This preclinical study used a murine model to assess whether commonly prescribed antipsychotic medications alter the gut microbiome and metabolome in ways that impair colonization resistance to enteric pathogens. The drugs evaluated were haloperidol, olanzapine, risperidone, and quetiapine. The investigators combined longitudinal microbiome sequencing, untargeted metabolomic fingerprinting of gut samples, behavioral testing, and a controlled enteric infection challenge to examine treatment-specific effects on host behavior, microbial community structure, gut metabolic profiles, and susceptibility to infection.
Antipsychotic exposure produced persistent behavioral changes in treated mice. The source reports these behavioral alterations as a measurable outcome of drug exposure, indicating that the drug regimens used had durable effects on host behavior in this model. The source did not provide specific behavioral metrics or quantitative results in the accessible summary.
Following antipsychotic treatment, mice exhibited increased susceptibility to infection with Citrobacter rodentium, an established murine model pathogen for enteric infection. The study found that quetiapine and olanzapine-treated animals experienced the greatest weight loss in the course of infection, consistent with worsened disease severity. Overall, antipsychotic exposure was associated with impaired colonization resistance to this enteric pathogen.
Microbiome sequencing across treatment groups revealed treatment-specific shifts in beta diversity, indicating that different antipsychotic drugs drove distinct community-level compositional changes. In contrast, there were no consistent alterations in alpha diversity reported across the drug treatments. Thus, while richness or within-sample diversity measures did not show a uniform pattern, between-sample community composition diverged according to the specific antipsychotic administered.
Untargeted metabolomic fingerprinting demonstrated robust, drug-specific metabolic reprogramming in the gut environment. The metabolomic changes were particularly notable in lipid and sterol metabolic pathways. These shifts suggest that antipsychotic exposure remodels the gut metabolic milieu in ways that are distinct for each drug, potentially altering substrates and signaling molecules available to both host and microbes.
Although compositional microbiome changes alone did not fully account for the observed functional outcomes (behavioral effects and infection susceptibility), integrating taxonomic sequencing with metabolomics revealed disruptions in bacterial taxa–metabolite networks. The combined analysis indicated loss of homeostatic metabolic modules and altered associations between specific bacterial taxa and metabolites. This network-level disruption provides a plausible mechanistic pathway linking antipsychotic-driven microbiome and metabolome perturbations to diminished colonization resistance.
The study authors interpret their findings as evidence of a potential mechanistic link between antipsychotic-induced disruption of the gut microbiome/metabolome and increased vulnerability to enteric infection. Key observations supporting this interpretation include persistent behavioral changes after drug exposure, increased severity of C. rodentium infection (notably with quetiapine and olanzapine), drug-specific shifts in microbiome beta diversity, and pronounced reprogramming of gut metabolic pathways—especially lipids and sterols—accompanied by breakdown of taxa–metabolite networks.
The source summary does not provide granular quantitative details, specific statistical outcomes, or full methodological parameters in this text. The authors declared no competing interests. Funding sources listed in the source include the National Institute of Diabetes and Digestive and Kidney Diseases (F30 DK139762), the Centers for Disease Control and Prevention (U54CK000601), the National Institute for Allergy and Infectious Diseases (K23AI144036), and institutional CTSA support (UL1-TR002378). Data and code were referenced via DOIs in the source; however, detailed datasets or code excerpts were not presented in the abstract-level text provided.
Overall, the reported results support that antipsychotic therapeutics can modify the gut microbial metabolic landscape and associated bacterial networks in ways that correlate with impaired colonization resistance to an enteric pathogen in mice. Further details, including exact effect sizes, dosing regimens, timelines, and statistical analyses, were not reported in the accessible source summary.