3-甲基腺嘌呤改善四氯化碳诱导的小鼠肝纤维化及其肠道菌群

3-Methyladenine ameliorates CCl4-induced liver fibrosis and gut microbiota in mice

目的探讨肠道菌群在3-甲基腺嘌呤(3-MA)改善四氯化碳(CCl4)介导小鼠肝纤维化过程中的作用。方法 15只小鼠随机分为正常对照组、肝纤维化组和3-MA处理组;用CCl4构建肝纤维化模型,3-MA处理组第3周开始额外给予3-MA。8周后处死小鼠并取其血液、肝组织及肠道内容物,分析血清ALT、AST和GGT水平、肝组织病理及肠道菌群情况。结果 3-MA处理组血清ALT和AST明显低于肝纤维化组[(68.6±4.2) U/L vs (111.0±7.8) U/L,(179.0±12.9) U/L vs (253.2±26.7) U/L,P<0.01],且肝组织病变程度减轻。PCoA及NMDS分析将3组小鼠肠道菌群区分。与正常对照组比较,肝纤维化组肠道群落Alpha多样性降低,毛螺菌科丰度显著下降,放线菌门、脱硫弧菌等肠道菌丰度显著升高(P<0.05)。与肝纤维化组比较,3-MA处理组肠道群落Alpha多样性增高,毛螺菌科、Blautia菌丰度明显增高,双歧杆菌丰度减低;较正常对照组乳酸杆菌丰度明显增高(P<0.05)。结论 3-MA改善了CCl4介导的小鼠肝纤维化,而肠道菌群可能在此过程中起着积极作用。

Objective To investigate the role of gut microbiota in the amelioration of liver fibrosis induced by CCl4 in mice by 3-methyladenine(3-MA). Methods Fifteen mice were randomly divided into normal control group, liver fibrosis group and 3-MA treatment group. The liver fibrosis model was established by injecting CCl4, and the mice in the 3-MA treatment group were injected 3-MA additionally from the third week onwards. After 8 weeks, all of the mice were sacrificed and their blood, liver tissue and fecal samples were collected to analyze serum ALT, AST, GGT levels, liver histopathology and gut microbiota. Results Compared with the liver fibrosis group, serum ALT and AST levels in 3-MA treatment group decreased obviously([68.6±4.2] U/L vs [111.0±7.8] U/L,[179.0±12.9] U/L vs [253.2±26.7] U/L, P<0.01), and the degree of hepatic histopathological changes was reduced. The intestinal flora in three groups were distinguished by principal coordinate analysis(PCoA) and non-metric multi-dimensional scaling(NMDS) analysis. Compared with the normal control group, there were decreased Alpha diversity of intestinal community, reduced significantly abundance of Lachnospiraceae, and increased obviously abundance of Actinobacteria and Desulfovibrionacea in the liver fibrosis group(P<0.05). Compared with the liver fibrosis group, there were increased Alpha diversity of intestinal community, increased significantly abundance of Lachnospiraceae and Blautia, and reduced abundance of Bifidobacteriaceae in the 3-MA treatment group(P<0.05). In addition, the abundance of Lactobacillaceae in the 3-MA treatment group was significantly higher than that in the normal control group(P<0.05). Conclusion 3-MA improves the liver fibrosis of mice induced by CCl4, and gut microbiota may play an active role in this process.