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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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