The role of xenobiotic disruption of microbiota, corresponding dysbiosis, and potential links to host metabolic diseases are of critical importance. In this study, we used a widely prescribed antipsychotic drug, risperidone, known to influence weight gain in humans, to induce weight gain in C57BL/6J female mice. We hypothesized that microbes essential for maintaining gut homeostasis and energy balance would be depleted following treatment with risperidone, leading to enhanced weight gain relative to controls. Thus, we performed metagenomic analyses on stool samples to identify microbes that were excluded in risperidone-treated animals but remained present in controls. We identified multiple taxa including Limosilactobacillus reuteri as a candidate for further study. Oral supplementation with L. reuteri protected against risperidone-induced weight gain (RIWG) and was dependent on cellular production of a specialized metabolite, reutericyclin. Further, synthetic reutericyclin was sufficient to mitigate RIWG. Both synthetic reutericyclin and L. reuteri restored energy balance in the presence of risperidone to mitigate excess weight gain and induce shifts in the microbiome associated with leanness. In total, our results identify reutericyclin production by L. reuteri as a potential probiotic to restore energy balance induced by risperidone and to promote leanness.
