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Microbiome. 2017 Aug 9;5(1):95. doi: 10.1186/s40168-017-0312-4.

Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism.

Author information

1
Human Microbiome Programme. School of Biomedical Sciences. Faculty of Health Sciences, Curtin University, Perth, WA, Australia.
2
Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, Australia.
3
School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.
4
School of Pharmacy, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.
5
Ribocon GmbH, Fahrenheitstr 1, 28359, Bremen, Germany.
6
BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland.
7
School of Medicine and Pharmacology, The University of Western Australia, Perth, WA, Australia.
8
Human Microbiome Programme. School of Biomedical Sciences. Faculty of Health Sciences, Curtin University, Perth, WA, Australia. Fergal.Ogara@curtin.edu.au.
9
Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, Australia. Fergal.Ogara@curtin.edu.au.
10
School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia. Fergal.Ogara@curtin.edu.au.
11
BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland. Fergal.Ogara@curtin.edu.au.

Abstract

BACKGROUND:

Statins are a class of therapeutics used to regulate serum cholesterol and reduce the risk of heart disease. Although statins are highly effective in removing cholesterol from the blood, their consumption has been linked to potential adverse effects in some individuals. The most common events associated with statin intolerance are myopathy and increased risk of developing type 2 diabetes mellitus. However, the pathological mechanism through which statins cause these adverse effects is not well understood.

RESULTS:

Using a murine model, we describe for the first time profound changes in the microbial composition of the gut following statin treatment. This remodelling affected the diversity and metabolic profile of the gut microbiota and was associated with reduced production of butyrate. Statins altered both the size and composition of the bile acid pool in the intestine, tentatively explaining the observed gut dysbiosis. As also observed in patients, statin-treated mice trended towards increased fasting blood glucose levels and weight gain compared to controls. Statin treatment affected the hepatic expression of genes involved in lipid and glucose metabolism. Using gene knockout mice, we demonstrated that the observed effects were mediated through pregnane X receptor (PXR).

CONCLUSION:

This study demonstrates that statin therapy drives a profound remodelling of the gut microbiota, hepatic gene deregulation and metabolic alterations in mice through a PXR-dependent mechanism. Since the demonstrated importance of the intestinal microbial community in host health, this work provides new perspectives to help prevent the statin-associated unintended metabolic effects.

KEYWORDS:

Bile acids; Dysbiosis; Gut microbiota; Pregnane X receptor; Short-chain fatty acids; Statins; Type 2 diabetes mellitus

PMID:
28793934
PMCID:
PMC5550934
DOI:
10.1186/s40168-017-0312-4
[Indexed for MEDLINE]
Free PMC Article

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