Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility
Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility
复制标题
肠道微生物介导的胆汁酸代谢对胆盐胶束增溶能力及药物溶解度的影响
DOI：
10.1021/acs.molpharmaceut.6b01155
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发表时间：
2017-04-01
影响因子：
4.9
通讯作者：
Griffin, Brendan T.
中科院分区：
文献类型：
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作者：
Enright, Elaine F.;Joyce, Susan A.;Griffin, Brendan T.
近年来，肠道微生物组作为人类宿主健康状况的决定因素越来越受到重视。分泌到肠道中的胆盐可以通过肠道细菌产生的酶进行生物转化。迄今为止，胆汁酸在宿主微生物界面的研究主要是针对对宿主代谢的影响。这项工作的目的是研究肠道微生物胆汁酸代谢的变化对胆盐胶束增溶能力的影响，从而在管腔内的药物溶解度。首先，通过比较（a）结合与去结合和（B）初级与次级胆汁盐的增溶能力，评估胆汁酸代谢（由微生物酶胆汁盐水解酶（BSH）和7 α-胆羟化酶在体内介导）对药物溶解度的影响。一系列水溶性差的药物（PWSD）被选为模型溶质的基础上增加的趋势，与胆汁胶束。随后，在含有宿主衍生胆汁酸的常规生物相关模拟肠液以及经改良含有微生物胆汁、酸代谢物的培养基中评价PWSD溶解度和溶出度。研究结果表明，胆汁酸甾体核心的去缀合（由BSH决定）;活性影响某些PWSD的胶束增溶能力;然而，这些差异似乎相对较小。相反，胆汁酸羟基化的程度，由微生物7 α-脱羟酶调节，被发现显着影响胆盐胶束的增溶能力的所有九种药物的研究（p < 0.05）。在含有三羟基胆汁盐牛磺胆酸钠（TCA）或二羟基胆汁盐牛磺脱氧胆酸钠（TDCA）的生物相关介质中的后续研究显示药物溶解度和溶出度发生变化。在生物相关介质中观察到的差异似乎是药物和两亲物（胆汁盐/卵磷脂），浓度依赖性。我们的研究表明，在宿主微生物界面发生的胆汁酸修饰可能导致肠道胆汁盐胶束溶解药物的能力改变，从而为在药物吸收过程中考虑肠道微生物群提供动力。在临床环境中，通过疾病或抗生素治疗破坏肠道微生物生态系统可能会改变胆汁酸池，对药物吸收和生物利用度产生潜在影响。
In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date; bile acid research at the host microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) arid 7 alpha-clehydroxylase, on drug solubility-was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile, acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH;activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7 alpha-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p < 0.05). Subsequent investigations in biorelevant media containing either the trihydroxy bile salt sodium taurocholate (TCA) or the dihydroxy bile salt sodium taurodeoxycholate (TDCA) revealed altered drug solubility and dissolution. Observed differences in biorelevant media appeared to be both drug-and amphiphile (bile salt/lecithin), concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host microbe interface could lead to alterations in the capacity of intestinal bile salt micelles, to solubilize drugs, providing impetus to consider the gut microbiota in the drug absorption process. In the clinical setting, disruption of the gut microbial ecosystem, through disease or antibiotic treatment, could transform the bile acid pool with potential implications for drug absorption and bioavailability.