Anti-psychotic therapeutics modify gut microbial metabolism and modulate susceptibility to gastrointestinal infection in mice.

Antipsychotic medications are widely prescribed and associated with increased infection risk, but underlying mechanisms remain unclear. We examined if antipsychotic-induced microbiome and metabolome alterations impair colonization resistance. Using a murine model, we evaluated haloperidol, olanzapine, risperidone, and quetiapine through longitudinal microbiome profiling, untargeted metabolomic fingerprinting, behavioral testing, and enteric infection challenge. Antipsychotic exposure induced persistent behavioral changes and increased susceptibility to Citrobacter rodentium , with quetiapine and olanzapine producing the greatest weight loss. Microbiome sequencing revealed treatment-specific shifts in beta diversity without consistent alpha diversity changes, while untargeted metabolomic analysis demonstrated robust, drug-specific metabolic reprogramming, particularly in lipid and sterol pathways. Although microbial compositional changes did not fully account for functional outcomes, their integration with metabolomics data revealed disrupted bacterial taxa-metabolite networks and loss of homeostatic metabolic modules. These results provide a potential mechanistic link between the disruptive effects of antipsychotics on the microbiome and impaired colonization resistance.