Reutericyclin mitigates risperidone-induced suppression of anaerobic energy expenditure

Recent studies from our laboratory demonstrated that the gut microbial community represents a thermogenic biomass, as cecectomy causes an ∼8% decrease in total energy expenditure (EE) via suppression of anaerobic EE. The composition of the microbial community also dictates the EE of the microbial biomass as treatment with the antipsychotic, risperidone, suppresses anaerobic EE in a microbiome-dependent manner. Finally, we have determined that a specialized metabolite produced by <i>Limosilactobacillus reuteri</i>, reutericyclin (RTC), opposes the weight-gain effects of risperidone. In the present study, we performed comprehensive evaluations of energy balance in female C57BL/6J mice treated with risperidone, RTC, or both, to identify mechanisms by which RTC affects energy balance to mitigate risperidone-induced weight gain. We observed that risperidone suppressed anaerobic EE, and that RTC coadministration ameliorated the anaerobic EE suppression and weight gain induced by risperidone. Because anaerobic EE is dependent on the gut microbiota, we performed 16S and whole genome shotgun sequencing on stool and cecal samples following whole animal calorimetry. Risperidone and RTC treatments reciprocally modified the relative abundance of taxa known to participate in fermentation, especially for the production of short-chain fatty acids, which have been correlated with health and leanness in both humans and mice. Together, our data demonstrate that treatment with RTC positively modulates anaerobic EE, possibly by enhancing fermentation of the gut microbial community, and may represent a novel therapeutic in the treatment of obesity.<b>NEW & NOTEWORTHY</b> The gut microbial community represents a thermogenic biomass. The composition of the microbial community dictates energy expenditure of the microbial biomass and is altered by xenobiotics and bacterial metabolites. This study demonstrates that treatment with reutericyclin positively modulates anaerobic energy expenditure and may represent a novel therapeutic in the treatment of obesity.