Akkermansia Muciniphila Suppresses Non-alcoholic Steatohepatitis-associated Liver Cancer in Mice by Recovering Intestinal Barrier Function
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摘要:目的
探究二代益生菌A. muciniphila是否可以预防非酒精性脂肪性肝炎(NASH)相关肝细胞癌(HCC),并初步探讨其作用机制。
方法构建NASH-HCC动物模型(称为STAM)。STAM小鼠从4周龄时开始口服0.9%氯化纳溶液或A. muciniphila。对肝组织进行HE染色和油红O染色评估NASH活动性,RT-PCR检测肝内炎性反应因子和回肠紧密连接蛋白的表达水平。
结果8周龄时,与STAM+0.9%氯化纳溶液组比较,STAM+A. muciniphila组肝组织脂肪变、气球样变和总的NAS评分降低,肝TNF-α、MCP-1、IL-1β、IL-6 mRNA表达水平降低(均P < 0.05);20周龄时,与STAM+0.9%氯化纳溶液组比较,STAM+A. muciniphila组肝表面肿瘤形成的数目减少,肿瘤体积缩小,血浆IL-6水平降低(均P < 0.05)。进一步研究发现A. muciniphila可恢复STAM小鼠的结肠黏膜层厚度和杯状细胞数量,增加回肠上皮细胞紧密连接蛋白ZO-1、Claudin-3和Occludin mRNA的表达水平。
结论A. muciniphila可通过改善肠道屏障功能抑制NASH向HCC的进展,可以作为预防NASH-HCC的候选药物。
Abstract:ObjectiveTo investigate whether the next-generation probiotics Akkermansia muciniphila can prevent non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC).
MethodsWe constructed a NASH-HCC model called STAM. STAM mice received oral saline or A. muciniphila starting at 4 weeks of age. Liver tissues were evaluated by HE staining and oil red O staining for NASH activity, and intrahepatic expression levels of inflammatory cytokines and ileal tight junction proteins were measured by RT-PCR.
ResultsAt 8 weeks of age, the steatosis, ballooning degeneration and NAS scores, TNF-α, MCP-1, IL-1β, and IL-6 mRNA expression were significantly decreased in the STAM+A. muciniphila group (both P < 0.05) compared with those in the STAM+saline group (all P < 0.05). At 20 weeks of age, the number of liver surface tumors formed, tumor size and IL-6 level were decreased in the STAM + A. muciniphila group (all P < 0.05). A. muciniphila restored the thickness of the colon mucosal layer and the number of goblet cells in STAM mice as well as increased the mRNA expression of the tight junction proteins ZO-1, Claudin-3, and Occludin in ileal epithelial cells.
ConclusionAkkermansia muciniphila can inhibit the progression of NASH to HCC by improving the intestinal barrier function and may serve as a candidate drug to prevent NASH-HCC.
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Competing interests: The authors declare that they have no competing interests.利益冲突声明:所有作者均声明不存在利益冲突。作者贡献:张武剑:实验实施、论文撰写李 桃:课题构思、实验设计与指导、数据处理及论文修改
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