Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids

Abstract

Background and Aims: The mechanisms of interindividual variation of lipid regulation by statins, such as the low-density lipoprotein cholesterol (LDL) lowering effects, are not fully understood yet. Here, we used a gut microbiota depleted mouse model to investigate the relation between the gut microbiota and the regulatory property of atorvastatin on blood lipids. Methods: Mice (C57BL/6) with intact gut microbiota or antibiotic induced abiotic mice (ABS) were put on standard chow diet (SCD) or high fat diet (HFD) for six weeks. Atorvastatin (10 mg/kg body weight/day) or a control vehicle were applied per gavage for the last four weeks of dietary treatment. Blood lipids including total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and sphingolipids were measured to probe microbiota-dependent effects of atorvastatin. The expression of genes involved in hepatic and intestinal cholesterol metabolism was analyzed with qRT-PCR. The alteration of the microbiota profile was examined using 16S rRNA qPCR in mice with intact gut microbiota. Results: HFD feeding significantly increased total blood cholesterol and LDL levels, as compared to SCD in both mice with intact and depleted gut microbiota. The cholesterol lowering effect of atorvastatin was significantly attenuated in mice with depleted gut microbiota. Moreover, we observed a global shift in the abundance of several sphingolipids upon atorvastatin treatment which was absent in gut microbiota depleted mice. The regulatory effect of atorvastatin on the expression of distinct hepatic and intestinal cholesterol-regulating genes, including Ldlr, Srebp2 and Npc1l1 was altered upon depletion of gut microbiota. In response to HFD feeding, the relative abundance of the bacterial phyla Bacteroidetes decreased, while the abundance of Firmicutes increased. The altered ratio between Firmicutes to Bacteroidetes was partly reversed in HFD fed mice treated with atorvastatin. Conclusions: Our findings support a regulatory impact of atorvastatin on the gut microbial profile and, in turn, demonstrate a crucial role of the gut microbiome for atorvastatin-related effects on blood lipids. These results provide novel insights into potential microbiota-dependent mechanisms of lipid regulation by statins, which may account for variable response to statin treatment.

Atorvastatin reverses high cholesterol‐induced cardiac remodelling and regulates mitochondrial quality‐control in a cholesterol‐independent manner: An experimental study

“…Atorvastatin has greater binding affinity to hepatic HMG‐CoA reductase 29 and belongs to lipophilic statins that can enter into cells by passive diffusion and thereby are widely distributed into different tissues, including heart tissue 30 . In this study, the AT treatment at 3 mg/kg every other day for 12 weeks didn't present lipid‐lowering effect in HFD‐fed mice, due to the much lower dose than the reported dosage range of 20–80 mg/kg on reducing cholesterol in mice in previous experiments 31,32 . Even so, we still observed that atorvastatin ameliorated cardiac remodelling and systolic dysfunction in hypercholesterolaemia mice by a cholesterol‐independent method in this study.…”

Targets of statins intervention in LDL-C metabolism: Gut microbiota

“…Although the relative abundance of Bacteroidetes decreased significantly after the HFD intervention, the relative abundance of Proteobacteria was observed to increase ( 50 ). In addition, the absolute abundance of the gut microbiota doubled by HFD intervention ( 51 ), which indicated that although the relative abundance of Bacteroidetes was reduced, the total number may not have changed significantly. We observed that SCFAs, BAS, TMAO, and LPS are related to the ability of the gut microbiota to regulate the LDL-C levels via metabolites ( Table 1 ).…”

“…Statins are well known as the most commonly used cholesterol-lowering drugs, which can directly reduce plasma cholesterol levels, especially LDL-C ( 110 ), by inhibiting cholesterol synthesis and HMGCR. The cholesterol-lowering effect of statins is closely related to the gut microbiota and can be impaired for the imbalance if gut microbiota ( 12 , 51 ). In addition, different statins, such as atorvastatin, simvastatin, and rosuvastatin, have different effects on different microbiota ( 111 ) and thereby affect MDM ( Table 2 ).…”

“…Therefore, it is challenging to observe changes in SREBP without being affected by cholesterol. Zimmermann et al discovered that atorvastatin intervention increased the average levels of SREBP2 expression in the liver of HFD mice, and the effect of atorvastatin was reversed in antibiotic-treated HFD mice ( 51 ). This suggests that antibiotics attenuate the SREBP2 response to a low-cholesterol state by eliminating the positive effect of gut microbiota-mediated lipid-lowering action of atorvastatin.…”

Role of the gut microbiome in cardiovascular drug response: The potential for clinical application

“…In mice with antibiotic induced microbiome depletion, the lipid lowering effects of atorvastatin were decreased and the expression of hepatic and intestinal cholesterol-regulating genes (Ldlr, Srebp2, and Npc1l1) was altered. 53 In addition to the effects on cholesterol, mice models exhibit changes in intestinal bile acid levels, which the authors hypothesize is due to the gut microbiome. It is postulated that bacteria are needed to enzymatically catalyze the deconjugation of bile acid so that bile can be passively absorbed from the intestine to circulation.…”