Clinical Pharmacy & Pharmacogenomics Life

Gut Bacteria May Keep Statin Response in Check

By Todd Neale, Senior Staff Writer, MedPage Today
Published: October 16, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

研究人員指出，許多在膽汁中的細菌叢會影響 statin 藥物的治療成效。
Various bacterial-derived bile acids appear to influence the response to statin treatment, researchers found.

根據 Rima Kaddurah-Daouk 在健康的受試者發現，於治療前的初級及次級膽酸濃度與 simvastatin 降 LDL-C 的成效具有強烈的相關性。
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.

研究人員指出：「腸道中的微生物菌叢是否能作為 statins 藥物的治療反應之特異性指標，需要進一步的觀察及證實。」「若能釐清其間的相關性，那麼我們或許可以藉由飲食等方面改變腸道的菌叢，從而提高 statins 藥物之治療成效。」
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."

實際上在個體間有許多差異都可能影響到 statin 的藥效，如基因便是其一。

【小風情不自禁地 Pubmed 了一下~ 】

　Atorvastatin vs. HMGCR, CETP, APOAI, ABCB1, CYP3A4, and CYP7A1
　　　　　- DNA Cell Biol. 2010 Oct;29(10):629-37.

　Atorvastatin vs. CYP7A1 A-204C and ABCG8 C1199A
　　　　　- J Clin Pharm Ther. 2010 Dec 3.

　Statins vs. SLCO1B1, APO-E and CETP, et al.
　　　　　- Drug Saf. 2011 Jan 1;34(1):1-19.  
　　　　　- Pharmacogenomics J. 2010 Feb;10(1):1-11.

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 等人結合了代謝體領域的研究者，探討包括基因體、微生物學和治療環境間對療效的交互作用。
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.

研究人員將自膽固醇研究與藥物基因學研究中的受試者分為兩個族群，以探討可能可以幫助預測 statin 治療成效的生物指標。設計將這些之前未服用任何藥物的健康受試者每天服用 simvastatin 40 mg 共六個禮拜，以觀察其治療成效。
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.

第一組隨機收納了 100 位受試者，並以其接受治療後 LDL-C 所降數值之範圍作為全距。
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.

由 statin 治療成效中挑選最好和最差各 24 人作為第二組 (48人)。
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.

研究人員對這些受試者進行代謝體學的評估分析，包含其代謝物與 cholesterol 合成、飲食中固醇類物質的吸收，以及膽酸形成之相關性。
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.

在全距組的資料顯示，在治療前此五種初級與次級膽酸物質之濃度越低，對 simvastatin 治療成效越好 (p < 0.02 for all)。
　- Taurocholic acid (TCA)
　- Glycocholic acid (GCA)
　- Taurochenodeoxycholic acid (TCDCA)
　- Glycochenodeoxycholic acid (GCDCA)
　- Glycoursodeoxycholic acid (GUDCA)

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).

在 48 人組的分析中顯示，在治療前 lithocholic acid (LCA), taurolithocholic acid (TLCA) 和 glycolithocholicacid (GLCA) 此三種次級膽酸產物的濃度越高，則對 statin 的治療成效越好 (p < 0.05 for all)。而這些次級膽酸產物皆是由腸道中之細菌所製造的。
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.

膽酸與 statins 在肝臟、腸道中均藉由相同轉運蛋白的作用，研究人員指出，實驗顯示在這些具有較高血中濃度之 simvastatin 的受試者，與具有較高次級膽酸產物濃度存在相關性。
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.

Kaddurah-Daouk 表示：「目前已知膽酸在內分泌訊息、身體系統性調控脂肪濃度之功能、肌肉功能以及免疫細胞的調節扮演著重要的腳色。」「然而它依然逃不過我們的法眼 (誤)，我們發現膽酸可能對 statin 的影響可能包括了治療效果和副作用等，顯示膽酸對於 statin 活性的調控是非常重要的。」
"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."

「近來，也有許多研究證實，腸道中的菌叢在心血管疾病中可能佔有重要的腳色，而我們的研究發現基因體、腸道菌叢與生理環境之交互作用所造成的影響，或許也能應用於對心血管疾病之治療上。」
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."

Kaddurah-Daouk也提到：「本研究結果僅能應用於 simvastatin 上，而其他 statin 之機轉或許與之不同，仍待其他研究證實、釐清。」
The investigators noted that their results could only be applied to simvastatin as metabolites and pathways for other statins might differ.

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.

MedPage Original Link:
http://www.medpagetoday.com/Cardiology/Dyslipidemia/29067?pfc=121&spc=234

Wind Chang

17 Oct 2011