Abstract
Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but its clinical use is limited by serious gastrointestinal and respiratory adverse effects, including constipation, ileus, and pneumonia. The mechanisms linking these complications remain poorly understood. We tested the hypothesis that clozapine disrupts the gut–lung microbiota axis and that this disruption contributes to systemic toxicity. Adult male and female C57BL/6J mice received oral clozapine (5 mg/kg/day) or vehicle for 14 days. Clozapine significantly reduced body weight and fecal output, indicating gastrointestinal hypomotility. 16S rRNA sequencing revealed region-specific and sex-dependent alterations in microbial communities across the lungs, small intestine, cecum, and colon. Untargeted plasma metabolomics identified systemic metabolic changes in both sexes, including increased D-pyroglutamic acid and glutathione, consistent with oxidative and metabolic stress. Correlation analyses demonstrated coordinated associations among reduced fecal output, altered intestinal taxa, and circulating metabolites, indicating disruption of an integrated microbiota–metabolite network. Functionally, clozapine pretreatment significantly decreased survival following lipopolysaccharide-induced acute lung injury, indicating increased pulmonary vulnerability. Together, these findings suggest that clozapine disrupts the gut–lung microbiota–metabolite axis, linking gastrointestinal hypomotility with heightened respiratory susceptibility. This microbiota-centered framework provides mechanistic insight into clozapine-associated systemic toxicity and highlights microbiota-targeted strategies as potential approaches to improve the safety of clozapine therapy in treatment-resistant schizophrenia.
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Acknowledgements
Yi Cai and Rumi Murayama were supported by Chiba University ALDIC-PhD Project. Dr. Xin Ding was supported by The First Affiliated Hospital of Zhengzhou University (China). We used the AI tool ChatGPT (OpenAI) to improve the readability of the manuscript; all authors reviewed and take full responsibility for the final content.
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This work was supported by the Chiba University ALDIC-PhD Project (to YC: JPMJSP2109) and by a research fund from Otsuka Pharmaceutical Co. Ltd.
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Dr. Hashimoto has received research support from Otsuka Pharmaceutical Co., Ltd. (Japan). Dr. Futamura is an employee of Otsuka Pharmaceutical Co., Ltd. (Japan). The other authors declare no competing interests related to this study.
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All animal procedures were performed in accordance with the Guidelines for Animal Experimentation of Chiba University, and the study protocol was approved by the Animal Care and Use Committee of Chiba University (approval no. 6-406 and 7-316), in accordance with the Japanese national guidelines for animal experimentation. Every effort was made to minimize animal suffering and reduce the number of animals used.
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Cai, Y., Eguchi, A., Murayama, R. et al. Clozapine disrupts the gut–lung microbiota axis, linking gastrointestinal hypomotility to increased respiratory vulnerability. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-04077-4
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DOI: https://doi.org/10.1038/s41398-026-04077-4
