Yan Meng, Hou Li, Cai Yaoyao, Wang Hanfei, Ma Yujun, Geng Qiming, Jiang Weiwei, Tang Weibing
Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, China.
Department of Pediatrics, Huai'an Maternal And Child Health Care center, Huai'an, China.
Front Pharmacol. 2022 Jun 13;13:906452. doi: 10.3389/fphar.2022.906452. eCollection 2022.
The farnesoid X receptor (FXR) is a key factor regulating hepatic bile acid synthesis and enterohepatic circulation. Repression of bile acid synthesis by the FXR is a potential strategy for treating cholestatic liver disease. However, the role of intestinal FXR on the intestinal barrier and intestinal microbiota needs further investigation. Intestinal tissues were collected from patients with biliary atresia or without hepatobiliary disease. Then, intestinal mRNA levels of FXR-related molecules were determined. To investigate the effect of FXR activation, bile-duct-ligation rats were treated with obeticholic acid [OCA (5 mg/kg/day)] or vehicle (0.5% methyl cellulose) per oral gavage for 14 days. The mRNA levels of intestinal FXR, SHP, TNF-α, FGF15 and bile acid transporter levels were determined. In addition, the intestinal permeability, morphologic changes, and composition of the intestinal microbiota were evaluated. Gut Microbiome was determined by 16S rDNA MiSeq sequencing, and functional profiling of microbial communities was predicted with BugBase and PICRUSt2. Finally, the role of OCA in injured intestinal epithelial cell apoptosis and proliferation was examined by pretreatment with lipopolysaccharide (LPS) in Caco-2 cells. The downstream of the FXR in ileum tissues was inhibited in biliary obstruction. Activation of the FXR signaling pathway by OCA significantly reduced liver fibrosis and intestinal inflammation, improved intestinal microbiota, and protected intestinal mucosa in BDL rats. OCA also altered the functional capacities of ileum microbiota in BDL rats. Significant differences existed between the controls and BDL rats, which were attenuated by OCA in the alpha diversity analysis. Principal coordinates analysis showed that microbial communities in BDL rats clustered separately from controls, and OCA treatment attenuated the distinction. Bugbase and PICRUSt2 analysis showed that OCA changed the composition and structure of the intestinal microbiota and improved the metabolic function of the intestinal microbiota by increasing the relative abundance of beneficial bacteria and reducing the relative abundance of harmful bacteria. Moreover, OCA reduced the apoptosis induced by LPS in Caco-2 cells. The FXR agonist, OCA, activates the intestinal FXR signaling pathway and improves the composition and structure of the intestinal microbiota and intestinal barrier in BDL rats.
法尼酯X受体（FXR）是调节肝脏胆汁酸合成和肠肝循环的关键因素。FXR抑制胆汁酸合成是治疗胆汁淤积性肝病的一种潜在策略。然而，肠道FXR在肠道屏障和肠道微生物群方面的作用尚需进一步研究。收集胆道闭锁患者或无肝胆疾病患者的肠道组织。然后，测定FXR相关分子的肠道mRNA水平。为了研究FXR激活的作用，对胆管结扎大鼠进行口服灌胃，用奥贝胆酸[OCA（5mg/kg/天）]或溶剂（0.5%甲基纤维素）处理14天。测定肠道FXR、小异二聚体伴侣（SHP）、肿瘤坏死因子-α（TNF-α）、成纤维细胞生长因子15（FGF15）的mRNA水平以及胆汁酸转运蛋白水平。此外，评估肠道通透性、形态学变化和肠道微生物群的组成。通过16S rDNA MiSeq测序确定肠道微生物群，并使用BugBase和PICRUSt2预测微生物群落的功能谱。最后，通过在Caco-2细胞中用脂多糖（LPS）预处理，研究OCA在受损肠上皮细胞凋亡和增殖中的作用。在胆道梗阻中，回肠组织中FXR的下游被抑制。OCA激活FXR信号通路可显著减轻肝纤维化和肠道炎症，改善肠道微生物群，并保护胆管结扎大鼠的肠黏膜。OCA还改变了胆管结扎大鼠回肠微生物群的功能能力。在α多样性分析中，对照组和胆管结扎大鼠之间存在显著差异，OCA可减弱这种差异。主坐标分析表明，胆管结扎大鼠的微生物群落与对照组分开聚集，OCA处理减弱了这种差异。Bugbase和PICRUSt2分析表明，OCA改变了肠道微生物群的组成和结构，并通过增加有益菌的相对丰度和降低有害菌的相对丰度改善了肠道微生物群的代谢功能。此外，OCA减少了LPS诱导的Caco-2细胞凋亡。FXR激动剂OCA激活肠道FXR信号通路，改善胆管结扎大鼠的肠道微生物群组成和结构以及肠道屏障。
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