[MedPage] 腸道菌叢與statins之治療成效

[pharmawind (Compulsive Disorder P't)]

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.

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


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。
[譯者按：]
 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. doi: 10.1111/j.1365-2710.2010.01227.x.
 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. Epub 2009 Nov 3.

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組。
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.

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



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