Unveiling the gut microbiome-immune-brain axis in schizophrenia

Schizophrenia (SCZ) is frequently associated with gastrointestinal disturbances, suggesting that gut microbiota alterations may contribute to disease pathophysiology through the gut-immune-brain axis. However, the mechanisms linking gut dysbiosis to neural dysfunction remain poorly defined. Here we show that gut microbiota from SCZ patients is associated with systemic immune dysregulation and altered brain-immune homeostasis in recipient mice. Transplantation of SCZ microbiota into wild-type BALB/cByJ mice induced ileal dysbiosis, intestinal inflammation, and barrier disruption, accompanied by elevated circulating IL-17 and IFNγ, reduced CD4 T cells, and a decreased CD4/CD8 ratio, consistent with a Th17/Th1-skewed immune profile. These changes coincided with microglial activation in the prefrontal cortex (PFC), synaptic protein deficits, and behavioral abnormalities, including hyperactivity, impaired working memory, and reduced social interaction. Importantly, post-mortem analyses of SCZ patient brains recapitulated these findings, revealing increased microglial activation and pro-inflammatory cytokine levels in the PFC. Together, our findings support a mechanistic pathway linking gut dysbiosis to immune dysfunction and synaptic pathology in SCZ, providing a conceptual framework for microbiota-targeted therapeutic strategies.