Reutericyclin mitigates risperidone-induced weight gain

Many microbiome studies focus on dysbiosis caused by antibiotics with little emphasis on other xenobiotics. In this study, we used the antipsychotic risperidone to induce weight gain in C57BL/6J female mice. We hypothesized that specific microbes are essential for maintaining gut homeostasis and performed metagenomic analyses on stool samples to identify microbes that were excluded in obese animals but remain present in healthy controls. We identified Lactobacillus reuteri as a candidate for further study. Oral supplementation with L. reuteri protected against risperidone-induced obesity and was dependent on its ability to produce a specialized metabolite, reutericyclin. Furthermore, synthetic reutericyclin was sufficient to prevent weight gain in mice that were co-treated with risperidone. Modeling shifts in the microbiome suggests that L. reuteri induces a unique microbial state that corresponds to organisms found in lean guts. Our data identifies reutericyclin production by L. reuteri as a probiotic to alter dysbiosis induced by risperidone.