Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment

Abstract

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.

Pharmacometabonomics and personalized medicine

“…73,74 Lower predose concentrations of xanthine, 2-hydroxyvaleric acid, succinic acid and stearic acid and higher predose concentrations of galactaric acid (hexaric acid) were all significantly correlated with greater LDL-C response in the GPR sub-group.…”

“…29 It is also clear that there is a complex and close interaction between the operation of the human genome and our microbiome and there is an explosion of interest in this area recently. 58,74,83,84,[90][91][92][93][94][95][96][97][98][99][100][101]102 Metabonomics is exceptional in its ability to simultaneously sample information on the metabolic products of the human genome as well as our microbiome. We therefore expect that improved personalized medicine can be achieved with the help of information from metabonomics, which is distinguished from human genomics by two critical points: (i) it samples both genetic and environmental information and (ii) it reports on the actual physiological state of a person as opposed to a state that might exist in the future.…”

Pharmacometabonomics in Humans: A New Tool for Personalized Medicine

“…This is typically done with technologies such as UPLC--MS with a triple quadrupole MS, by liquid chromatography --electrochemical analysis (LC--ECA), which targets only those compounds able to undergo electrochemical oxidation or reduction, [17] or by gas chromatography --mass spectrometry (GC--MS). [18] On the other hand, GC--MS, LC--MS and ultra performance liquid chromatography (UPLC)--MS can be used in an untargeted fashion, as can NMR spectroscopy. In an untargeted approach, the detector is used in an unbiased fashion, and without prior selection of what sort of metabolites are to be analysed.…”

“…A targeted GC--MS and LC--MS study of patients from the same CAP study was reported later. [18] Pre--dose plasma levels of taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), glycochenodeoxycholic acid, (GCDCA) and glycoursodeoxycholic acid (GUDCA), were found to be negatively correlated with post--dose % LDL--C reduction in 100 patients representing the full range of patient responses. Pre--dose levels of two bile acids, chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), were positively correlated to post--treatment simvastatin levels in this same full--range patient subset.…”

Investigation of Host–Gut Microbiota Modulation of Therapeutic Outcome

“…The following section illustrates the roles of the gut microbiota in modulating pharmacokinetic processes and the therapeutic implications. The list of affected drugs is presented in Table 1 ( Sousa et al, 2008;Clayton et al, 2009;Kaddurah-Daouk et al, 2011;Saitta et al, 2014).…”