丁香酸调控胆汁酸代谢和肠道屏障改善胆汁淤积肝病的研究

Syringic Acid Improves Cholestatic Liver Disease by Regulating Bile Acid Metabolism and Intestinal Barrier

    摘要
  • 摘要:
      目的  基于胆汁酸代谢和肠道屏障探讨丁香酸对胆汁淤积小鼠的调控作用。
      方法  20只小鼠随机分为对照组、模型组和丁香酸低、高剂量(70、140 mg·kg-1)组。连续7 d灌胃给予相应药物, 于第5天给药2 h后腹腔注射α-萘异硫氰酸酯(ANIT)诱导肝内胆汁淤积小鼠模型。末次给药后, 记录小鼠体质量及肝质量变化; 检测小鼠血清中肝功能指标、组织病理学变化, qPCR验证小鼠结肠组织中紧密连接蛋白闭锁小带蛋白-1(ZO-1)、闭合蛋白(Occludin)、紧密连接蛋白-5(Claudin-5) mRNA的表达, 采用非靶向代谢组学分析血清中代谢产物的变化, 检测肝脏和粪便中总胆汁酸变化。
      结果  丁香酸可以显著降低模型组小鼠血清中丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP)活性和总胆红素(TBIL)、直接胆红素(DBIL)水平(P＜0.05，P＜0.01), 减轻肝脏损伤和坏死; 降低模型组小鼠结肠的淋巴细胞浸润, 恢复隐窝形态。丁香酸高剂量组能显著升高结肠中ZO-1、Occludin、Claudin-5的mRNA表达水平(P＜0.05);显著上调11个代谢物, 下调29个代谢物, 代谢产物主要涉及次生代谢物的生物合成、次级胆汁酸生物合成和胆汁分泌通路。丁香酸降低肝脏中总胆汁酸含量及增加粪便总胆汁酸的排出(P＜0.05，P＜0.01)。
      结论  丁香酸可以显著改善胆汁淤积小鼠肠道屏障的受损, 并且促进胆汁酸的代谢, 这可能是丁香酸改善胆汁淤积的关键调控环节。

     

    Abstract:
      OBJECTIVE  To explore the regulatory effect of syringic acid in cholestatic mice based on bile acid metabolism and intestinal barrier.
      METHODS  Twenty mice were randomly divided into control group, model group and low and high dose of syringic acid (70, 140 mg·kg-1) groups. Intrahepatic cholestasis was induced by intraperitoneal injection of α-naphthalene isothiocyanate after 2 h of administration on the fifth day. After the last dose, the changes of body weight and liver mass of mice were recorded. Liver function indexes in serum and histopathology were detected, qPCR verified the expression of tight junction proteins Zonula Occludens Protein 1 (ZO-1), Occludin and Claudin-5 in mouse colon tissues, the changes of metabolites in serum were analyzed by using nontargeted metabolomics, and the changes of total bile acids in liver and feces were detected.
      RESULTS  Syringic acid could significantly reduce the serum alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) activity, total bilirubin (TBIL) and direct bilirubin (DBIL) levels (P < 0.05, P < 0.01) in the model group mice, and reduce liver damage and necrosis. Syringic acid reduced lymphocyte infiltration in the colon of mice in the model group and restored crypt morphology, while the high-dose syringic acid group significantly increased the mRNA expression levels of ZO-1, Occludin, and Claudin-5 in the colon (P < 0.05). The high-dose intervention of syringic acid significantly upregulated 11 metabolites and 29 metabolites, and the metabolites mainly involved the biosynthesis of secondary metabolites, secondary bile acid biosynthesis and bile secretion pathways. Syringic acid reduced the content of total bile acids in the liver and increased the excretion of total bile acids in feces (P < 0.05, P < 0.01).
      CONCLUSION  Syringic acid can significantly improve the phenotype of cholestasis in cholestatic mice, improve the damage of intestinal barrier, and promote the metabolism of bile acids in cholestatic mice, which may be the key pathway for syringic acid to improve cholestasis.

     

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