Enhanced Efficacy of Low-dose Lovastatin through Probiotic-Mediated Absorption: Insights from In Vitro and In Vivo Studies

Abstract

Abstract Background Growing evidence highlights the crucial role of gut microbiota in drug metabolism, affecting both efficacy and toxicity. Probiotics, as part of the gut microbiota, possess a diverse array of enzymes and are likely involved in drug interactions. Our previous study demonstrated the ability of Lacticaseibacillus paracasei Zhang (LCZ), a probiotic strain, to metabolize lovastatin, a widely used lipid-lowering drug, in monoculture. However, the impact of LCZ on lovastatin metabolism, activity, efficacy, and toxicity in vivo remains an important area for investigation. Results In this study, we comprehensively assessed the effect of LCZ on lovastatin from in vitro to in vivo settings. In vitro experiments utilizing targeted and non-targeted metabolomics analysis revealed that LCZ transformed lovastatin into its activated form, lovastatin hydroxy acid, both in monoculture and a simulated human digestion system. In vivo investigations demonstrated that the combination of LCZ with low-dose lovastatin displayed enhanced efficacy in reducing blood lipids in hyperlipidemic hamsters. However, analysis of microbiota sequencing, metabolite analysis, and liver transcriptomics revealed that the improved efficacy was attributed to enhanced lovastatin absorption rather than direct drug metabolism by LCZ in the gut. Furthermore, the impact of LCZ on lovastatin was dose-dependent, with higher lovastatin doses resulting in increased absorption and potential toxicity. Conclusions The combination of probiotics with drugs can significantly influence the gut microbiome, particularly gut metabolites. These altered metabolites have the potential to interact with drugs, affecting their solubility, absorption, efficacy, and toxicity. This study sheds light on the interactions between probiotics and drugs, particularly from a safety perspective, providing insights into probiotic-drug co-treatment strategies and precision probiotics for personalized medicine.