Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105.
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109.
Toxicol Sci. 2019 Mar 1;168(1):40-60. doi: 10.1093/toxsci/kfy271.
The gut microbiome regulates important host metabolic pathways including xenobiotic metabolism and intermediary metabolism, such as the conversion of primary bile acids (BAs) into secondary BAs. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known regulators for xenobiotic biotransformation in liver. However, little is known regarding the potential effects of PXR and CAR on the composition and function of the gut microbiome. To test our hypothesis that activation of PXR and CAR regulates gut microbiota and secondary BA synthesis, 9-week-old male conventional and germ-free mice were orally gavaged with corn oil, PXR agonist PCN (75 mg/kg), or CAR agonist TCPOBOP (3 mg/kg) once daily for 4 days. PCN and TCPOBOP decreased two taxa in the Bifidobacterium genus, which corresponded with decreased gene abundance of the BA-deconjugating enzyme bile salt hydrolase. In liver and small intestinal content of germ-free mice, there was a TCPOBOP-mediated increase in total, primary, and conjugated BAs corresponding with increased Cyp7a1 mRNA. Bifidobacterium, Dorea, Peptociccaceae, Anaeroplasma, and Ruminococcus positively correlated with T-UDCA in LIC, but negatively correlated with T-CDCA in serum. In conclusion, PXR and CAR activation downregulates BA-metabolizing bacteria in the intestine and modulates BA homeostasis in a gut microbiota-dependent manner.
肠道微生物组调节重要的宿主代谢途径，包括外源代谢物和中间代谢物，如初级胆汁酸（BAs）向次级 BAs 的转化。核受体孕烷 X 受体（PXR）和组成型雄烷受体（CAR）是肝脏中外源生物转化的著名调节剂。然而，关于 PXR 和 CAR 对肠道微生物组的组成和功能的潜在影响知之甚少。为了验证我们的假设，即 PXR 和 CAR 的激活调节肠道微生物群和次级 BA 合成，我们用玉米油、PXR 激动剂 PCN（75mg/kg）或 CAR 激动剂 TCPOBOP（3mg/kg）对 9 周龄雄性常规和无菌小鼠进行口服灌胃，每天一次，连续 4 天。PCN 和 TCPOBOP 减少了双歧杆菌属中的两个分类群，这与 BA 去结合酶胆汁盐水解酶的基因丰度降低相对应。在无菌小鼠的肝脏和小肠内容物中，TCPOBOP 介导的总胆汁酸、初级胆汁酸和结合胆汁酸增加与 Cyp7a1 mRNA 增加相对应。双歧杆菌、Dorea、消化球菌科、厌氧oplasma 和瘤胃球菌与 LIC 中的 T-UDCA 呈正相关，但与血清中的 T-CDCA 呈负相关。总之，PXR 和 CAR 的激活下调了肠道中 BA 代谢细菌，并以肠道微生物群依赖的方式调节 BA 动态平衡。
