BackgroundStatins 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.ResultsUsing 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).ConclusionThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0312-4) contains supplementary material, which is available to authorized users.

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Exposure of proteins to radicals in the presence of O(2) brings about multiple changes in the target molecules. These alterations include oxidation of side chains, fragmentation, cross-linking, changes in hydrophobicity and conformation, altered susceptibility to proteolytic enzymes, and formation of new reactive groups, including hydroperoxides. These processes can result in the loss of structural or enzymatic activity. Backbone fragmentation is known to occur via a number of mechanisms, most of which involve hydrogen abstraction from the alpha-carbon site on the backbone. In this study, we demonstrate that initial attack at a side chain site, the beta-position (C-3), can give rise to formation of alpha-carbon radicals, and hence backbone cleavage, via the formation and subsequent beta-scission of C-3 alkoxyl radicals. This beta-scission reaction is rapid (k estimated to be >10(7) s(-)(1)) even with primary alkoxyl radicals derived from Ala residues, and occurs when the alkoxyl radicals are generated from a variety of precursors, including hydroperoxides and nitrate esters. These reactions release the former side chain as a reactive aldehyde or ketone; thus, Ala peptides release high yields of methanal (formaldehyde). This product has been quantified with a number of oxidized peptides and proteins, and can account for up to 64% of the initial attacking radicals with some Ala peptides. When quantified together with the hydroperoxide precursors, these species account for up to 80% of the initial radicals, confirming that this is a major process. Methanal causes cell toxicity and DNA damage and is an animal carcinogen and a genotoxic agent in human cells. Thus, the formation and subsequent reaction of alkoxyl radicals formed at the C-3 position on aliphatic amino acid side chains on peptides and proteins can give rise to both backbone fragmentation and the release of further reactive species which can cause cell toxicity and mutagenicity.

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