Enteric microbiome metabolites correlate with response to simvastatin treatment

• Published in: PloS one Vol. 6; no. 10; p. e25482
• Main Authors: Kaddurah-Daouk, Rima, Baillie, Rebecca A, Zhu, Hongjie, Zeng, Zhao-Bang, Wiest, Michelle M, Nguyen, Uyen Thao, Wojnoonski, Katie, Watkins, Steven M, Trupp, Miles, Krauss, Ronald M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.10.2011; Public Library of Science (PLoS)
• Subjects: Acids; Analysis; Antilipemic agents; Bacteria; Bile; Bile acids; Bile Acids and Salts - metabolism; Biology; Body mass; Body mass index; Body size; Cardiovascular diseases; Cholesterol; Cholesterol tests; Cholesterol, LDL - blood; Demography; Deoxycholic acid; Diet; Digestive system; Digestive tract; Disease control; Drosophila melanogaster; Environmental management; Female; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - microbiology; Gene mapping; Gene polymorphism; Genetic analysis; Genetics; Health aspects; Humans; Intestinal microflora; Intestine; Lipoproteins (low density); Liver; Liver-Specific Organic Anion Transporter 1; Low density lipoprotein; Low density lipoproteins; Male; Medical treatment; Medicine; Metabolites; Metabolomics; Metagenome - drug effects; Middle Aged; Models, Biological; Organic Anion Transporters - genetics; Pharmacogenetics; Pharmacogenomics; Pharmacology; Polymorphism; Polymorphism, Single Nucleotide - genetics; Population studies; Simvastatin; Simvastatin - pharmacology; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Statins; Transporter; Treatment Outcome; Type 2 diabetes; Variability; North Carolina; California; United States > US; West Sacramento California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025482

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.