Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats
Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats
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肠道稳态对大鼠化学诱导的促肿瘤炎症和肝癌发生的深远影响
DOI：
10.1016/j.jhep.2012.06.011
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发表时间：
2012-10-01
影响因子：
25.7
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Zhang, Hui-Lu;Yu, Le-Xing;Wang, Hong-Yang
背景和目的：由于其解剖学联系，肝脏不断暴露于肠道来源的细菌产物或代谢物。肠道稳态的破坏与许多人类疾病有关。本研究的目的是确定肠道稳态在肝细胞癌（HCC）发生和进展中的作用。方法：将青霉素或葡聚糖硫酸钠（DSS）破坏肠道稳态以及益生菌恢复肠道稳态应用于大鼠肝癌发生的二乙基亚硝胺（DEN）模型。结果：肝硬化和HCC患者的血清内毒素水平显着升高。大鼠的慢性 DEN 治疗与肠道菌群亚群失衡有关，包括乳杆菌属、双歧杆菌属和肠球菌属的显着抑制以及肠道炎症。青霉素或DSS分别诱导肠道菌群失调或肠道炎症，显着促进肿瘤形成。服用益生菌可以显着减轻肠道菌群失调，改善肠道炎症，最重要的是，减少肝脏肿瘤的生长和多样性。有趣的是，益生菌不仅抑制具有病原体相关分子模式（PAMP）的内毒素的易位，而且还抑制损伤相关分子模式（DAMP）的激活，例如高迁移率族盒1（HMGB1）。因此，促炎和抗炎细胞因子的产生有利于减少肝脏中的致瘤性炎症。结论：数据强调了肠道稳态在 HCC 发病机制中的重要性。益生菌对肠道微生物群的调节可能代表了治疗或预防 HCC 发展的治疗干预的新途径。 (c) 2012 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background & Aims: Due to its anatomic connection, the liver is constantly exposed to gut-derived bacterial products or metabolites. Disruption of gut homeostasis is associated with many human diseases. The aim of this study was to determine the role of gut homeostasis in initiation and progression of hepatocellular carcinoma (HCC).Methods: Disruption of intestinal homeostasis by penicillin or dextran sulfate sodium (DSS) and its restoration by probiotics were applied in a diethylnitrosamine (DEN) model of rat hepatocarcinogenesis.Results: Patients with liver cirrhosis and HCC had significantly increased serum endotoxin levels. Chronic DEN treatment of rats was associated with an imbalance of subpopulations of the gut microflora including a significant suppression of Lactobacillus species, Bifidobacterium species and Enterococcus species as well as intestinal inflammation. Induction of enteric dysbacteriosis or intestinal inflammation by penicillin or DSS, respectively, significantly promoted tumor formation. Administration of probiotics dramatically mitigated enteric dysbacteriosis, ameliorated intestinal inflammation, and most importantly, decreased liver tumor growth and multiplicity. Interestingly, probiotics not only inhibited the translocation of endotoxin, which bears pathogen-associated molecular patterns (PAMPs) but also the activation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1). As a result, the production of pro- and anti-inflammatory cytokines was skewed in favor of a reduced tumorigenic inflammation in the liver.Conclusions: The data highlights the importance of gut homeostasis in the pathogenesis of HCC. Modulation of the gut microbiota by probiotics may represent a new avenue for therapeutic intervention to treat or prevent HCC development. (c) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.