Background and Aims

The mechanisms of interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering effects of statins are not fully understood. Here, we investigated the implication of the gut microbiota for the LDLc lowering property of atorvastatin. 

Methods

Mice (C57BL/6) with either intact gut microbiota (conventional mice, n=24) or with antibiotic-induced depleted gut microbiota (gnotobiotic mice, n=16) were put on standard chow diet (SCD) (n=11) or high fat diet (HFD) (n=29) for six weeks. Atorvastatin (Ator, 10mg/kg bodyweight/day) or control vehicle was applied per gavage for four weeks. Blood levels of LDLc and glucose and weight gain were compared between the groups. In mice with intact gut microbiome the alteration of the microbiota profile was examined using 16S rRNA qPCR. 

Results 

HFD feeding significantly increased blood LDLc levels as compared to SCD (HFD: 36.8±1.4 mg/dl vs. SCD: 22.0±1.8 mg/dl; P<0.01) in conventional mice with intact gut microbiota. The LDLc lowering effect of atorvastatin was significantly attenuated in gnotobiotic mice (SPF+HFD+Ator: 31.0±1.8 mg/dl vs. gnotobiotic mice + HFD + Ator: 46.4±3 mg/dl; P<0.01). Atorvastatin treatment had no significant effects on weight gain or blood glucose levels in HFD fed mice with depleted gut microbiota. Upon HFD feeding the relative abundance of the bacterial phyla Bacteroides was decreased while the abundance of Firmicutes was increased. The increased ratio between Firmicutes to Bacteroides was reversed in HFD fed mice treated with atorvastatin. 

Conclusions 

Our findings support the regulatory impact of atorvastatin on the gut microbiata profile and demonstrate a crucial role of the gut microbiota for the LDLc lowering effect of atorvastatin. The results provide novel insight into potential microbiota-related mechanisms underlying interindividual variation in the LDLc lowering effects of statins.