Exploring The Impact And Mechanism Of Lacticaseibacillus Casei Zhang On Lovastatin Metabolism And Efficacy

The safety and efficacy of drugs in clinical treatment have always been of great concern.Recent studies have revealed that the human gut microbiota can affect drug metabolism,thereby altering their safety and efficacy.Probiotics,a class of microorganisms that promote human health,are increasingly being used in food,nutraceuticals,and pharmaceuticals,but their effects on drug metabolism,efficacy,and toxicity remain largely unknown.In this study,we investigated the effects of Lacticaseibacillus casei Zhang(LCZ),a probiotic strain,on drug metabolism through the integration of metabolomics,culturomics,and bionics technology.We further assessed the safety and efficacy of LCZ-drug combination therapy in animal experiments and explored the interaction mechanism between LCZ and drugs by employing transcriptomics,metagenomics,and metabolomics.The main results of this study were as follows:(1)LCZ presented a wide range of capabilities in drug metabolism,with 12 out of 36 drugs tested being metabolized by LCZ in vitro.Interestingly,LCZ was observed to be particularly effective in degrading of lovastatin,a lipid-lowering drug,resulting in the formation of its more active metabolite,lovastatin hydroxy acid,through the cleavage of theδ-lactone bond.Furthermore,LCZ was observed to maintain strain viability and lovastatin metabolizing activity after 24 hours of digestion in a dynamic gastrointestinal model.(2)The metabolism of lovastatin by LCZ was subject to inter-individual variation based on the composition of human fecal microbial communities.Specifically,LCZ was capable of metabolizing lovastatin in communities where the relative abundance of Lactobacillaceae over 1%.(3)Combining LCZ and low-dose lovastatin therapy exhibited considerable efficacy in reducing blood levels of TC,TG,LDL-c,and HDL-c in hyperlipidemic golden hamsters,while also decreasing hepatic fat accumulation.Notably,this combination therapy had no adverse effects on renal or hepatocellular function,and did not increase the risk of rhabdomyolysis.(4)When administered along with lovastatin,LCZ was discovered to have a minimal influence on lovastatin metabolism in the intestines of golden hamsters.Conversely,LCZ was found to enhance the absorption of lovastatin,leading to a noteworthy elevation in blood levels of lovastatin.The multi-omics analysis provided compelling evidence that a combination treatment of LCZ and lovastatin had a significant impact on the gut microbiota and metabolism of golden hamster.Particularly,12 metabolites,exhibiting similar polarity to lovastatin,such as ursocholic acid,lyngbic acid,and myristoylglycine,were significantly elevated,potentially enhancing the solubility and absorption of lovastatin.This study provided a comprehensive assessment of the impact of probiotic LCZ on lovastatin metabolism and efficacy by vitro experiments and in vivo models.Findings in this research presented a valuable approach for investigating probiotic-drug interactions in the future.Our results suggested that LCZ could facilitate the absorption of lovastatin in vivo and enhance its therapeutic potential,thereby providing a safer and more effective treatment option for hyperlipidemia patients and offering new insights into precision probiotics.