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Edited by Sven Pettersson, Karolinska Institutet, Stockholm, Sweden, and accepted by the Editorial Board January 11, 2016 (received for review September 12, 2015)
Significance
Hepatocellular carcinoma is the second most deadly cancer type globally, requiring the development of alternative or complementary therapeutic and prophylactic methods. Here, when feeding a mouse model with a novel probiotic mixture 1 wk before the tumor inoculation, we observed a reduction of the tumor weight and size by 40% compared with the control. Our results revealed that the probiotics’ beneficial effect is closely related with the abundance of certain beneficial bacteria that produce antiinflammatory metabolites, which subsequently regulate the proinflammatory immune cell population via the crosstalk between gut and tumor. We believe that our study highlights the extraordinary potential of probiotics in extraintestine cancers and can be adapted to the study of other cancers.
Abstract
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 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.
Footnotes
↵1J.L. and C.Y.J.S. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: gipa{at}hku.hk or elnezami{at}hku.hk.
Author contributions: N.L., G.P., and H.E.-N. designed research; J.L. and C.Y.J.S. performed research; J.L. and C.Y.J.S. analyzed data; J.L., C.Y.J.S., Y.N., and J.P. wrote the paper; and J.L., C.Y.J.S., and Y.N. visualized the data.
Conflict of interest statement: C.Y.J.S., N.L., and H.E.-N. are holders of a patent under the publication number US 2015/0164964A1, “Method and compositions for treating cancer using probiotics.”
This article is a PNAS Direct Submission. S.P. is a guest editor invited by the Editorial Board.
Data deposition: The data reported in this paper have been deposited in the Sequence Read Archive (SRA) database, www.ncbi.nlm.nih.gov/sra (accession no. SRP062583).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1518189113/-/DCSupplemental.
References
Probiotics suppressed liver cancer growth in mice
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