Metagenome-based characterization of the gut virome in patients with schizophrenia

Schizophrenia (SCZ) is a multifactorial psychiatric disorder increasingly linked to gut microbial dysbiosis. While bacterial alterations have been widely studied, the role of the gut virome in SCZ remains largely unexplored. This study aimed to characterize the gut virome in SCZ and identify potential viral biomarkers associated with the disease.

We analyzed fecal metagenomic data from 171 individuals (90 SCZ patients and 81 controls) using the Chinese Gut Virus Catalog (cnGVC). We assessed gut virome diversity, identified SCZ-associated vOTUs, explored virus-bacteria correlations, and evaluated diagnostic potential using random forest models. In addition, we examined follow-up samples from SCZ patients to assess the impact of antipsychotic treatment on the gut virome.

We identified 171 vOTUs that differed significantly between SCZ patients and controls, with 124 enriched in SCZ-mainly from Siphoviridae and Flandersviridae. Correlation analysis revealed altered virus-bacteria interactions in SCZ, including disease-specific associations with Akkermansia and Clostridia. A random forest classifier based on virome features achieved an AUC of 93.2%, outperforming the bacterial model. External validation using ASD and PD cohorts yielded lower AUCs (61.2-67.0%), suggesting disease specificity. In follow-up samples collected after three months of treatment, we observed partial changes in alpha diversity, while beta diversity remained stable, indicating that antipsychotic therapy may alter specific viral taxa without broadly reshaping the overall gut virome structure.

This study provides evidence of distinct gut virome alterations in SCZ and identifies specific viral markers with strong diagnostic potential. These findings highlight the underappreciated role of the gut virome in psychiatric disorders and support its utility as a non-invasive biomarker for SCZ diagnosis and future therapeutic development.