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

Abstract

Gut microbiota reportedly affects both efficacy and toxicity in drug metabolism. Probiotics possess several enzymes and are increasingly used in clinical and food settings. However, the effect of probiotics on in vivo drug metabolism, activity, efficacy, and toxicity remains a pressing topic of investigation. We assessed the effects of the probiotic Lacticaseibacillus paracasei Zhang (LCZ) on lovastatin in vitro and in vivo. In vitro experiments indicated that LCZ metabolically activates lovastatin into lovastatin hydroxy acid. Subsequent in vivo investigations revealed that the combination of LCZ and low-dose lovastatin significantly improved the anti-hyperlipidemic effect in golden hamsters. However, the enhanced efficacy was not attributed to LCZ-mediated metabolism but rather to the modulation of the gut metabolite environment, facilitating lovastatin absorption. Increased lovastatin absorption elevated the expression of genes responsible for liver bile acid metabolism and lovastatin transformation, thereby enhancing drug efficacy. Furthermore, the effect of LCZ on lovastatin was dose-dependent, with higher lovastatin doses prompting increased absorption and potential toxicity. Comprehensive analyses of the metagenome and metabolites of commensal gut microbes, as well as the serum metabolome of the host, helped elucidate the mechanisms of probiotic-mediated absorption. This study highlights the interactions between probiotics and drugs from a safety perspective, providing insights into probiotic–drug co-treatment strategies and precision probiotics for personalized medicine.