Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Gastroenterology. 2018 Dec;155(6):1741-1752.e5. doi: 10.1053/j.gastro.2018.08.022. Epub 2018 Aug 23.
BACKGROUND & AIMS: Intestinal bacteria can modify the composition of bile acids and bile acids, which are regulated by the farnesoid X receptor, affect the survival and growth of gut bacteria. We studied the effects of obeticholic acid (OCA), a bile acid analogue and farnesoid X receptor agonist, on the intestinal microbiomes of humans and mice.
We performed a phase I study in 24 healthy volunteers given OCA (5, 10, or 25 mg/d for 17 days). Fecal and plasma specimens were collected at baseline (day 0) and on days 17 (end of dosing) and 37 (end of study). The fecal specimens were analyzed by shotgun meta-genomic sequencing. A Uniref90 high-stringency genomic analysis was used to assign specific genes to the taxonomic signature of bacteria whose abundance was associated with OCA. Male C57BL/6 mice were gavage fed daily with water, vehicle, or OCA (10 mg/kg) for 2 weeks. Small intestine luminal contents were collected by flushing with saline and fecal pellets were collected at baseline and day 14. Mouse samples were analyzed by 16S-tagged sequencing. Culture experiments were performed to determine the taxonomic-specific effects of bile acids and OCA on bacterial growth.
Suppression of endogenous bile acid synthesis by OCA in subjects led to a reversible induction of gram-positive bacteria that are found in the small intestine and are components of the diet and oral microbiota. We found that bile acids decreased proliferation of these bacteria in minimum inhibitory concentration assays. In these organisms, there was an increase in the representation of microbial genomic pathways involved in DNA synthesis and amino acid metabolism with OCA treatment of subjects. Consistent with these findings, mice fed OCA had lower endogenous bile acid levels and an increased proportion of Firmicutes, specifically in the small intestine, compared with mice fed water or vehicle.
In studying the effects of OCA in humans and mice, we found evidence for interactions between bile acids and features of the small intestinal microbiome. These findings indicate that farnesoid X receptor activation alters the intestinal microbiota and could provide opportunities for microbiome biomarker discovery or new approaches to engineering the human microbiome. ClinicalTrials.gov, NCT01933503.
肠道细菌可以改变胆汁酸的组成，而胆汁酸受法尼醇 X 受体调节，影响肠道细菌的存活和生长。我们研究了胆汁酸类似物和法尼醇 X 受体激动剂奥贝胆酸（OCA）对人类和小鼠肠道微生物组的影响。
我们在 24 名健康志愿者中进行了一项 I 期研究，给予志愿者 OCA（5、10 或 25mg/d，共 17 天）。在基线（第 0 天）和第 17 天（给药结束）和第 37 天（研究结束）采集粪便和血浆标本。通过 shotgun 元基因组测序分析粪便标本。使用 Uniref90 高严格性基因组分析将特定基因分配给与 OCA 相关的细菌分类特征的丰度。雄性 C57BL/6 小鼠每天用生理盐水、载体或 OCA（10mg/kg）灌胃 2 周。用生理盐水冲洗收集小肠腔内容物，收集基线和第 14 天的粪便颗粒。通过 16S 标记测序分析小鼠样本。进行培养实验以确定胆汁酸和 OCA 对细菌生长的分类特异性影响。
OCA 抑制受试者内源性胆汁酸合成导致可逆性诱导革兰阳性菌，这些细菌存在于小肠中，是饮食和口腔微生物群的组成部分。我们发现胆汁酸在最低抑菌浓度测定中降低了这些细菌的增殖。在这些生物体中，用 OCA 处理受试者后，与 DNA 合成和氨基酸代谢相关的微生物基因组途径的代表增加。与这些发现一致，与给予水或载体的小鼠相比，给予 OCA 的小鼠的内源性胆汁酸水平较低，并且小肠中的厚壁菌门比例增加。
在研究 OCA 对人类和小鼠的影响时，我们发现了胆汁酸与小肠微生物组特征之间相互作用的证据。这些发现表明法尼醇 X 受体激活改变了肠道微生物群，并为微生物组生物标志物的发现或工程人类微生物组的新方法提供了机会。ClinicalTrials.gov，NCT01933503。
