title: Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice.
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.
authors.affiliation: Systems Biology and Bioinformatics Group, School of Biological Sciences, Faculty of Sciences, The University of Hong Kong, Hong Kong S.A.R., China;
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong S.A.R., China;
authors.forename: Cecilia Ying Ju
authors.initials: CY
authors.lastname: Sung
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China;
authors.forename: Nikki
authors.initials: N
authors.lastname: Lee
authors.affiliation: Systems Biology and Bioinformatics Group, School of Biological Sciences, Faculty of Sciences, The University of Hong Kong, Hong Kong S.A.R., China;
authors.forename: Yueqiong
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Insititute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio 70211, Finland; Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio 70211, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.affiliation: Systems Biology and Bioinformatics Group, School of Biological Sciences, Faculty of Sciences, The University of Hong Kong, Hong Kong S.A.R., China; gipa@hku.hk elnezami@hku.hk.
authors.forename: Gianni
authors.initials: G
authors.lastname: Panagiotou
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong S.A.R., China; Insititute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio 70211, Finland; gipa@hku.hk elnezami@hku.hk.
authors.forename: Hani
authors.initials: H
authors.lastname: El-Nezami
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000382:microbiology / Q000473:pathology*; D008113:Liver Neoplasms / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D018919:Neovascularization, Physiologic; D019936:Probiotics
keywords: IL-17; Th17; hepatocellular carcinoma; metagenome; probiotics