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

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

Separation and recovery of exotic radiolanthanides from irradiated tantalum targets for half-life measurements.

The current knowledge of the half-lives (T1/2) of several radiolanthanides is either affected by a high uncertainty or is still awaiting confirmation. The scientific information deriving from this imprecise T1/2 data has a significant impact on a variety of research fields, e.g., astrophysics, fundamental nuclear sciences, and nuclear energy and safety. The main reason for these shortcomings in the nuclear databases is the limited availability of suitable sample material together with the difficulties in performing accurate activity measurements with low uncertainties. In reaction to the urgent need to improve the current nuclear databases, the long-term project "ERAWAST" (Exotic Radionuclides from Accelerator Waste for Science and Technology) was launched at Paul Scherrer Institute (PSI). In this context, we present a wet radiochemical separation procedure for the extraction and purification of dysprosium (Dy), terbium (Tb), gadolinium (Gd), and samarium (Sm) fractions from highly radioactive tantalum specimens, in order to obtain 154Dy, 157-158Tb, 148,150Gd, and 146Sm samples, needed for T1/2 determination studies. Ion-exchange chromatography was successfully applied for the separation of individual lanthanides. All separations were conducted in aqueous phase. The separation process was monitored via γ-spectrometry using suitable radioactive tracers. Both the purity and the quantification of the desired radiolanthanides were assessed by inductively coupled plasma mass spectrometry. Test experiments revealed that, prior to the Dy, Tb, Gd, and Sm separation, the removal of hafnium, lutetium, and barium from the irradiated tantalum material was necessary to minimize the overall dose rate exposure (in the mSv/h range), as well to obtain pure lanthanide fractions. With the herein proposed separation method, exotic 154Dy, 157-158Tb, 148,150Gd, and 146Sm radionuclides were obtained in sufficient amounts and purity for the preparation of samples for envisaged half-life measurements. During the separation process, fractions containing holmium, europium, and promethium radionuclides were collected and stored for further use