Probiotic enhances cholesterol drug efficacy but raises safety concerns at high doses

A recent study published in Engineering has shed light on the complex interactions between probiotics and drugs, particularly focusing on the effects of the probiotic Lacticaseibacillus paracasei Zhang (LCZ) on the cholesterol-lowering drug lovastatin. The research, conducted by a team from Inner Mongolia Agricultural University, reveals that while low doses of LCZ can significantly enhance the efficacy of lovastatin, higher doses may lead to increased toxicity.

The study began with in vitro experiments, where the researchers observed that LCZ could metabolize lovastatin into its active form, lovastatin hydroxy acid. This metabolic conversion suggested that LCZ might enhance the drug's activity. However, the in vivo experiments in Syrian golden hamsters painted a more nuanced picture. The researchers administered various combinations of LCZ and lovastatin to hyperlipidemic hamsters and monitored their health outcomes. [All in vivo experiments were conducted following the protocols approved by the Inner Mongolia Agricultural University Laboratory Animal Ethical Committee (IACUC-20220007).]

In the in vivo phase, the researchers found that combining LCZ with low-dose lovastatin (2.5 mg/kg) led to a significant reduction in body weight and blood lipid levels, with no adverse effects on liver, kidney, or muscle function. This combination therapy was more effective than lovastatin alone, indicating that LCZ could enhance the drug's absorption and efficacy. However, when higher doses of lovastatin (10 mg/kg and 20 mg/kg) were combined with LCZ, the hamsters exhibited increased mortality rates. This suggests that while LCZ can boost lovastatin absorption, it may also exacerbate the drug's toxicity at higher doses.

To understand the underlying mechanisms, the researchers analyzed the gut microbiota and metabolites of the hamsters. They found that LCZ altered the gut metabolite environment, potentially enhancing the solubility and absorption of lovastatin. This modulation of the gut environment likely contributed to the increased efficacy observed with low-dose combinations. However, at higher doses, the enhanced absorption led to toxic levels of lovastatin in the bloodstream.

The study also included a detailed analysis of liver gene expression, revealing that the combination therapy upregulated genes involved in bile acid and drug metabolism. This upregulation suggests that the enhanced absorption of lovastatin led to increased metabolic activity in the liver, further supporting the observed therapeutic effects.

The findings highlight the importance of dose control in probiotic-drug combinations. While LCZ can significantly enhance the efficacy of low-dose lovastatin, the potential for increased toxicity at higher doses underscores the need for careful clinical evaluation. The study provides valuable insights into the interactions between probiotics and drugs, emphasizing the potential benefits and risks of such combinations.

Future research should focus on clinical trials to further explore the therapeutic potential and safety of LCZ-lovastatin combinations in humans. Additionally, more detailed studies on the gut microbiota and metabolite profiles could help elucidate the precise mechanisms underlying these interactions. This research not only contributes to the field of pharmacomicrobiomics but also has important implications for personalized medicine, where probiotic interventions could be tailored to optimize drug efficacy and minimize adverse effects.