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

Abstract

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...