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.

众所周知，异生素感应核受体孕烷 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。关于它们对肠道微生物组的生理功能知之甚少。在这项研究中，我们利用基因工程小鼠发现了 PXR/CAR 的二价激效作用，可调节肠道微生物组的丰富度。 PXR或CAR的缺失增加了微生物的丰富度，而两种受体的缺失则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杆菌科和螺杆菌的数量。 PXR和CAR的缺乏增加了具有胆汁盐水解酶活性的乳杆菌的相对丰度，相应于粪便中初级牛磺酸结合胆汁酸（BA）的减少，这可能导致牛磺酸和非结合胆汁酸（BA）的内部负担更高，这两者都它们与炎症、氧化应激和细胞毒性有关。 PXR/CAR 对肠道微生物组的基本影响与这些受体的药理学和毒理学激活不同。鉴定出常见的 PXR/CAR 靶向细菌，其中大多数被这些受体抑制。与野生型小鼠相比，h PXR -TG 小鼠具有独特的微生物特征。这项研究首次揭示了 PXR 和 CAR 对肠道微生物组的基本功能。