Abstract
BACKGROUND: Increasing evidence indicates the role of microbiome-gut-brain axis in schizophrenia (SZ). However, few studies have examined the potential links among the gut microbiome, brain structure and function, and clinical manifestation in SZ patients, and the effects of prolonged antipsychotic treatment are often neglected. STUDY DESIGN: A total of 171 participants were enrolled, including 27 drug-naïve first-episode SZ patients (FSZ), 72 chronically antipsychotics-treated SZ patients (CSZ), and 72 healthy controls (HCs). Multi-omics data, including fecal 16S rRNA sequencing, structural and functional brain imaging analyses, and assessments of psychotic symptoms and cognitive function, were obtained to characterize the microbiome-gut-brain axis in SZ patients. Correlation and mediation analyses were conducted to assess the relationships among the gut microbiome, neuroimaging features, and clinical manifestations. STUDY RESULTS: Compared with HCs, 3 key diagnostic genera were identified in SZ, characterized by decreased abundance of Blautia (FSZ/CSZ < HCs) and increased abundance of Proteus and Arthrobacter (FSZ > CSZ > HCs). This microbial dysbiosis was accompanied by down-regulated bile acids biosynthesis and up-regulated lipid metabolism. Further analyses revealed a tripartite relationship among the key microbial genera, altered brain structure and function, and clinical manifestation in separate SZ subgroups. Importantly, higher abundance of Proteus may result in lower scores on several cognitive domains by disrupting gray matter volume and regional homogeneity in specific brain regions. CONCLUSIONS: This work advances our knowledge of microbiota-gut-brain disturbances and its potential role on cognitive performance in SZ. Moreover, our results highlight the importance of considering antipsychotic exposure in gut-brain research.