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(Gut Bacteria) Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment
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"We have observed that the pretreatment levels of bile acids derived from gut bacteria and nutrient inputs are correlated with response to simvastatin. It is becoming increasingly clear that gut microbial symbiots are critical for normal digestion and defense, and also play an important role in development of [cardiovascular] disease [15] and in metabolizing orally ingested therapeutics [12]. There is increasing recognition that intestinal bacteria can metabolize drugs and alter an individual's response to drug treatment depending on specific bacterial strains present"
"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."
Gut Bacteria May Keep Statin Response in Check
By Todd Neale, Senior Staff Writer, MedPage Today
Published: October 16, 2011
Primary source: PLoS ONE
Source reference:
Kaddurah-Daouk R, et al "Enteric microbiome metabolites correlate with response to simvastatin treatment" PLoS ONE 2011; DOI:10.1371/journal.pone.0025482.
Various bacterial-derived bile acids appear to influence the response to statin treatment, researchers found.
Pretreatment levels of several primary and secondary bile acids were strongly associated with the low-density lipoprotein (LDL) cholesterol-lowering ability of simvastatin in healthy individuals, according to Rima Kaddurah-Daouk, PhD, of Duke University, and colleagues.
The findings, reported online in PLoS ONE, "warrant further evaluation of interactions of specific markers for gut microbiota and therapeutic response to statins," the researchers wrote. "Identification of the basis for such interactions may in turn lead to dietary or other interventions that can improve statin efficacy by altering gut microflora."
Action Points
· Explain that pretreatment levels of secondary bile acids, produced by intestinal bacteria, were found to correlate with the lowering of LDL cholesterol in response to simvastatin.
· Note that higher pretreatment levels of these bacterial-derived bile acids were found in good responders to simvastatin but not in poor responders.
There is variability among individuals in the therapeutic response to statins, and previous studies have shown that genetics can only account for part of it.
Kaddurah-Daouk and colleagues turned to the field of metabolomics, which incorporates the interactions between a person's genome, microbiome, and environment in explaining response to treatments.
To search for biomarkers that might help predict response to statin therapy, the researchers used two groups of participants from the Cholesterol and Pharmacogenetics Study. The latter was designed to identify factors related to the response to six weeks of treatment with simvastatin 40 mg in healthy, drug-naive volunteers.
One group consisted of 100 randomly selected individuals across the spectrum of LDL cholesterol-lowering response to statin therapy and constituted the full-range group.
The second group was made up of 48 individuals -- 24 from the top 10% and 24 from the bottom 10% in terms of response to statin therapy, who were the good and poor performers, respectively.
In all of these participants, the researchers used a metabolomics platform to measure a panel of metabolites related to cholesterol synthesis, dietary sterol absorption, and bile acid formation.
In the full-range group, there was a correlation between lower pretreatment levels of five primary and secondary bile acids:
· Taurocholic acid (TCA)
· Glycocholic acid (GCA)
· Taurochenodeoxycholic acid (TCDCA)
· Glycochenodeoxycholic acid (GCDCA)
· Glycoursodeoxycholic acid (GUDCA)
The full-range group had a greater LDL cholesterol-lowering response to simvastatin (P<0.02 for all).
In the good and poor responders, higher pretreatment levels of three secondary bile acids -- lithocholic acid (LCA), taurolithocholic acid (TLCA), and glycolithocholic acid (GLCA) -- were associated with a better response to statin therapy (P<0.05 for all). These secondary bile acids are produced by intestinal bacteria.
Bile acids and statins use the same transporters in the liver and intestine, and the researchers observed that an increased plasma concentration of simvastatin was associated with higher levels of several secondary bile acids in the study groups.
"Bile acids are known to be important endocrine signals, functioning in the systemic control of lipid levels, muscle function, and immune cell regulation," the authors wrote. "It has not escaped our attention that all of these pathways are affected by statins, either as therapeutic targets or side effects, suggesting that bile acids may be important mediators of statin activities."
They concluded that the 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."
The investigators noted that their results could only be applied to simvastatin as metabolites and pathways for other statins might differ.
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