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. The authors want to thank Inês Melo-Marques, Tatiana Catarino, Nuno Beltrão and Conceição Egas for technical support. We are indebted to the Biobanc HCB-IDIBAPS, Spain for sample and data procurement.
This work was funded by Portuguese national funds through Fundação para a Ciência e a Tecnologia (FCT) projects UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020, and IN1458_GAinPD_COMPETE2030-FEDER-00675300. EC is supported by a fellowship under the Cure Parkinson’s UK Grant CP:SC01. ARPS is supported by PD/BD/2020.06543.BD PhD fellowship.
AM is supported by a contract under project COMPETE2030-FEDER-00676000. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal Ana Raquel Pereira-Santos, Emanuel Candeias, Ana Maranha, Ana Raquel Esteves, Susana Alarico, Nuno Empadinhas & Sandra Morais Cardoso CIBB – Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal Ph.D. Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal Department of Life Sciences and Centre for Functional Ecology-Science for People & the Planet, Associate Laboratory TERRA University of Coimbra, 3000-456, Coimbra, Portugal Coimbra Local Health Unit, Coimbra, Portugal Coimbra Institute for Biomedical Imaging and Translational Research, Coimbra, Portugal Faculty of Medicine, University of Coimbra, Coimbra, Portugal Miguel Bajouco, Nuno Madeira & Sandra Morais Cardoso Correspondence to Sandra Morais Cardoso.
The authors declare no competing interests. Human participants and tissue samples. All procedures involving human participants were approved by the relevant Ethics Committees of the Coimbra University Hospital, approval no.
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