PT - JOURNAL ARTICLE AU - Feng Zhu AU - Wei Wang AU - Qingyan Ma AU - Zai Yang AU - Yajuan Fan AU - Yanmei Ju AU - Ruijin Guo AU - Qi Wang AU - Xin Mu AU - Bingbing Zhao AU - Yuan Gao AU - Xiaoyan He AU - Fengjie Gao AU - Li Qian AU - Ce Chen AU - Yunchun Chen AU - Chengge Gao AU - Xian-cang Ma TI - Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice AID - 10.1101/2020.04.11.021915 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.04.11.021915 4099 - http://biorxiv.org/content/early/2020/04/13/2020.04.11.021915.short 4100 - http://biorxiv.org/content/early/2020/04/13/2020.04.11.021915.full AB - Objective Gut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia.Design Gut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse.Results Both microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors.Conclusion microbiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia.Significance of this studyWhat is already known about this subject?➢ Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA).➢Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms.➢Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters.What are the new findings?➢Patients with schizophrenia displayed increased rates of IA and increased SCFA production compared with healthy controls, and increased SCFA is associated with IA in patients.➢A unique microbiota signature including enriched SCFA-producing bacterial species can distinguish patients with IA from other patients and controls.➢Small molecules in the serum of immune-activated patients with schizophrenia enhance LPS-induced immune response of cultured peripheral blood mononuclear cell (PBMCs), which is partially mediated by SCFA signaling.➢SCFA intake upregulates both peripheral and brain inflammation and potentiates the expression of schizophrenia-like behaviors in mice prenatally exposed to IA.How might it impact on clinical practice in the foreseeable future?➢Interference of SCFA signaling or targeted destruction of SCFA-producing bacteria may provide a new approach for the prevention and treatment of schizophrenia.➢Immune activation status of patients should be an important condition considered when selecting immunotherapy for future precision psychiatric therapy.Competing Interest StatementThe authors have declared no competing interest.