Gut Microbiome as an Important Dimension of Biological Heterogeneity in Schizophrenia

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Dear Editor

Akira Sawa and colleagues[1] noted that the clinical diagnosis of schizophrenia (SCZ) lack objective biomarker and that people living with schizophrenia (PLWS) show biologically heterogeneous, which also represents a major challenge for mechanism-driven precision medicine. Rather than searching for a single pathogenic microorganism, greater attention should be paid to whether alterations in the whole structure and function of the gut microbiome contribute to distinct biological subtypes among PLWS. Previous studies have reported alterations in the gut microbiota of PLWS[2]. However, current studies have not yet established whether these alterations are functionally relevant. We believe that future research in PLWS should gradually shift its focus from ‘which microorganisms are altered’ to ‘which microbial functions are altered’. Faecal microbiota transplantation helps advance the field towards functional validation. Transplantation of gut microbiota from PLWS into mice can induce some schizophrenia-related behavioural phenotypes[3,4]. These findings support the transferable biological effects of PLWS-associated gut microbiota.

Vasileva et al.[5] reported an association between the gut microbiota and treatment-resistant SCZ and also suggested that clozapine itself can alter microbial composition. These findings indicate that microbiome heterogeneity may not only correspond to disease subtypes, under the context of precision medicine, microbial functional markers may also have potential value in predicting treatment response and metabolic adverse effects.

The review published in The BMJ described immune-inflammatory, metabolic, and redox abnormalities, as well as dysfunction of glutamatergic and NMDA receptor signalling as being relation to SCZ[1]. The gut microbiome may be one of the links between peripheral homeostatic disturbances and neurotransmitters and neural circuits in the brain. A priority for precision medicine in SCZ may be to place greater emphasis on microbial function and and to explore whether microbial functional features can be integrated with metabolomic, immunological, and neuroimaging measures for the biological stratification of PLWS, rather than focusing solely on individual microbial species as biomarkers.

Jianzhong Yin, Wenxia Du, Ying Qian, Yantuanjin Ma, Ten Zhang, Zhuohang Che, Rudang Hong, Junjie Zhu

Correspondence: Jianzhong Yin (yinjianzhong2005@sina.com)
Author Contributions: Wenxia Du, Ying Qian and Yantuanjin Ma contributed equally to this work as first authors.

Reference
1.Sawa A, Chiappelli J, Hamrah OP, et al. Schizophrenia: advances in pathophysiology, management, and precision medicine. BMJ. 2026;394:e635470.
2.McGuinness AJ, Davis JA, Dawson SL, et al. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Mol Psychiatry. 2022 Apr;27(4):1920-1935.
3.Zheng P, Zeng B, Liu M, et al. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv. 2019;5:eaau8317.
4.Zhu F, Guo R, Wang W, et al. Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice. Mol Psychiatry. 2020 Nov;25(11):2905-2918.
5.Vasileva SS, Yang Y, Baker A, et al. Associations of the Gut Microbiome With Treatment Resistance in Schizophrenia. JAMA Psychiatry. 2024 Mar 1;81(3):292-302.

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Schizophrenia: advances in pathophysiology, management, and precision medicine

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Gut Microbiome as an Important Dimension of Biological Heterogeneity in Schizophrenia

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Schizophrenia: advances in pathophysiology, management, and precision medicine

Check this box if you would like your letter to appear anonymously:: Last Name: YinFirst name and middle initial: JianzhongEmail:

yinjianzhong2005@sina.com

Address: No. 2 Hongsheng Road, Dali City, Yunnan Province, China, 671003Occupation: ProfessorsOther Authors: Wenxia Du (Kunming Medical University, Kunming 650500, China); Ying Qian (Kunming Medical University, Kunming 650500, China); Yantuanjin Ma (Kunming Medical University, Kunming 650500, China); Teng Zhang (School of Economics and Management, Baoshan University, Baoshan 678000, China); Zhuohang Che (Kunming Medical University, Kunming 650500, China); Rudan Hong (Dali University, Dali 671003, China); Junjie Zhu (Dali University, Dali 671003, China)Affiliation: School of Public Health, Dali UniversityBMJ: Additional Article Info: Rapid response