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Emerging evidence has linked the gut microbiota to schizophrenia. However, the functional changes in the gut microbiota and the biological role of individual bacterial species in schizophrenia have not been explored systematically. Here, we characterized the gut microbiota in schizophrenia using shotgun metagenomic sequencing of feces from a discovery cohort of 90 drug free patients and 81 controls, as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We screened 83 schizophrenia associated bacterial species and constructed a classifier comprising 26 microbial biomarkers that distinguished patients from controls with a 0.896 area under the receiver operating characteristics (ROC) curve (AUC) in the discovery cohort and 0.765 ROC AUC in the validation cohort. Our analysis of fecal metagenomes revealed that schizophrenia-associated gut brain modules (GBMs) included short chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters including glutamate, GABA, and nitric oxide. The schizophrenia enriched gut bacterial species include several oral cavity resident microbes, such as Streptococcus vestibulari. We transplanted S. vestibularis into the gut of the mice with antibiotic induced microbiota depletion to explore its functional role. We observed that this microbe transiently inhabited the mouse gut and this was followed by hyperactivity and deficit in social behaviors, accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, our study identified 26 schizophrenia associated bacterial species representing potential microbial targets for future treatment, as well as GBMs, some of which may give rise to new microbial metabolites involved in the development of schizophrenia.

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