Abstract
Structural and functional brain abnormalities in schizophrenia (SZ) are well-documented, yet the role of the glymphatic system remains largely unexplored. Given emerging evidence linking the microbiome-gut-brain axis to SZ, this study aims to investigate the glymphatic system function in SZ patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) and to explore its associations with gut microbiota and cognitive performance. Multi-omics data were obtained from a cohort of 87 SZ patients and 70 healthy controls (HCs), including fecal 16S rRNA sequencing, DTI-ALPS index analysis, and cognitive assessments. Correlation and mediation analyses were conducted to explore the relationships among the gut microbiome, DTI-ALPS index, and cognitive performance. Compared to HCs, patients with SZ exhibited significantly lower DTI-ALPS indices in the left, right, and bilateral hemispheres. These indices were positively associated with multiple cognitive domains. In addition, gut microbial dysbiosis was observed in SZ, characterized by a decrease in butyrate-producing bacteria and an increase in pathogenic bacteria. Exploratory analyses further revealed a tripartite link among the key microbial genera, DTI-ALPS indices, and cognitive performance. Notably, the higher abundance of Proteus as well as the lower abundance of Blautia and Faecalibacterium may contribute to poorer cognitive performance, potentially through disruptions in the right DTI-ALPS index. These findings provide novel insights into glymphatic dysfunction in SZ and highlight a potential microbiota-glymphatic-cognition pathway contributing to cognitive impairments.