Salivary Metabolomics Reveals that Metabolic Alterations Precede the Onset of Schizophrenia

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.