P.1.015 - Influence of prebiotic intake on olanzapine-mediated weight gain, central receptors, peripheral biomarkers, and gut microbiota

Abstract

Olanzapine is the first-line antipsychotic treatment for schizophrenia, but often leads to secondary health concerns such as metabolic syndrome and weight gain. Studies in rats have shown that chronic olanzapine administration induces weight gain [1] and reduces hippocampal glutamate N-methyl-D-Aspartate receptor (NMDAR) levels, the latter which may hinder the recovery of cognitive function in schizophrenia patients. We have shown that dietary augmentation of beneficial gut bacteria using the commercially available prebiotic Bimuno ™ galacto-oligosaccharides (B-GOS ® ) increases central levels of NMDAR subunits in rodents [2,3]. The aim of this study was to determine whether the effects of olanzapine on weight gain and peripheral effects are influenced by B-GOS® intake in rats. Adult female Sprague-Dawley rats were provided with a B-GOS ® (0.5g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. Weight gain and water intake were monitored daily. We determined whether B-GOS ® influenced olanzapine-associated weight gain, and central NMDAR and serotonin receptor expression. Circulating levels of acetate, IL-1β, IL-8 and TNFα as well as liver acetyl-CoA Carboxylase (ACC), white adipose tissue acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Two-way ANOVAs were used to analyse all data, with repeated measures included to explore weight gain. Olanzapine induced significant weight gain (p ® -fed rats. Significant effect of treatment was observed on hippocampal GluN1 mRNA abundance (p = 0.034), where olanzapine significantly increased (+17%) levels in the absence of B-GOS ® (p = 0.040). Plasma acetate concentrations increased following B-GOS ® 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 ® . Co-administration of B-GOS ® and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOS ® elevated faecal Bifidobacterium Spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS ® , was without effect. The current study demonstrates a potential strategy to reduce olanzapine-mediated weight gain in schizophrenia without compromising a key central pharmacological action of this antipsychotic. We also demonstrate a NMDAR augmenting effect, supporting a potential pro-cognitive effect of the prebiotic. Our data also implies that elevated TNFα in B-GOS ® /olanzapine rats may contribute to the reduction in olanzapine-induced weight gain as pro-inflammatory TNFα is a recognised appetite suppressant. These data suggest that inclusion of B-GOS ® as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis.