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 David 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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Liver Neoplasms
Liver
Fermentation
Inulin
Hepatocellular Carcinoma
Volatile Fatty Acids
Fibers
Nutrition
Bacteria
Cholestyramine Resin
Enzyme inhibition
Cholestasis
Dietary Fiber
Bile Acids and Salts
Dysbiosis
Inflammation
Fats
Health
Anti-Bacterial Agents
Microbiota

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., ... 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
Singh, Vishal ; Yeoh, Beng San ; Chassaing, Benoit ; Xiao, Xia ; Saha, Piu ; Aguilera Olvera, Rodrigo ; Lapek, John D. ; Zhang, Limin ; Wang, Wei-bei ; Hao, Sijie ; Flythe, Michael D. ; Gonzalez, David J. ; Cani, Patrice D. ; Conejo-Garcia, Jose R. ; Xiong, Na ; Kennett, Mary J. ; Joe, Bina ; Patterson, Andrew David ; Gewirtz, Andrew T. ; Vijay-Kumar, Matam. / Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. In: Cell. 2018 ; Vol. 175, No. 3. pp. 679-694.e22.
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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.",
author = "Vishal Singh and Yeoh, {Beng San} and Benoit Chassaing and Xia Xiao and Piu Saha and {Aguilera Olvera}, Rodrigo and Lapek, {John D.} and Limin Zhang and Wei-bei Wang and Sijie Hao and Flythe, {Michael D.} and Gonzalez, {David J.} and Cani, {Patrice D.} and Conejo-Garcia, {Jose R.} and Na Xiong and Kennett, {Mary J.} and Bina Joe and Patterson, {Andrew David} and Gewirtz, {Andrew T.} and Matam Vijay-Kumar",
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Singh, V, Yeoh, BS, Chassaing, B, Xiao, X, Saha, P, Aguilera Olvera, R, Lapek, JD, Zhang, L, Wang, W, Hao, S, Flythe, MD, Gonzalez, DJ, Cani, PD, Conejo-Garcia, JR, Xiong, N, Kennett, MJ, Joe, B, Patterson, AD, Gewirtz, AT & Vijay-Kumar, M 2018, 'Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer', Cell, vol. 175, no. 3, pp. 679-694.e22. https://doi.org/10.1016/j.cell.2018.09.004

Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. / Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit; Xiao, Xia; Saha, Piu; Aguilera Olvera, Rodrigo; Lapek, John D.; Zhang, Limin; Wang, Wei-bei; Hao, Sijie; Flythe, Michael D.; Gonzalez, David J.; Cani, Patrice D.; Conejo-Garcia, Jose R.; Xiong, Na; Kennett, Mary J.; Joe, Bina; Patterson, Andrew David; Gewirtz, Andrew T.; Vijay-Kumar, Matam.

In: Cell, Vol. 175, No. 3, 18.10.2018, p. 679-694.e22.

Research output: Contribution to journalArticle

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T1 - Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer

AU - Singh, Vishal

AU - Yeoh, Beng San

AU - Chassaing, Benoit

AU - Xiao, Xia

AU - Saha, Piu

AU - Aguilera Olvera, Rodrigo

AU - Lapek, John D.

AU - Zhang, Limin

AU - Wang, Wei-bei

AU - Hao, Sijie

AU - Flythe, Michael D.

AU - Gonzalez, David J.

AU - Cani, Patrice D.

AU - Conejo-Garcia, Jose R.

AU - Xiong, Na

AU - Kennett, Mary J.

AU - Joe, Bina

AU - Patterson, Andrew David

AU - Gewirtz, Andrew T.

AU - Vijay-Kumar, Matam

PY - 2018/10/18

Y1 - 2018/10/18

N2 - 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.

AB - 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.

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Singh V, Yeoh BS, Chassaing B, Xiao X, Saha P, Aguilera Olvera R et al. Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Cell. 2018 Oct 18;175(3):679-694.e22. https://doi.org/10.1016/j.cell.2018.09.004