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

Feng Zhu; Ruijin Guo; Wei Wang; Yanmei Ju; Qi Wang; Qingyan Ma; Qiang Sun; Yajuan Fan; Yuying Xie; Zai Yang; Zhuye Jie; Binbin Zhao; Liang Xiao; Lin Yang; Tao Zhang; Bing Liu; Liyang Guo; Xiaoyan He; Yunchun Chen; Ce Chen; Chengge Gao; Xun Xu; Huanming Yang; Jian Wang; Yonghui Dang; Lise Madsen; Susanne Brix; Karsten Kristiansen; Huijue Jia; Xiancang Ma

doi:10.1038/s41380-019-0475-4

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

Feng Zhu, Ruijin Guo, Wei Wang, Yanmei Ju, Qi Wang, Qingyan Ma, Qiang Sun, Yajuan Fan, Yuying Xie, Zai Yang, Zhuye Jie, Binbin Zhao, Liang Xiao, Lin Yang, Tao Zhang, Bing Liu, Liyang Guo, Xiaoyan He, Yunchun Chen, Ce ChenChengge Gao, Xun Xu, Huanming Yang, Jian Wang, Yonghui Dang, Lise Madsen, Susanne Brix, Karsten Kristiansen^*, Huijue Jia, Xiancang Ma

^*Corresponding author for this work

Genome Research and Molecular Bio Medicine

31 Citations (Scopus)

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.

Original language	English
Journal	Molecular Psychiatry
Number of pages	14
ISSN	1359-4184
DOIs	https://doi.org/10.1038/s41380-019-0475-4
Publication status	Published - 1 Nov 2020

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Zhu, F., Guo, R., Wang, W., Ju, Y., Wang, Q., Ma, Q., Sun, Q., Fan, Y., Xie, Y., Yang, Z., Jie, Z., Zhao, B., Xiao, L., Yang, L., Zhang, T., Liu, B., Guo, L., He, X., Chen, Y., ... Ma, X. (2020). Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice. Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0475-4

Zhu, F, Guo, R, Wang, W, Ju, Y, Wang, Q, Ma, Q, Sun, Q, Fan, Y, Xie, Y, Yang, Z, Jie, Z, Zhao, B, Xiao, L, Yang, L, Zhang, T, Liu, B, Guo, L, He, X, Chen, Y, Chen, C, Gao, C, Xu, X, Yang, H, Wang, J, Dang, Y, Madsen, L, Brix, S, Kristiansen, K, Jia, H & Ma, X 2020, 'Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice', Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0475-4

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title = "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{\textquoteright} 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{\textquoteright} and the controls{\textquoteright} 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.",

author = "Feng Zhu and Ruijin Guo and Wei Wang and Yanmei Ju and Qi Wang and Qingyan Ma and Qiang Sun and Yajuan Fan and Yuying Xie and Zai Yang and Zhuye Jie and Binbin Zhao and Liang Xiao and Lin Yang and Tao Zhang and Bing Liu and Liyang Guo and Xiaoyan He and Yunchun Chen and Ce Chen and Chengge Gao and Xun Xu and Huanming Yang and Jian Wang and Yonghui Dang and Lise Madsen and Susanne Brix and Karsten Kristiansen and Huijue Jia and Xiancang Ma",

year = "2020",

month = nov,

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doi = "10.1038/s41380-019-0475-4",

language = "English",

journal = "Molecular Psychiatry",

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T1 - Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice

AU - Zhu, Feng

AU - Guo, Ruijin

AU - Wang, Wei

AU - Ju, Yanmei

AU - Wang, Qi

AU - Ma, Qingyan

AU - Sun, Qiang

AU - Fan, Yajuan

AU - Xie, Yuying

AU - Yang, Zai

AU - Jie, Zhuye

AU - Zhao, Binbin

AU - Xiao, Liang

AU - Yang, Lin

AU - Zhang, Tao

AU - Liu, Bing

AU - Guo, Liyang

AU - He, Xiaoyan

AU - Chen, Yunchun

AU - Chen, Ce

AU - Gao, Chengge

AU - Xu, Xun

AU - Yang, Huanming

AU - Wang, Jian

AU - Dang, Yonghui

AU - Madsen, Lise

AU - Brix, Susanne

AU - Kristiansen, Karsten

AU - Jia, Huijue

AU - Ma, Xiancang

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41380-019-0475-4

DO - 10.1038/s41380-019-0475-4

M3 - Journal article

C2 - 31391545

AN - SCOPUS:85070322459

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

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

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