Schizophrenia is a debilitating mental disorder and often has a prodromal period, referred to as clinical high risk (CHR) for psychosis, prior to the first episode. The etiology and pathogenesis of schizophrenia remain unclear. Despite the human gut microbiome being associated with schizophrenia, the role of the oral microbiome, which is a vital player in the mouth–body connection, is not well understood. To address this, we performed 16S rRNA gene sequencing to investigate the salivary microbiome in 85 patients with drug-naïve first-episode schizophrenia (FES), 43 individuals at CHR, and 80 healthy controls (HCs). The salivary microbiome of FES patients was characterized by higher α-diversity and lower β-diversity heterogeneity than those of CHR subjects and HCs. Proteobacteria, the predominant phylum, was depleted, while Firmicutes and the Firmicutes/Proteobacteria ratio was enriched, in a stepwise manner from HC to CHR to FES. H2S-producing bacteria exhibited disease-stage-specific enrichment and could be potential diagnostic biomarkers for FES and CHR. Certain salivary microbiota exhibited disease-specific correlation patterns with symptomatic severities, peripheral pro-inflammatory cytokines, thioredoxin, and S100B in FES. Furthermore, the metabolic functions from inferred metagenomes of the salivary microbiome were disrupted in FES, especially amino acid metabolism, carbohydrate metabolism, and xenobiotic degradation. This study has established a link between salivary microbiome alterations and disease initiation and provided the hypothesis of how the oral microbiota could influence schizophrenia.

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Schizophrenia is a complex and highly heterogeneous mental illness with a prodromal period called clinical high risk (CHR) for psychosis before onset. Metabolomics is greatly promising in analyzing the pathology of complex diseases and exploring diagnostic biomarkers. Therefore, we conducted salivary metabolomics analysis in 83 first-episode schizophrenia (FES) patients, 42 CHR individuals, and 78 healthy controls with ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The mass spectrometry raw data have been deposited on the MetaboLights (ID: MTBLS3463). We found downregulated aromatic amino acid metabolism, disturbed glutamine and nucleotide metabolism, and upregulated tricarboxylic acid cycle in FES patients, which existed even in the CHR stage and became more intense with the onset of the schizophrenia. Moreover, differential metabolites can be considered as potential diagnostic biomarkers and indicate the severity of the different clinical stages of disease. Furthermore, three disordered pathways were closely related to peripheral indicators of inflammatory response, oxidative stress, blood–brain barrier damage, and salivary microbiota. These results indicate that the disorder of oral metabolism occurs earlier than the onset of schizophrenia and is concentrated and intensified with the onset of disease, which may originate from the dysbiotic salivary microbiota and cause the onset of schizophrenia through the peripheral inflammatory response and redox system, suggesting the importance of oral–brain connection in the pathogenesis of schizophrenia.

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