Cholestatic liver disease is characterized by disturbances in the intestinal microbiota and excessive accumulation of toxic bile acids (BA) in the liver. Melatonin (MT) can improve liver diseases. However, the underlying mechanism remains unclear. This study aimed to explore the mechanism of MT on hepatic BA synthesis, liver injury, and fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed and Mdr2^–/– mice. MT significantly improved hepatic injury and fibrosis with a significant decrease in hepatic BA accumulation in DDC-fed and Mdr2^–/– mice. MT reprogramed gut microbiota and augmented fecal bile salt hydrolase activity, which was related to increasing intestinal BA deconjugation and fecal BA excretion in both DDC-fed and Mdr2^–/– mice. MT significantly activated the intestinal farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF-15) axis and subsequently inhibited hepatic BA synthesis in DDC-fed and Mdr2^–/– mice. MT failed to improve DDC-induced liver fibrosis and BA synthesis in antibiotic-treated mice. Furthermore, MT provided protection against DDC-induced liver injury and fibrosis in fecal microbiota transplantation mice. MT did not decrease liver injury and fibrosis in DDC-fed intestinal epithelial cell-specific FXR knockout mice, suggesting that the intestinal FXR mediated the anti-fibrosis effect of MT. In conclusion, MT ameliorates cholestatic liver diseases by remodeling gut microbiota and activating intestinal FXR/FGF-15 axis-mediated inhibition of hepatic BA synthesis and promotion of BA excretion in mice.

中文翻译：

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褪黑激素通过肠-肝轴改善胆汁淤积性肝病

胆汁淤积性肝病的特点是肠道微生物群紊乱和肝脏中有毒胆汁酸（BA）的过度积累。褪黑激素（MT）可以改善肝脏疾病。然而，其根本机制仍不清楚。本研究旨在探讨 MT 对 3,5-二乙氧基羰基-1,4-二氢可力丁 (DDC) 喂养和Mdr2 ^–/–小鼠肝脏 BA 合成、肝损伤和纤维化的机制。MT 显着改善了 DDC 喂养和Mdr2 ^–/–小鼠的肝损伤和纤维化，并显着减少了肝脏 BA 的积累。MT 重新编程了肠道微生物群并增强了粪便胆盐水解酶活性，这与 DDC 喂养和Mdr2 ^–/–小鼠肠道 BA 解离和粪便 BA 排泄增加有关。MT 显着激活肠道法尼醇 X 受体 (FXR)/成纤维细胞生长因子 15 (FGF-15) 轴，随后抑制 DDC 喂养和Mdr2 ^–/–小鼠的肝脏 BA 合成。MT 未能改善抗生素治疗小鼠中 DDC 诱导的肝纤维化和 BA 合成。此外，MT 在粪便微生物群移植小鼠中提供针对 DDC 诱导的肝损伤和纤维化的保护作用。MT 并未减少 DDC 喂养的肠上皮细胞特异性 FXR 敲除小鼠的肝损伤和纤维化，表明肠道 FXR 介导了 MT 的抗纤维化作用。总之，MT 通过重塑小鼠肠道菌群和激活肠道 FXR/FGF-15 轴介导的肝脏 BA 合成抑制和促进 BA 排泄来改善胆汁淤积性肝病。