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

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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. Dysregulated fermentation of dietary soluble fibers by gut microbiota induces cholestasis, hepatic inflammation, and liver cancer in mice.

Original languageEnglish (US)
Pages (from-to)679-694.e22
JournalCell
Volume175
Issue number3
DOIs
StatePublished - Oct 18 2018

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Singh, V., Yeoh, B. S., Chassaing, B., Xiao, X., Saha, P., Aguilera Olvera, R., Lapek, J. D., Zhang, L., Wang, W. B., Hao, S., Flythe, M. D., Gonzalez, D. J., Cani, P. D., Conejo-Garcia, J. R., Xiong, N., Kennett, M. J., Joe, B., Patterson, A. D., Gewirtz, A. T., & Vijay-Kumar, M. (2018). Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Cell, 175(3), 679-694.e22. https://doi.org/10.1016/j.cell.2018.09.004