Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota

Olanzapine is an effective antipsychotic drug but since it causes significant weight gain, it is not well tolerated by psychosis patients. The prebiotic, B-GOS (R), attenuates metabolic dysfunction in obese subjects, and in rodents, alters central NMDA receptors and may affect serotonin receptors that are relevant in psychosis. We have determined whether B-GOS (R) influenced olanzapine-associated weight gain and central NMDA and serotonin receptors. Circulating acetate, IL-1 beta, IL-8 and TNF alpha, liver acetyl-CoA carboxylase (ACC), white adipose tissue (WAT) acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Adult female Sprague-Dawley rats were administered a B-GOS (R) (0.5 g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. The intake of B-GOS (R) significantly attenuated olanzapine-induced weight gain without altering frontal cortex 5-HT2AR blockade. Cortical GluN1 levels were elevated by olanzapine in the presence of B-GOS (R). Plasma acetate concentrations increased following B-GOS (R) or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOS (R). Co-administration of B-GOS (R) and olanzapine also elevated plasma TNFa, which is reported to influence lipid metabolism. Finally, B-GOS (R) elevated faecal Bifidobacteriumspp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS (R), was without effect. These data suggest that inclusion of B-GOS (R) as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis. The role of acetate in these effects requires further investigation.