A microbiota-targeted strategy to attenuate antipsychotic-induced weight gain
University College Cork
Background: Atypical antipsychotics such as olanzapine are an essential treatment for psychotic-spectrum disorders, but their use is associated with significant weight gain and increased cardiometabolic disease risk. Attenuating these side effects could improve the tolerability and adherence to antipsychotic medications. Evidence suggests that the microbiome plays a role in antipsychotic-induced weight gain, thus targeting the microbiome may be a viable therapeutic strategy to attenuate the side effect profile of antipsychotics like olanzapine. Furthermore, metabolomics approaches are being increasingly employed to elucidate disease pathophysiology and potential therapeutic targets, but these strategies have not yet been applied to the problem of antipsychotic-induced obesity and hyperphagia. Aims: The primary aims of this study are to (1) investigate if combined microbiome-targeted treatments (probiotic [APC1472], prebiotic [xanthohumol], and their combination) with olanzapine attenuate antipsychotic-induced obesity, metabolic dysfunction, and hyperphagia in female Sprague-Dawley rats, and (2) analyse blood plasma using discovery metabolomics to generate potential mechanistic and therapeutic targets related to the side effects of olanzapine. Methods: Animals were treated with olanzapine (2 mg/kg body weight) alone (n=12), olanzapine with probiotic (n=11), olanzapine with prebiotic (n=11), olanzapine with probiotic and prebiotic (n=12) or control vehicle (n=12) twice a day via intraperitoneal injection for 31 days. Changes in body weight, adiposity, glucose metabolism, dietary intake, anxiety-like behaviour, plasma biomarkers (corticosterone, insulin, ghrelin), and hypothalamic and hepatic gene expression were examined. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) and subsequent metabolomic analysis using Progensis QI and Metaboanalyst were used to characterise plasma differences between the olanzapine treatment group and controls. Results: After the study conclusion, quality control issues with the probiotic formulation were discovered, limiting the interpretability of the data from those treatment groups. However, the olanzapine treatment displayed increased weight gain, dietary intake, and hypothalamic genes related to ghrelinergic signalling. Olanzapine did not increase adiposity, change hepatic gene expression, plasma biomarkers, or hypothalamic genes related to anorexigenic signalling. No treatments attenuated olanzapine-induced weight gain. There were no observed differences in anxiety-like behaviour between any groups. Lastly, the metabolomics investigation revealed several highly differentially expressed metabolites; two androstanoids and one endocannabinoid (oleamide). Conclusion: These findings indicate that olanzapine-associated increases in hypothalamic ghrelinergic signalling can occur before or without the onset of peripheral changes in metabolic health. Although the attenuation of olanzapine-associated increases in hypothalamic ghrelinergic signalling could not be assessed due to the quality control issues with the probiotic, targeting ghrelinergic signalling via microbiome-targeted approaches warrants further research. Additionally, the metabolomics analyses highlight oleamide as a novel metabolite that is potentially at the intersection of the endocannabinoid system, the microbiota, and olanzapine treatment, but further research is needed to clarify if the observed increase in oleamide is due to changes in host and/or microbial metabolism.
Olanzapine , Metabolomics , Microbiome , In vivo , Hypothalamus , Obesity
Lipuma, T. C. 2023. A microbiota-targeted strategy to attenuate antipsychotic-induced weight gain. MSc Thesis, University College Cork.