<p>Xanomeline–trospium is a first-in-class muscarinic receptor–based antipsychotic that improves schizophrenia symptoms without dopamine D₂ receptor antagonism. Although gastrointestinal (GI) adverse effects have been reported, its broader effects on host microbiota and susceptibility to respiratory injury remain unclear. We investigated the effects of xanomeline and xanomeline–trospium on gut and lung microbiota, host metabolism, and outcomes in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in male and female mice. Adult mice received vehicle, xanomeline, or xanomeline–trospium for 15 days. Body weight was monitored longitudinally, fecal output was measured, gut and lung microbiota were profiled using 16S rRNA sequencing, and untargeted serum metabolomics was performed using UPLC–QTOF/MS. ALI was induced by intratracheal LPS administration, and survival was assessed for seven days. Xanomeline induced weight loss in female mice and constipation in both sexes, and these effects were attenuated by trospium co-administration. Xanomeline–trospium was associated with sex- and region-associated alterations in gut microbiota, with greater remodeling in the cecum and colon, and also altered lung microbiota composition in both sexes. Integrated multi-omics analyses revealed sex-associated links among specific bacterial taxa, circulating metabolites, and host phenotypes. In the ALI model, xanomeline–trospium significantly increased LPS-induced mortality in female mice but not in male mice; however, formal interaction analysis did not support a significant sex-dependent treatment effect. These findings suggest that xanomeline–trospium alters gut–lung microbiota and host metabolic networks and may influence respiratory vulnerability.</p>