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. 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

Jose A Caparrós-Martín  1   2   3 , Ricky R Lareu  2   4 , Joshua P Ramsay  2   3 , Jörg Peplies  5 , F Jerry Reen  6 , Henrietta A Headlam  7 , Natalie C Ward  2   3   7 , Kevin D Croft  7 , Philip Newsholme  2   3 , Jeffery D Hughes  4 , Fergal O'Gara  8   9   10   11
Affiliations

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

Jose A Caparrós-Martín et al. Microbiome. .

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.

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Conflict of interest statement

Ethics approval

Ethics approval was obtained from the Curtin University Animal Ethics Committee, and all procedures were in strict accordance with guidelines for the care and use of laboratory animals specified by this committee (reference number AEC-2014-36).

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Changes in the gut microbial composition in response to ND-statins. a Principal coordinates analysis projection plot showing ordination of the samples using the Bray-Curtis dissimilarity matrices. Dots correspond to one individual within each control (vehicle, green) and statin (pravastatin, blue; atorvastatin, red) cohorts combined with normal diet. Lines connect each sample to the centroid of the corresponding treatment. Ellipses limits represent 95% confidence for the group centroid. b Biological diversity was quantified by the Shannon and Simpson indices of diversity as implemented in the R package vegan [67]. The higher the Shannon and Simpson indices, the greater the diversity. Pielou evenness (J) was calculated as J = H′ / log(S), where H′ is the Shannon index and log(S) is the natural logarithm of the number of OTUs. The lower the Pielou index, the less even the community. Each black point represents one individual, and the coloured dots and brackets show the mean and standard deviation (SD), respectively. The effect of the treatment was evaluated by one-way ANOVA followed by Dunnett’s post hoc test. *P ≤ 0.05; **P ≤ 0.01. c, d Distinctive gut microbiota composition associated with statin consumption revealed by linear discriminant analysis (LDA). Graphs represent the LDA scores of the differentially abundant OTUs associated with the pravastatin (c) or atorvastatin (d) treatment. Taxa enriched in the gut of mice treated with statins are represented with negative LDA scores. Positive LDA scores represent OTUs enriched in the control cohort (vehicle). Heatmaps on the right show the averaged relative abundance (log10 transformed) of the discriminative OTUs for the indicated treatments
Fig. 2
Fig. 2
Statins induce a functional dysbiosis. a, b Levels of the indicated SCFA in the caecum (a) or serum (b) of wild-type mice fed with ND and treated with statins (pravastatin, grey; atorvastatin, black) or without treatment (vehicle, white). Barplots represent the mean ± standard deviation (SD) calculated from at least three biological replicates. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; one-way ANOVA and pairwise comparisons by Dunnett’s post hoc test
Fig. 3
Fig. 3
Statins alter the overall composition of the bile acid pool in the gut. a Relative levels of the indicated primary and secondary bile acids in the faecal content of the caecum of mice control (white) or mice treated with pravastatin (grey) or atorvastatin (black) and fed with ND. Bars represent the mean ± SD calculated from at least four biological replicates. b Relative expression in the liver of Cyp7a1 and Cyp27a1 by qPCR. Data are represented as the mean ± SD determined from at least three biological replicates. n.s. non-significant; *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; one-way ANOVA and pairwise comparisons by Dunnett’s post hoc test
Fig. 4
Fig. 4
Statins affect the expression in the liver of genes related with lipid and glucose metabolism. a–e qPCR analysis of the indicated genes in the liver of wild-type control (vehicle, white) and statin-treated (pravastatin, grey; atorvastatin, black) mice fed with ND. Barplots represent the mean ± SD determined from at least three biological replicates. n.s. non-significant; *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; one-way ANOVA followed by Dunnett’s post hoc test
Fig. 5
Fig. 5
PXR activity regulates the changes in the BA pool of the gut induced by statins. a Relative levels of the indicated primary and secondary bile acids in the gut of Pxr −/− mice control (white) or mice treated with pravastatin (grey) or atorvastatin (black) and fed with ND. Bars represent the mean ± SD calculated from at least four biological replicates. b Relative expression in the liver of Cyp7a1 and Cyp27a1 by qPCR. Barplots represent the mean ± SD determined from three biological replicates. **P ≤ 0.01; one-way ANOVA followed by Dunnett’s post hoc test
Fig. 6
Fig. 6
A PXR-dependent mechanism underlies the observed statin-associated secondary effects. Proposed mechanism by which statins may increase the risk of developing T2DM. Activation of PXR in the liver by statins and/or their derived metabolites deregulates BA metabolism (a). Based on the antimicrobial properties of statins (b) and BAs (c), the structure and diversity of the gut microbiota is affected. Progressive selection of BA- and statin-tolerant microbes alters the potential metabolism of the gut microbiota and results in a dysbiotic community defective in the production of butyric acid (d). Lower production of butyrate by the gut microbiota together with the aberrant expression in the liver of genes related to glucose metabolism (e) may predispose the host to develop new onset of T2DM
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