Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice
Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice
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DOI：
10.1073/pnas.1518189113
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发表时间：
2016-03-01
影响因子：
11.1
通讯作者：
El-Nezami, Hani
中科院分区：
文献类型：
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作者：
Li, Jun;Sung, Cecilia Ying Ju;El-Nezami, Hani
益生菌在降低胃肠道炎症和预防结直肠癌中的有益作用已被频繁证实，但其免疫调节作用及其抑制肠外肿瘤生长的机制尚未被探索。在这里，我们采用小鼠模型和元基因组测序来研究益生菌喂养在控制s.c.肝细胞癌（HCC）和抑制肿瘤进展的潜在机制。我们的研究结果表明，Prohep，一种新型的益生菌混合物，显着减缓肿瘤生长，并减少肿瘤的大小和重量的40%，与对照组相比。从机制的角度来看，下调的IL-17细胞因子及其主要生产者Th 17细胞，其水平急剧下降，在益生菌喂养后的肿瘤减少中发挥关键作用。细胞染色显示，益生菌治疗组肿瘤中Th 17细胞减少主要是由于来自肠和外周血的迁移性Th 17细胞频率降低所致。此外，鸟枪-宏基因组测序揭示了肠道微生物代谢产物与HCC发展之间的串扰。益生菌将肠道微生物群落转向某些有益细菌，包括普雷沃氏菌和颤杆菌，它们是已知的β代谢物生产者，随后降低了Th 17极化并促进了肠道中β Treg/Tr 1细胞的分化。总的来说，我们的研究为益生菌治疗调节微生物群并影响肠道中T细胞分化的调节机制提供了新的见解，这反过来又改变了肠外肿瘤微环境中促炎细胞因子的水平。
The beneficial roles of probiotics in lowering the gastrointestinal inflammation and preventing colorectal cancer have been frequently demonstrated, but their immunomodulatory effects and mechanism in suppressing the growth of extraintestinal tumors remain unexplored. Here, we adopted a mouse model and meta-genome sequencing to investigate the efficacy of probiotic feeding in controlling s.c. hepatocellular carcinoma (HCC) and the underlying mechanism suppressing the tumor progression. Our result demonstrated that Prohep, a novel probiotic mixture, slows down the tumor growth significantly and reduces the tumor size and weight by 40% compared with the control. From a mechanistic point of view the down-regulated IL-17 cytokine and its major producer Th17 cells, whose levels decreased drastically, played critical roles in tumor reduction upon probiotics feeding. Cell staining illustrated that the reduced Th17 cells in the tumor of the probiotic-treated group is mainly caused by the reduced frequency of migratory Th17 cells from the intestine and peripheral blood. In addition, shotgun-metagenome sequencing revealed the crosstalk between gut microbial metabolites and the HCC development. Probiotics shifted the gut microbial community toward certain beneficial bacteria, including Prevotella and Oscillibacter, that are known producers of antiinflammatory metabolites, which subsequently reduced the Th17 polarization and promoted the differentiation of antiinflammatory Treg/Tr1 cells in the gut. Overall, our study offers novel insights into the mechanism by which probiotic treatment modulates the microbiota and influences the regulation of the T-cell differentiation in the gut, which in turn alters the level of the proinflammatory cytokines in the extraintestinal tumor microenvironment.