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 metagenome 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 probiotictreated 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.H epatocellular carcinoma (HCC) is one of the most common cancers, the sixth most common neoplasm, and the second most deadly type of cancer worldwide (1). The traditional HCC treatment, including surgical treatment, local ablation therapy, and chemotherapy, could offer potential cure, yet patients are facing many limitations including the poor hepatic reserve. HCC is clearly a disease for which alternative therapeutic strategies must be developed. A better understanding of the interactions between cancer cells and stromal components in the tumorassociated proinflammatory microenvironment would be important for the management of this disease.The tumor microenvironment is infiltrated with various immune cells such as T cells, macrophages, neutrophils, natural killer (NK) cells, and myeloid-derived suppressor cells. Inflammation is known to play a pivotal role in tumor development by escalating tumor angiogenesis and cell growth. Once a solid tumor is formed, inflammation arises in the tumor-promoting direction. At the same time, new vasculature is needed in the tumor to provide nutrients and oxygen to support the growth of cancer cells, and this process plays a critical role in HCC, a highly vascularized tumor (2). Inflammation and angiogene...
T helper 17 (TH17) is a novel subset of T helper cells that has recently been identified in the hepatocellular carcinoma (HCC) tumor environment. Its presence seems to be linked with HCC progression, possibly via facilitating angiogenesis. The origin of tumor-associated TH17 may be related to the gut, in which the differentiation of T cells, especially TH17 cells, is affected by microbiota. As TH17 may appear to be a new therapeutic target against tumor-promoting inflammation, strategies such as using probiotics to polarize the response away from TH17 may be beneficial to slow down tumor progression. This paper will attempt to discuss the potential linkage between HCC progression, TH17, and gut microbiota and the possible therapeutic implications of probiotics to modulate TH17-mediated response for tumor growth.
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