PDF(Sci-hub)
Abstract：
Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids (BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. hPXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.
摘要：
众所周知，外源性生物敏感核受体孕烷X受体（PXR）和组成型雄甾烷受体（CAR）的药理激活可增加药物代谢并减少炎症。关于它们在肠道微生物组中的生理功能知之甚少。在这项研究中,我们发现了使用基因工程小鼠调节肠道微生物组丰富度的PXR/CAR的二价功能。PXR或CAR的缺乏增加了微生物的丰富度，两种受体的缺失协同增加了微生物的丰富度。PXR和CAR缺乏增加了促炎细菌螺旋杆菌科和螺杆菌。PXR和CAR的缺乏增加了乳酸菌的相对丰度，具有胆盐水解酶活性，对应于粪便中初级牛磺酸结合胆汁酸（BAs）的减少，这可能导致更高的牛磺酸和未结合的BAs的内部负担，两者都与炎症有关，氧化应激，和细胞毒性。PXR/CAR对肠道微生物组的基础作用不同于这些受体的药理和毒理学激活。确定了常见的PXR/CAR靶向细菌，其中大部分被这些受体抑制。与野生型小鼠相比,hPXR-TG小鼠具有不同的微生物谱。这项研究首次揭示了PXR和CAR对肠道微生物组的基础功能。
