (2020)Cite this article

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Abstract

Accumulating evidence suggests that gut microbiota plays a role in the pathogenesis of schizophrenia via the microbiota–gut–brain axis. This study sought to investigate whether transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities. The results revealed that transplantation of fecal microbiota from schizophrenic patients into antibiotic-treated mice caused behavioral abnormalities such as psychomotor hyperactivity, impaired learning and memory in the recipient animals. These mice also showed elevation of the kynurenine–kynurenic acid pathway of tryptophan degradation in both periphery and brain, as well as increased basal extracellular dopamine in prefrontal cortex and 5-hydroxytryptamine in hippocampus, compared with their counterparts receiving feces from healthy controls. Furthermore, colonic luminal filtrates from the mice transplanted with patients’ fecal microbiota increased both kynurenic acid synthesis and kynurenine aminotransferase II activity in cultured hepatocytes and forebrain cortical slices. Sixty species of donor-derived bacteria showed significant difference between the mice colonized with the patients’ and the controls’ fecal microbiota, highlighting 78 differentially enriched functional modules including tryptophan biosynthesis function. In conclusion, our study suggests that the abnormalities in the composition of gut microbiota contribute to the pathogenesis of schizophrenia partially through the manipulation of tryptophan–kynurenine metabolism.

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Data availability

Metagenomic sequencing data for donors and mice samples have been deposited in the CNGB Nucleotide Sequence Archive (CNSA) database under accession identification CNP0000119.

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Acknowledgements

This study was supported by the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF-CRF-2016-005), Shenzhen Municipal Government of China (Nos. JCYJ20170817145523036 and DRC-SZ [2015]162), Innovation Team Project of Natural Science Fund of Shaanxi Province (2017KCT-20), and Key Program of Natural Science Fund of Shaanxi Province (2018ZDXD-SF-036).

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Author notes

  1. These authors contributed equally: Feng Zhu, Ruijin Guo, Wei Wang, Yanmei Ju, Qi Wang

Authors and Affiliations

  1. Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, China

    Feng Zhu

  2. BGI-Shenzhen, 518083, Shenzhen, China

    Ruijin Guo, Yanmei Ju, Qi Wang, Qiang Sun, Zhuye Jie, Liang Xiao, Tao Zhang, Xun Xu, Huanming Yang, Jian Wang, Lise Madsen, Susanne Brix, Karsten Kristiansen & Huijue Jia

  3. China National Genebank, 518120, Shenzhen, China

    Ruijin Guo, Yanmei Ju, Zhuye Jie, Liang Xiao, Tao Zhang, Xun Xu & Huijue Jia

  4. Shenzhen Key Laboratory of Human Commensal Microorganisms and Health Research, BGI-Shenzhen, 518083, Shenzhen, China

    Ruijin Guo, Yanmei Ju, Zhuye Jie & Huijue Jia

  5. Macau University of Science and Technology, Taipa, 999078, Macau, China

    Ruijin Guo & Huijue Jia

  6. Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, 710061, Xi’an, China

    Wei Wang, Qingyan Ma, Yajuan Fan, Zai Yang, Binbin Zhao, Lin Yang, Liyang Guo, Xiaoyan He, Yunchun Chen, Ce Chen, Chengge Gao & Xiancang Ma

  7. Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, 710061, Xi’an, China

    Wei Wang, Qingyan Ma, Yajuan Fan, Zai Yang, Binbin Zhao, Lin Yang, Liyang Guo, Xiaoyan He, Yunchun Chen, Ce Chen, Chengge Gao & Xiancang Ma

  8. Clinical Research Center for Psychiatric Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, 710061, Xi’an, China

    Wei Wang, Qingyan Ma, Yajuan Fan, Zai Yang, Binbin Zhao, Lin Yang, Liyang Guo, Xiaoyan He, Yunchun Chen, Ce Chen, Chengge Gao & Xiancang Ma

  9. BGI Education Center, University of Chinese Academy of Sciences, 518083, Shenzhen, China

    Yanmei Ju & Qi Wang

  10. Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada

    Qiang Sun

  11. Department of Statistics and Probability, Michigan State University, East Lansing, MI, USA

    Yuying Xie

  12. Shenzhen Engineering Laboratory of Detection and Intervention of Human Intestinal Microbiome, BGI-Shenzhen, 518083, Shenzhen, China

    Liang Xiao

  13. Shenzhen Key Laboratory of Cognition and Gene Research, BGI-Shenzhen, 518083, Shenzhen, China

    Tao Zhang

  14. Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK

    Bing Liu

  15. James D. Watson Institute of Genome Sciences, 310058, Hangzhou, China

    Huanming Yang & Jian Wang

  16. School of Forensic Medicine, Xi’an Jiaotong University, 76 Yanta West Road, 710061, Xi’an, China

    Yonghui Dang

  17. Institute of Marine Research (IMR), P.O. Box 7800, 5020, Bergen, Norway

    Lise Madsen

  18. Department of Biology, University of Copenhagen, Universitetsparken 13, Copenhagen, 2100, Denmark

    Lise Madsen

  19. Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark

    Lise Madsen & Karsten Kristiansen

  20. Department of Biotechnology and Biomedicine, Technical University of Denmark, 2800 Kgs, Lyngby, Denmark

    Susanne Brix

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  1. Feng Zhu
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Contributions

XM, HJ, RG, FZ and ZJ conceived the study. FZ, ZY, FZ, LY, BZ, and QM did mice experiment. WW, QM, YF, LG, YD, YC, CC, CG, and XM recruited volunteers and collected samples for the study. WW, QM. YF, ZY, LY, and FZ collected faeces. YJ, QW, RG, QS, and YX performed the analyses. ZY, FZ, LY, BZ, and QM performed the mice experiment. KK, SB, and LM advised on the mice experiments. FZ, HJ, RG, YJ, and QW interpreted the results and wrote the paper. All authors contributed to revision of the paper.

Corresponding authors

Correspondence to Karsten Kristiansen, Huijue Jia or Xiancang Ma.

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Zhu, F., Guo, R., Wang, W. et al. Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice. Mol Psychiatry 25, 2905–2918 (2020). https://doi.org/10.1038/s41380-019-0475-4

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  • DOI: https://doi.org/10.1038/s41380-019-0475-4

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