Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure

•Risperidone-induced weight gain correlates with an altered gut microbiome.•Risperidone-induced weight gain occurs due to suppressed energy expenditure.•Transfer of risperidone-treated microbiota or phage suppresses energy expenditure.•Reduction in energy expenditure is attributable to non-aerobic resting metabolism.•Transfer of risperidone-treated microbiota suppresses non-aerobic resting metabolism.Risperidone is increasingly used for psychiatric disorders and is known to cause robust weight gain in humans. This study demonstrates that risperidone-induced weight gain correlates with alterations in the bacterial composition of the gut in mice. The observed weight gain is mediated through suppression of energy expenditure, specifically by reducing non-aerobic resting metabolic rate. The effect can be reproduced by transferring the gut microbiota or associated bacteriophage (bacterial viruses) from risperidone-treated animals to naïve animals. Thus, gut bacteria and their associated viruses can affect changes in resting metabolic rates leading to weight gain.

Risperidone is a second-generation antipsychotic that causes weight gain. We hypothesized that risperidone-induced shifts in the gut microbiome are mechanistically involved in its metabolic consequences. Wild-type female C57BL/6J mice treated with risperidone (80 μg/day) exhibited significant excess weight gain, due to reduced energy expenditure, which correlated with an altered gut microbiome. Fecal transplant from risperidone-treated mice caused a 16% reduction in total resting metabolic rate in naïve recipients, attributable to suppression of non-aerobic metabolism. Risperidone inhibited growth of cultured fecal bacteria grown anaerobically more than those grown aerobically. Finally, transplant of the fecal phage fraction from risperidone-treated mice was sufficient to cause excess weight gain in naïve recipients, again through reduced energy expenditure. Collectively, these data highlight a major role for the gut microbiome in weight gain following chronic use of risperidone, and specifically implicates the modulation of non-aerobic resting metabolism in this mechanism.