Abstract
BACKGROUND: Maintaining gut microbial homeostasis is crucial for human health, as imbalances in the gut microbiota (GM) can lead to various diseases, including metabolic syndrome (MS), exacerbated by the use of antipsychotic medications such as olanzapine (OLZ). Understanding the role of the GM in OLZ-induced MS could lead to new therapeutic strategies. This study used metagenomic analysis to explore the impact of OLZ on the GM composition and examined how probiotics can mitigate its adverse effects in a rat model. Changes in weight, blood pressure, and lipid levels, which are key parameters defining MS, were assessed. Additionally, this study investigated serotonin, dopamine, and histopathological changes to explore their possible link with the microbiota-gut-brain axis (MGBA). RESULTS: OLZ had an antagonistic effect on serotonin and dopamine receptors, and it was consistently found to alter the composition of the GM, with an increase in the relative abundance (RA) of the Firmicutes/Bacteroidetes phyla ratio and TM7 genera, indicating that the anticommonsal action of OLZ affects appetite and energy expenditure, contributing to obesity, dyslipidemia and increased blood pressure, which are core components of MS. Hepatic steatosis and intestinal damage in OLZ-treated rat tissues further indicate its role in MS. Conversely, the administration of probiotics, either alone or in combination with OLZ, was found to mitigate these OLZ-induced symptoms of MS by altering the GM composition. These alterations included increases in the abundances of the taxa Bacteroidetes, Actinobacteria, Prevotella, Blautia, Bacteroides, Bacteroidales, and Ruminococcaceae and a decrease in Firmicute abundance. These changes helped maintain gut barrier integrity and modulated neurotransmitter levels, suggesting that probiotics can counteract the adverse metabolic effects of OLZ by restoring the GM balance. Moreover, this study highlights the modulation of the MGBA by OLZ as a potential mechanism through which probiotics modulate serotonin and dopamine levels, influencing metabolic health. CONCLUSION: These findings emphasise the significant impact of OLZ on the GM and its contribution to MS. These findings suggest that interventions targeting the GM, such as probiotics, could mitigate the metabolic side effects of OLZ. Future research should focus on developing integrative treatment approaches that consider the health of the gut microbiome in managing antipsychotic-induced adverse effects.