Objective Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. Design Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. Results Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. Conclusions The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

中文翻译：

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尽管 NAFLD 中初级和次级胆汁酸的产生增加，但肝脏胆汁酸信号传导受到抑制


目的 胆汁酸是脂质和葡萄糖代谢的调节剂，并调节肝脏和其他组织的炎症。胆酸和鹅去氧胆酸（CDCA）等初级胆汁酸在肝脏中产生，并通过肠道微生物转化为脱氧胆酸（DCA）和石胆酸等次级胆汁酸。在这里，我们研究了胆汁酸在非酒精性脂肪性肝病 (NAFLD) 发病机制中的可能作用，以及肠道微生物组对 NAFLD 中胆汁酸信号传导的影响。设计 测定 NAFLD 患者、高脂饮食喂养的大鼠及其对照组的血清胆汁酸水平和成纤维细胞生长因子 19 (FGF19)、肝脏基因表达谱和肠道微生物组组成。结果 NAFLD 患者血清中初级胆汁酸和次级胆汁酸浓度升高。在 NAFLD 中，法尼醇 X 受体 (FXR) 拮抗性 DCA 增加，而激动性 CDCA 减少。细胞色素 P450 7A1、Na+-牛磺胆酸共转运多肽和对氧磷酶 1 的 mRNA 表达增加，小异二聚体伙伴和胆汁盐输出泵的 mRNA 表达没有变化，以及血清 FGF19 降低，是 FXR 和成纤维细胞生长因子受体 4 (FGFR4) 受损的证据NAFLD 中介导的信号传导。 NAFLD 患者肠道中的牛磺酸和甘氨酸代谢细菌增加，反映了次级胆汁酸的产生增加。在高脂肪饮食喂养的大鼠中观察到肝脏基因表达和肠道微生物组的类似变化。结论 血清胆汁酸谱、肝脏基因表达模式和肠道微生物组组成一致支持 NAFLD 中胆汁酸产生升高。 FXR 拮抗胆汁酸比例的增加至少部分解释了肝脏 FXR 介导和 FGFR4 介导的信号传导受到抑制。我们的研究表明，未来 NAFLD 干预可能会针对 FXR 信号传导的组成部分，包括胆汁酸转化肠道微生物组。