Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer
Open accessAbstract
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.
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Soluble fiber such as inulin may induce liver cancer in mice with a disrupted gut microbiota.
“a different study showed that soluble fiber such as inulin may induce liver cancer in mice with a disrupted gut microbiota”
From Melanoma and microbiota: Current understanding and future directions (2024) · cites this paper as [147]
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[30] Microsomal lipid peroxidation
Buege, J. A., & Aust, S. D. (1978) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(78)52032-6 · Cited by 13,433 · see citing works
Eng, J. K., McCormack, A. L., & Yates, J. R. (1994) · Journal of the American Society for Mass Spectrometry · doi:10.1016/1044-0305(94)80016-2 · Cited by 6,484 · see citing works
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., et al. (2013) · Nature · doi:10.1038/nature12721 · Cited by 5,549 · see citing works
Hepatocellular Carcinoma: Epidemiology and Molecular Carcinogenesis
El‐Serag, H. B., & Rudolph, K. L. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.04.061 · Cited by 5,417 · see citing works
Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-Y, M., Glickman, J. N., & Garrett, W. S. (2013) · Science · doi:10.1126/science.1241165 · Cited by 5,413 · see citing works
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J. R., Pfeffer, K., Coffer, P. J., et al. (2013) · Nature · doi:10.1038/nature12726 · Cited by 4,838 · see citing works
Metagenomic Analysis of the Human Distal Gut Microbiome
Gill, S. R., Pop, M., DeBoy, R. T., Eckburg, P. B., Turnbaugh, P. J., Samuel, B. S., Gordon, J. I., Relman, D. A., Fraser-Liggett, C. M., & Nelson, K. E. (2006) · Science · doi:10.1126/science.1124234 · Cited by 4,699 · see citing works
Elias, J. E., & Gygi, S. P. (2007) · Nature Methods · doi:10.1038/nmeth1019 · Cited by 3,925 · see citing works
Nasir, O. (2013) · Kidney & Blood Pressure Research · doi:10.1159/000350152 · Cited by 2,331 · see citing works
Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome
Yoshimoto, S., Loo, T. M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., Iwakura, Y., Oshima, K., Morita, H., Hattori, M., et al. (2013) · Nature · doi:10.1038/nature12347 · Cited by 2,219 · see citing works
Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5
Vijay-Kumar, M., Aitken, J. D., Carvalho, F. A., Cullender, T. C., Mwangi, S., Srinivasan, S., Sitaraman, S. V., Knight, R., Ley, R. E., & Gewirtz, A. T. (2010) · Science · doi:10.1126/science.1179721 · Cited by 2,068 · see citing works
Self-citationDietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome
Chassaing, B., Koren, O., Goodrich, J. K., Poole, A. C., Srinivasan, S., Ley, R. E., & Gewirtz, A. T. (2015) · Nature · doi:10.1038/nature14232 · Cited by 2,055 · see citing works
Self-citationThe microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon
Donohoe, D. R., Garge, N., Zhang, X., Sun, W., O'Connell, T. M., Bunger, M. K., & Bultman, S. J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.02.018 · Cited by 2,003 · see citing works
Cani, P. D., Neyrinck, A. M., Fava, F., Knauf, C., Burcelin, R., Tuohy, K. M., Gibson, G. R., & Delzenne, N. M. (2007) · Diabetologia · doi:10.1007/s00125-007-0791-0 · Cited by 1,776 · see citing works
Self-citationPromotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4
Dapito, D. H., Mencin, A., Gwak, G.-Y., Pradere, J.-P., Jang, M.-K., Mederacke, I., Caviglia, J. M., Khiabanian, H., Adeyemi, A., Bataller, R., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.007 · Cited by 1,346 · see citing works
Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome
Perry, R. J., Peng, L., Barry, N. A., Cline, G. W., Zhang, D., Cardone, R. L., Petersen, K. F., Kibbey, R. G., Goodman, A. L., & Shulman, G. I. (2016) · Nature · doi:10.1038/nature18309 · Cited by 1,299 · see citing works
McAlister, G. C., Nusinow, D. P., Jedrychowski, M. P., Wühr, M., Huttlin, E. L., Erickson, B. K., Rad, R., Haas, W., & Gygi, S. P. (2014) · Analytical Chemistry · doi:10.1021/ac502040v · Cited by 1,263 · see citing works
Kim, M. H., Kang, S. G., Park, J. H., Yanagisawa, M., & Kim, C. H. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.04.056 · Cited by 1,127 · see citing works
Fiolet, T., Srour, B., Sellem, L., Kesse-Guyot, E., Allès, B., Méjean, C., Deschasaux, M., Fassier, P., Latino-Martel, P., Beslay, M., et al. (2018) · BMJ · doi:10.1136/bmj.k322 · Cited by 1,057 · see citing works
Donohoe, D. R., Collins, L. B., Wali, A., Bigler, R., Sun, W., & Bultman, S. J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.08.033 · Cited by 993 · see citing works
Dewulf, E. M., Cani, P. D., Claus, S. P., Fuentes, S., Puylaert, P. G., Neyrinck, A. M., Bindels, L. B., de Vos, W. M., Gibson, G. R., Thissen, J.-P., et al. (2013) · Gut · doi:10.1136/gutjnl-2012-303304 · Cited by 825 · see citing works
