Acetate-producing Prevotella copri aggravates schizophrenia behavior by modulating serotonin metabolism

Background: Schizophrenia is a complex mental disorder with approximately 1% lifetime risk worldwide, while the differential diagnosis based on currently clinical criteria is still difficult. A growing literature has demonstrated the biological interactions between gut microbiome and host brain. The metagenomic features may shed the light on how the gut-brain axis works in schizophrenia.Results: A case-control study including 111 fecal metagenomic samples was performed to selected the schizophrenia-associated microbial species and functional modules in comparison with bipolar disorder. The clinical rating scales of both mental diseases were partially explained by gut microbiome. Among these, the Prevotella copri was screened out by an integrated approach. The functional annotation and anaerobic culture further confirmed its acetate-producing ability, which was also supported by the changes in serum acetate of schizophrenia patients. Increasing both engraftment of Prevotella copri type strain or acetate intake independently induced schizophrenia-like behaviors in mice. Using transcriptomic and metabolomic analysis, the dysregulation of serotonin metabolism across colon, serum and prefrontal cortex was observed after engrafting Prevotella copri type strain. The proteins involved in biosynthesis, transportation and degradation of serotonin were significantly elevated after increasing acetate intake.Conclusions: This study suggests that the acetate-producing Prevotella copri selected from clinical metagenome can promote schizophrenia-like behaviors in mice by modulating serotonin metabolism. Larger replication studies and further detailed molecular validation are necessary for the generalizability and future clinical applications of the schizophrenia-specific microbial features.