Clozapine disrupts the gut-lung microbiota axis, linking gastrointestinal hypomotility to increased respiratory vulnerability.

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.