The fine-tuned induction of both direct and indirect defenses is thought to reduce the costs of constitutive defense protection

ute to a more personalized approach to therapy. Citation: Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng Z-B, Wiest MM, et al. Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment. PLoS ONE 6: e25482. doi:10.1371/journal.pone.0025482 Editor: Herman Tse, The University of Hong Kong, Hong Kong Received April 26, 2011; Accepted September 5, 2011; Published October 13, 2011 Salvianic acid A biological activity Copyright: 2011 Kaddurah-Daouk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work is supported by National Institute of General Medical Sciences grants R24, GM078233, “The Metabolomics Research Network for Drug Response Phenotype”; and U01 HL069757, “Pharmacogenomics and Risk of Cardiovascular Disease”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: RKD is equity holder in a biotechnology company in the metabolomics domain, and also an inventor on patents in the metabolomics field. RKD, RMK, RAB, and SW are inventors on a patent application on statin effects on metabolism. RAB is an employee of Rosa and Company. SW is an employee of Tethys Bioscience. MT is an employee of SRI International. In none of these cases do these affiliations alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. E-mail: [email protected]; [email protected] Introduction Statins are HMG-CoA reductase inhibitors that are widely used to reduce plasma levels of LDL cholesterol and the risk for coronary artery disease . However, statins also have a number of other important biological actions that may contribute to treatment benefit or adverse events, for applications of metabolomics in personalized medicine and where biochemical data is being used to inform about treatment outcomes. While it is well established that response to therapeutics can be affected by genetic and environmental factors, the enteric microbiome might also play a role in uncharacterized ways. Metabolomics provides a unique method to characterize the net 1 October 2011 | Volume 6 | Issue 10 | e25482 Gut Metabolites and Simvastatin Response interactions among these contributing factors. Numerous studies, by members of this group and others, have identified genetic polymorphisms that contribute to variability in the LDL-C response to statins, but only a small proportion of the variance has been explained by these factors. Some statins are administered as inactive precursor drugs that are activated by endogenous biotransformation pathways, and there is increasing interest in the role of gut bacteria in the metabolism of drugs including simvastatin. Metabolomics can capture a unique portrait of the state and changes of the gut microbiota by direct measurements of metabolite production. Recently several metabolites produced by the gut microbiome were implicated ” in cardiovascular disease, highlighting for the first time an important and complementary role that the 18089725” gut microbiome plays in cardiovascular health, and indicating the need to study net interactions between genome, gut microbiome and the environment. Given that the primary cellular action of statins is well upstream of the factors that modulate plasma lipoprotein metabolism, there are many potential pathways th