Characterization of risperidone-induced weight gain mediated by alterations of the gut microbiome and suppression of host energy expenditure

The atypical antipsychotic risperidone is associated with weight gain and cardio-metabolic side effects. In light of growing evidence implicating the gut microbiome in the host’s energy regulation and in xenobiotic metabolism, it is hypothesized that risperidone-induced weight gain is mediated through alterations in the gut microbiome.

The impact of chronic and short-term risperidone treatment on the gut microbiome of pediatric, psychiatric patients was examined in a cross-sectional and prospective design. Chronic treatment with risperidone was associated with a significant increase in body mass index (BMI) and a significant reduction in the ratio of Bacteroidetes to Firmicutes, as compared to naïve psychiatric controls. Predictive metagenomic analyses, indicate that gut microbiota dominating the risperidone-treated patients are enriched for pathways, such as short-chain fatty acid production, which have been implicated in weight gain.

Alterations in the microbiome due to risperidone treatment were further demonstrated in wild-type female mice and shown to be a result of a reduction in host energy expenditure. Risperidone-treated mice exhibit significant weight gain and an altered gut microbiome relative to controls while maintaining normal food intake behavior and digestive efficiency, indicating that increased weight gain is due to reduced energy expenditure. Moreover, fecal transfer from risperidone-treated mice to a second cohort of naïve mice was performed via daily gastric gavage and aerobic and non-aerobic resting metabolic rates (RMR) were monitored using combined calorimetry. This transfer has no effect on aerobic RMR in recipients, but induces a significant suppression of non-aerobic RMR in mice receiving stool from risperidone-treated donors establishing a causal effect of the altered gut microbiome upon energy expenditure. Finally, daily transfer of phage, a subset of the gut microbiome, isolated from the gut of risperidone treated donors was also sufficient to cause excess weight gain in naïve recipients animals through suppression of energy expenditure. Together, these data highlight a major role for the gut microbiome for weight gain following chronic use of risperidone, and demonstrate that the mechanism depends upon suppression of energy expenditure.