The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice

Zheng, Peng; Zeng, Benhua; Liu, Meiling; Chen, Jianjun; Pan, Junxi; Yu, Han; Liu, Yiyun; Cheng, Ke; Zhou, Chanjuan; Wang, Haiyang; Zhou, Xinyu; Gui, Siwen; Perry, Seth W.; Wong, Ma‐Li; Licinio, Júlio; Wei, Hong; Xie, Peng

doi:10.1126/sciadv.aau8317

Cited by 455 publications

(398 citation statements)

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“…However, several recent analyses indicate that many taxonomic associations might be presented only at levels subordinate to species 17,34,35 . Accordingly, most of the schizophrenia-associated microbial species revealed by the MWAS results were not identified in previous studies by using 16S rRNA gene sequencing 14,18,36 . There are more overlaps of findings at genus level between our findings and the previous studies (Supplementary Table 5b), including 6 in the study of Zheng et al ( Acidaminococcus, Akkermansia, Alistipes, Citrobacter, Dialister, Veillonella ) 14 , 1 in the study of Schwarz et al ( Lactobacillus ) 36 , 1 in the study of Shen et al ( Methanobrevibacter ) 18 .…”

Section: Discussioncontrasting

confidence: 59%

“…Accordingly, most of the schizophrenia-associated microbial species revealed by the MWAS results were not identified in previous studies by using 16S rRNA gene sequencing 14,18,36 . There are more overlaps of findings at genus level between our findings and the previous studies (Supplementary Table 5b), including 6 in the study of Zheng et al ( Acidaminococcus, Akkermansia, Alistipes, Citrobacter, Dialister, Veillonella ) 14 , 1 in the study of Schwarz et al ( Lactobacillus ) 36 , 1 in the study of Shen et al ( Methanobrevibacter ) 18 . Surprisingly, gut microbiota diversities based on genus level taxonomy and annotated genes were higher in schizophrenic patients compared to controls.…”

Section: Discussioncontrasting

confidence: 59%

“…The gut microbiota is reported to play an important role in neurogenerative processes, and perturbation of the microbiota and microbial products have been demonstrated to affect behavior 8–10 . Changes in the gut microbiota have been associated with neurological 11 and neurodevelopmental disorders 12,13 , including schizophrenia 14 . It was recently reported that fecal transfer of the gut microbiota from patients with schizophrenia induces schizophrenia-associated behaviors in germ-free recipient mice accompanied with altered levels of glutamate, glutamine, and GABA in the hippocampus 13 .…”

Section: Introductionmentioning

confidence: 99%

“…Taxa and functional profiling of the microbiota composition is a premise for functional understanding of the gut microbiota 17 . Previous studies were based on 16S rRNA gene amplicon sequencing of relatively small cohorts 14,18–20 and hence failed to provide detailed functional profiling of the gut microbiota in schizophrenia. Metagenomic shotgun sequencing combined with bioinformatics tools enables better characterization of the microbiota 21 , including a more accurate prediction of biological features of the microbes and their impacts on host physiology 22 .…”

Section: Introductionmentioning

confidence: 99%

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

Zhu

Wang

et al. 2019

Preprint

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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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Section: Discussioncontrasting

confidence: 59%

Section: Discussioncontrasting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Zhu

Wang

et al. 2019

Preprint

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“…Other studies induced depression‐like behavior in rodents by fecal transplant from human MDD patients . Another study observed schizophrenia‐like behavior in mice after fecal transplantation from human schizophrenia patients …”

Section: Gut Microbiotamentioning

confidence: 99%

Alzheimer's disease and symbiotic microbiota: an evolutionary medicine perspective

Fox

Knorr

Haptonstall

2019

Annals of the New York Academy of Sciences

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Microorganisms resident in our bodies participate in a variety of regulatory and pathogenic processes. Here, we describe how etiological pathways implicated in Alzheimer's disease (AD) may be regulated or disturbed by symbiotic microbial activity. Furthermore, the composition of symbiotic microbes has changed dramatically across human history alongside the rise of agriculturalism, industrialization, and globalization. We postulate that each of these lifestyle transitions engendered progressive depletion of microbial diversity and enhancement of virulence, thereby enhancing AD risk pathways. It is likely that the human life span extended into the eighth decade tens of thousands of years ago, yet little is known about premodern geriatric epidemiology. We propose that microbiota of the gut, oral cavity, nasal cavity, and brain may modulate AD pathogenesis, and that changes in the microbial composition of these body regions across history suggest escalation of AD risk. Dysbiosis may promote immunoregulatory dysfunction due to inadequate education of the immune system, chronic inflammation, and epithelial barrier permeability. Subsequently, proinflammatory agents—and occasionally microbes—may infiltrate the brain and promote AD pathogenic processes. APOE genotypes appear to moderate the effect of dysbiosis on AD risk. Elucidating the effect of symbiotic microbiota on AD pathogenesis could contribute to basic and translational research.

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Perturbations in Gut Microbiota Composition in Psychiatric Disorders

et al. 2021

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The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice

Abstract: New findings suggest that schizophrenia may be linked to gut bacteria.

Cited by 455 publications

References 42 publications

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

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

Alzheimer's disease and symbiotic microbiota: an evolutionary medicine perspective

Perturbations in Gut Microbiota Composition in Psychiatric Disorders

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