Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer.

Vishal Singh, Beng San Yeoh, Benoit Chassaing, Xia Xiao, Piu Saha, Rodrigo Aguilera Olvera, John D Lapek, Limin Zhang, Wei-Bei Wang, Sijie Hao, Michael D Flythe, David J Gonzalez, Patrice D Cani, Jose R Conejo-Garcia, Na Xiong, Mary J Kennett, Bina Joe, Andrew D Patterson, Andrew T Gewirtz, Matam Vijay-Kumar

Journal: Cell 2019;175(3):679-694.e22

PMID: 30340040

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Abstract

Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.

Address: UT-Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA.; Graduate Program in Immunology and Infectious Diseases, Pennsylvania State University, State College, PA 16802, USA.; Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.; Department of Nutritional Sciences, Pennsylvania State University, State College, PA 16802, USA.; Department of Pharmacology, University of California, San Diego, CA 92093, USA.; Department of Veterinary and Biomedical Sciences, Pennsylvania State University, State College, PA 16802, USA; CAS and State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan, China.; Department of Veterinary and Biomedical Sciences, Pennsylvania State University, State College, PA 16802, USA.; Department of Biomedical Engineering, Pennsylvania State University, State College, PA 16802, USA.; USDA-Agriculture Research Service, University of Kentucky, Lexington, KY 40546, USA.; WELBIO (Walloon Excellence in Life Sciences and Biotechnology), Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.; UT-Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Medical Microbiology and Immunology, University of Toledo, Toledo, OH 43614, USA. Electronic address: [email protected].

DOI: 10.1016/j.cell.2018.09.004

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MeSH Terms: Animals, Carcinoma, Hepatocellular, Cell Line, Tumor, Cholestasis, Diet, High-Fat, Dietary Fiber, Dysbiosis, Fermentation, Gastrointestinal Microbiome, Inulin, Liver Neoplasms, Male, Mice, Mice, Inbred C57BL