Abstract：
Pregnane X receptor (PXR) is essential in the regulation of liver homeostasis, and the gut microbiota is closely linked to liver physiologic and pathologic status. We previously found that activation of PXR significantly promotes liver enlargement through interaction with yes-associated protein (YAP). However, whether gut microbiota contributes to PXR-induced hepatomegaly and the involved mechanisms remain unclear. In this study, C57BL/6 mice were administered the mouse-specific agonist pregnenolone 16α-carbonitrile (PCN) for 5 days. Depletion of gut microbiota was achieved using broad-spectrum antibiotics (ABX) and fecal microbiota transplantation (FMT) was performed to restore the gut microbia. The composition of gut microbiota was analyzed by 16S rRNA sequencing, while the expression of PXR, YAP, and their downstream target genes and proteins were assessed. The results indicated that PCN treatment altered the composition and abundance of specific bacterial taxa. Furthermore, depletion of gut microbiota using ABX significantly attenuated PCN-induced hepatomegaly. FMT experiments further demonstrated that the fecal microbiota from PCN-treated mice could induce liver enlargement. Mechanistic studies revealed that ABX treatment impeded the PXR and YAP activation induced by PCN, as evidenced by decreased expression of PXR, YAP, and their downstream targets. Moreover, alterations in PXR and YAP activation were likely contributing to hepatomegaly in recipient mice following FMT from PCN-treated mice. Collectively, the current study demonstrated that gut microbiota is involved in PCN-induced hepatomegaly via regulating PXR and YAP activation, providing potential novel insights into the involvement of gut microbiota in PXR-mediated hepatomegaly. SIGNIFICANCE STATEMENT: This work describes that the composition of gut microbiota is altered in mouse pregnane X receptor (PXR) agonist pregnenolone 16α-carbonitrile (PCN)-induced hepatomegaly. Treatment with an antibiotic cocktail depletes the intestinal microbiota, leading to the impairment of liver enlargement caused by PCN. Additionally, fecal microbiota transplantation from PCN-treated mice induces liver enlargement. Further study revealed that gut microbiota is involved in hepatomegaly via regulating PXR and yes-associated protein activation.
摘要：
孕烷X受体（PXR）在调节肝脏稳态中至关重要，肠道菌群与肝脏生理和病理状态密切相关。我们先前发现，PXR的激活通过与Yes相关蛋白（YAP）的相互作用显着促进肝脏增大。然而,肠道菌群是否与PXR诱导的肝肿大有关,相关机制尚不清楚.在这项研究中,向C57BL/6小鼠施用小鼠特异性激动剂PCN持续5天。使用广谱抗生素（ABX）实现肠道微生物群的消耗，并进行粪便微生物群移植（FMT）以恢复肠道微生物。通过16SrRNA测序分析肠道菌群的组成，而PXR的表达，评估YAP及其下游靶基因和蛋白质。结果表明，PCN处理改变了特定细菌分类群的组成和丰度。此外，使用ABX消耗肠道微生物区可显着减轻PCN诱导的肝肿大。FMT实验进一步证明,来自PCN处理的小鼠的粪便微生物群可以诱导肝脏增大。机制研究表明，ABX治疗阻碍了PCN诱导的PXR和YAP活化，PXR的表达降低证明了这一点，YAP,和他们的下游目标。此外，在接受PCN治疗的小鼠FMT后,PXR和YAP激活的改变可能导致受体小鼠肝肿大.总的来说，目前的研究表明，肠道菌群通过调节PXR和YAP激活参与PCN诱导的肝肿大，为肠道微生物群参与PXR介导的肝肿大提供潜在的新见解。意义陈述这项工作描述了在mPXR激动剂PCN诱导的肝肿大中肠道微生物群的组成改变。用抗生素鸡尾酒（ABX）治疗会耗尽肠道微生物群，导致PCN引起的肝脏肿大的损害。此外,从PCN处理的小鼠的粪便微生物群移植（FMT）诱导肝脏增大。进一步的研究表明，肠道菌群通过调节PXR和YAP激活参与肝肿大。
