Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice

Abstract

Interindividual differences in hypolipidemic effect of simvastatin are observed in clinic, and metabolomic studies have uncovered the association between variations of bacterial-derived metabolites and therapeutic outcomes. In current study, we investigated the gut microbial-involved mechanisms underlying the different responses to simvastatin. Male C57BL/6J mice were given high-fat/cholesterol diet (HFD) 8 weeks and then orally administered simvastatin (20 mg/kg, once a day) for 4 weeks with or without antibiotic (100 mg/kg Imipenem : Cilastatin Sodium). We observed simvastatin reduced the levels of serum TC, LDL, HDL and TG in HFD-fed mice, but this effect was attenuated by antibiotic which altered gut microbiota composition. Subsequent metabolomic study indicated that gut microbiota modulation changed the serum metabolic and bile acid profiles in simvastatin-treated mice. Moreover, our results showed that simvastatin stimulated the expression of hepatic CYP7A1, CYP7B1 and Farnesoid X receptor (FXR) in HFD-fed mice, which were impaired by gut microbiota modulation. In summary, our results revealed that the hypolipidemic effect of simvastatin was correlated with the composition of gut microbiota, and the attenuated hypolipidemic effect of simvastatin by gut microbiota modulation was associated with the suppression on hepatic CYP7A1, CYP7B1 and FXR proteins that regulate bile acids synthesis from cholesterol.

Pharmacomicrobiomics: The Holy Grail to Variability in Drug Response?

“…This modulation of the gut microbiota via antibiotics further impacted the expression of serum metabolites such as phospholipids, bile acids, and hepatic cholesterol 7 alpha‐hydroxylase genes ( CYP7A1 , CYP7B1 ). These hepatic genes also regulate the bile acid biosynthesis from cholesterol . Therefore, in summary, He et al .…”

“…Positive correlations have been observed between plasma concentrations of simvastatin and bacterial‐derived primary and secondary bile acids, especially in good responders . He et al ., in 2017, using a metabolomics survey, demonstrated that simvastatin reduced the levels of serum total cholesterol, low‐density lipoprotein, high‐density lipoprotein, and triglyceride in mice fed with high‐fat diet, which, however, could be attenuated by antibiotic treatment that in turn modulated the composition of gut microbiota . This modulation of the gut microbiota via antibiotics further impacted the expression of serum metabolites such as phospholipids, bile acids, and hepatic cholesterol 7 alpha‐hydroxylase genes ( CYP7A1 , CYP7B1 ).…”

Unraveling Host-Gut Microbiota Dialogue and Its Impact on Cholesterol Levels

“…Only a few studies have shown the impact of the microbiota on statin efficacy. Still, these studies suggested that the microbiota participated in statin's effect (He et al, 2017) and was responsible for statin metabolization (Yoo et al, 2014) and that the microbiota from patients unresponsive to statin was different from that of responsive patients (Sun et al, 2018).…”

An in vitro evaluation of the effects of different statins on the structure and function of human gut bacterial community

“…It has been reported that gut microbiota play roles in the mediation of lovastatin metabolism and consequent pharmacokinetics interactions [15]. The hypolipidemic effects of SIM [16], ROS [17], and ATO [18] were shown to be correlated with the compositions of mice gut microbiota. Statins have certain antibacterial functions and have been described as novel adjuvant antibiotics [10], but we know little about the statin effects on the human gut bacterial microbiota.…”