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

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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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.

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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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