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

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

doi:10.1038/s41380-019-0475-4

Cited by 209 publications

(161 citation statements)

References 72 publications

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“…Furthermore, some microbes harboring these GBMs were significantly associated with the serum levels of several neurotransmitters and tryptophan metabolites. Parallel to the present study, our previous animal study demonstrated that transplantation of fecal microbiota from medication-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities and dysregulated kynurenine metabolism 66 . The consistent findings of altered tryptophan-kynurenine metabolism revealed by human serum metabolite analysis, microbiota-based GBM prediction, and mouse studies suggest that this pathway is an important link between schizophrenia and gut microbiota dysbiosis.…”

Section: Discussionsupporting

confidence: 69%

Metagenome-wide association of gut microbiome features for schizophrenia

et al. 2020

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Evidence is mounting that the gut-brain axis plays an important role in mental diseases fueling mechanistic investigations to provide a basis for future targeted interventions. However, shotgun metagenomic data from treatment-naïve patients are scarce hampering comprehensive analyses of the complex interaction between the gut microbiota and the brain. Here we explore the fecal microbiome based on 90 medication-free schizophrenia patients and 81 controls and identify a microbial species classifier distinguishing patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.896, and replicate the microbiome-based disease classifier in 45 patients and 45 controls (AUC = 0.765). Functional potentials associated with schizophrenia include differences in short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters. Transplantation of a schizophrenia-enriched bacterium, Streptococcus vestibularis, appear to induces deficits in social behaviors, and alters neurotransmitter levels in peripheral tissues in recipient mice. Our findings provide new leads for further investigations in cohort studies and animal models.

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Section: Discussionsupporting

confidence: 69%

Metagenome-wide association of gut microbiome features for schizophrenia

et al. 2020

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“…Furthermore, some microbes presenting these GBMs were significantly associated with the serum levels of several neurotransmitters and tryptophan metabolites. Parallel to the present study, our previous animal study demonstrated that transplantation of fecal microbiota from drug-free patients with schizophrenia into specific pathogen-free mice could cause schizophrenia-like behavioral abnormalities and dysregulated kynurenine metabolism 67 . The consistent findings of altered tryptophan-kynurenine metabolism revealed by human serum metabolite analysis, microbiota-based GBM prediction, and mouse studies suggest that this pathway is an important link between schizophrenia and gut microbiota dysbiosis.…”

Section: Discussionsupporting

confidence: 69%

Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus

Zhu

Wang

et al. 2019

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46Emerging evidence has linked the gut microbiota to schizophrenia. However, the 47 functional changes in the gut microbiota and the biological role of individual bacterial 48 species in schizophrenia have not been explored systematically. Here, we 49 characterized the gut microbiota in schizophrenia using shotgun metagenomic 50 sequencing of feces from a discovery cohort of 90 drug-free patients and 81 controls, 51 as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We 52 screened 83 schizophrenia-associated bacterial species and constructed a classifier 53 comprising 26 microbial biomarkers that distinguished patients from controls with a 54 0.896 area under the receiver operating characteristics curve (AUC) in the discovery 55 cohort and 0.765 AUC in the validation cohort. Our analysis of fecal metagenomes 56 revealed that schizophrenia-associated gut-brain modules included short-chain fatty 57 acids synthesis, tryptophan metabolism, and synthesis/degradation of 58 neurotransmitters including glutamate, γ-aminobutyric acid, and nitric oxide. The 59 schizophrenia-enriched gut bacterial species include several oral cavity-resident 60 microbes, such as Streptococcus vestibularis. We transplanted Streptococcus 61 vestibularis into the gut of the mice with antibiotic-induced microbiota depletion to 62 explore its functional role. We observed that this microbe transiently inhabited the 63 mouse gut and this was followed by hyperactivity and deficit in social behaviors, 64 accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, 65 our study identified 26 schizophrenia-associated bacterial species representing 66 potential microbial targets for future treatment, as well as gut-brain modules, some of 67 which may give rise to new microbial metabolites involved in the development of 68 schizophrenia. 69 70 Schizophrenia is a severe psychiatric disorder associated with hallucinations, 71 delusions, and thought disorders perturbing perception and social interaction 1 . The 72 etiology of schizophrenia is not elucidated, but assumed to be multifactorial involving 73 genetic and environmental factors. Abnormalities of neurotransmitter systems have 74 been extensively studied especially focusing on aberration of signaling involving 75 dopamine, glutamate, and γ-aminobutyric acid (GABA) 2-4 . Increasing evidence 76 indicates that schizophrenia may be a systemic disorder with neuropsychiatric 77 conditions in addition to psychosis 5 . Furthermore, the importance of inflammation 6 78 and the involvement of the gastrointestinal system 7 in schizophrenia have received 79 attention. 80 The gut microbiota is reported to play an important role in neurogenerative 81 processes, and perturbation of the microbiota and microbial products have been 82 demonstrated to affect behavior 8-10 . Changes in the gut microbiota have been 83 associated with neurological 11 and neurodevelopmental disorders 12,13 , including 84 schizophrenia 14 . It was recently reported that fecal tr...

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“…Participants were recruited as described in our previous studies[25, 43]. This study is a subproject affiliated with a publicly registered clinical trial for gut microbiome investigation in schizophrenia (Identifier: NCT02708316; https://clinicaltrials.gov) that was approved by the Medical Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University.…”

Section: Methodsmentioning

confidence: 99%

“…Fresh stool sample was collected in hospital and an aliquot was stored in commercial fecal sample collection tubes with N -octylpyridinium bromide-based-based reagent (MGIEasy, MGI, Shenzhen, China) for metagenomic sequencing, and a second aliquot was immediately stored at −80 °C for each subject. DNA was extracted from feces as previously described[25].…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, many recent studies identified gut microbiota dysbiosis in schizophrenia[21, 22, 23, 24]. Our previous study indicates that the same gut microbiota alterations seen in schizophrenic patients can cause schizophrenia-like abnormal behaviors in mice[25]. Moreover, our recent metagenome-wide association study (MWAS) further identified 83 schizophrenia-associated bacterial species and 27 altered neuroactive potentials of gut microbiota in schizophrenic patients, including SCFA production (manuscript recently accepted by Nature Communications ).…”

Section: Introductionmentioning

confidence: 99%

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Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

Zhu

Wang

et al. 2020

Preprint

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Objective: Gut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia. Design: Gut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse. Results: Both microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, Gut microbiota chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors.Conclusion: microbiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia. Summary Significance of this study What is already known about this subject?Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA).Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms. Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters. What are the new findings?

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

Cited by 209 publications

References 72 publications

Metagenome-wide association of gut microbiome features for schizophrenia

Metagenome-wide association of gut microbiome features for schizophrenia

Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus

Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

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