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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 micro...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290826/ https://www.ncbi.nlm.nih.gov/pubmed/32466086 http://dx.doi.org/10.3390/jcm9051596 |
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author | Zimmermann, Friederike Roessler, Johann Schmidt, David Jasina, Andrzej Schumann, Paul Gast, Martina Poller, Wolfgang Leistner, David Giral, Hector Kränkel, Nicolle Kratzer, Adelheid Schuchardt, Sven Heimesaat, Markus M. Landmesser, Ulf Haghikia, Arash |
author_facet | Zimmermann, Friederike Roessler, Johann Schmidt, David Jasina, Andrzej Schumann, Paul Gast, Martina Poller, Wolfgang Leistner, David Giral, Hector Kränkel, Nicolle Kratzer, Adelheid Schuchardt, Sven Heimesaat, Markus M. Landmesser, Ulf Haghikia, Arash |
author_sort | Zimmermann, Friederike |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7290826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72908262020-06-17 Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids Zimmermann, Friederike Roessler, Johann Schmidt, David Jasina, Andrzej Schumann, Paul Gast, Martina Poller, Wolfgang Leistner, David Giral, Hector Kränkel, Nicolle Kratzer, Adelheid Schuchardt, Sven Heimesaat, Markus M. Landmesser, Ulf Haghikia, Arash J Clin Med Article 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. MDPI 2020-05-25 /pmc/articles/PMC7290826/ /pubmed/32466086 http://dx.doi.org/10.3390/jcm9051596 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zimmermann, Friederike Roessler, Johann Schmidt, David Jasina, Andrzej Schumann, Paul Gast, Martina Poller, Wolfgang Leistner, David Giral, Hector Kränkel, Nicolle Kratzer, Adelheid Schuchardt, Sven Heimesaat, Markus M. Landmesser, Ulf Haghikia, Arash Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids |
title | Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids |
title_full | Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids |
title_fullStr | Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids |
title_full_unstemmed | Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids |
title_short | Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids |
title_sort | impact of the gut microbiota on atorvastatin mediated effects on blood lipids |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290826/ https://www.ncbi.nlm.nih.gov/pubmed/32466086 http://dx.doi.org/10.3390/jcm9051596 |
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