Self-citationDietary Supplement Use in the United States, 2003–2006
Bailey, R. L., Gahche, J. J., Lentino, C. V., Dwyer, J. T., Engel, J. S., Thomas, P. R., Betz, J. M., Sempos, C. T., & Picciano, M. F. (2010) · Journal of Nutrition · doi:10.3945/jn.110.133025 · Cited by 814 · see citing works
Wrzosek, L., Miquel, S., Noordine, M.-L., Bouet, S., Curt, M. J.-C., Robert, V., Philippe, C., Bridonneau, C., Cherbuy, C., Masselot, C. R., et al. (2013) · BMC Biology · doi:10.1186/1741-7007-11-61 · Cited by 807 · see citing works
The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites
Kaiko, G. E., Ryu, H., Koues, O. I., Collins, P. L., Solnica‐Krezel, L., Pearce, E. J., Pearce, E. L., Oltz, E. M., & Stappenbeck, T. S. (2016) · Cell · doi:10.1016/j.cell.2016.05.018 · Cited by 738 · see citing works
den Abbeele, P. V., Belzer, C., Goossens, M., Kleerebezem, M., de Vos, W. M., Thas, O., Weirdt, R. D., Kerckhof, F., & de Wiele, T. V. (2012) · The ISME Journal · doi:10.1038/ismej.2012.158 · Cited by 639 · see citing works
Zou, J., Chassaing, B., Singh, V., Pellizzon, M., Ricci, M. R., Flythe, M. D. D., Kumar, M. V., & Gewirtz, A. T. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.11.003 · Cited by 564 · see citing works
Self-citationGut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells
Belcheva, A., Irrazabal, T., Robertson, S. J., Streutker, C., Maughan, H., Rubino, S., Moriyama, E. H., Copeland, J. K., Surendra, A., Kumar, S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.04.051 · Cited by 473 · see citing works
Liver injury from herbal and dietary supplements
Navarro, V. J., Khan, I. A., Bjornsson, E. S., Seeff, L. B., Serrano, J., & Hoofnagle, J. H. (2016) · Hepatology · doi:10.1002/hep.28813 · Cited by 462 · see citing works
Beer spoilage bacteria and hop resistance
Sakamoto, K., & Konings, W. N. (2003) · International Journal of Food Microbiology · doi:10.1016/s0168-1605(03)00153-3 · Cited by 446 · see citing works
Deletion of TLR5 results in spontaneous colitis in mice
Vijay–Kumar, M., Sanders, C. J., Taylor, R. T., Kumar, A., Aitken, J. D., Sitaraman, S. V., Neish, A. S., Uematsu, S., Akira, S., Williams, I. R., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci33084 · Cited by 420 · see citing works
Self-citationLiver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network
Navarro, V. J., Barnhart, H., Bonkovsky, H. L., Davern, T., Fontana, R. J., Grant, L., Reddy, R. K., Seeff, L. B., Serrano, J., Sherker, A. H., et al. (2014) · Hepatology · doi:10.1002/hep.27317 · Cited by 418 · see citing works
Martínez‐Chantar, M. L., Vázquez–Chantada, M., Ariz, U., Martínez, N., Varela‐Rey, M., Luka, Z., Capdevila, A., Rodríguez, J., Aransay, A. M., Matthiesen, R., et al. (2008) · Hepatology · doi:10.1002/hep.22159 · Cited by 302 · see citing works
Mechanisms of bile acid mediated inflammation in the liver
Li, M., Cai, S., & Boyer, J. L. (2017) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2017.06.001 · Cited by 272 · see citing works
Inulin-type fructans and reduction in colon cancer risk: review of experimental and human data
Pool-Zobel, B. L. (2005) · British Journal Of Nutrition · doi:10.1079/bjn20041349 · Cited by 267 · see citing works
Cai, S., Ouyang, X., Chen, Y., Soroka, C. J., Wang, J., Mennone, A., Wang, Y., Mehal, W. Z., Jain, D., & Boyer, J. L. (2017) · JCI Insight · doi:10.1172/jci.insight.90780 · Cited by 258 · see citing works
Grąt, M., Wronka, K. M., Krasnodębski, M., Masior, Ł., Lewandowski, Z., Kosińska, I., Grąt, K., Stypułkowski, J., Rejowski, S., Wasilewicz, M. P., et al. (2016) · Transplantation Proceedings · doi:10.1016/j.transproceed.2016.01.077 · Cited by 208 · see citing works
Louis, P., & Flint, H. J. (2007) · Applied and Environmental Microbiology · doi:10.1128/aem.02561-06 · Cited by 192 · see citing works
Decrease of serum paraoxonase activity in chronic renal failure.
DANTOINE, T. F., Debord, J., Charmes, J. P., Merle, L., Marquet, P., Lachâtre, G., & Leroux-Robert, C. (1998) · Journal of the American Society of Nephrology · doi:10.1681/asn.v9112082 · Cited by 188 · see citing works
Lack of soluble fiber drives diet-induced adiposity in mice
Chassaing, B., Miles, J. P., Pellizzon, M., Ulman, E. A., Ricci, M. R., Zhang, L., Patterson, A. D., Vijay–Kumar, M., & Gewirtz, A. T. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00172.2015 · Cited by 185 · see citing works
Self-citationSingh, V., Chassaing, B., Zhang, L., Yeoh, B. S., Xiao, X., Kumar, M., Baker, M. T., Cai, J., Walker, R. E., Borkowski, K., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.028 · Cited by 175 · see citing works
Self-citationPark, J., Goergen, C. J., HogenEsch, H., & Kim, C. H. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502046 · Cited by 166 · see citing works
Yamada, S., Takashina, Y., 渡辺, 光., Nagamine, R., Saito, Y., Kamada, N., & Saito, H. (2018) · Oncotarget · doi:10.18632/oncotarget.24066 · Cited by 129 · see citing works
Janssen, A. W. F., Houben, T., Katiraei, S., Dijk, W., Boutens, L., van der Bolt, N., Wang, Z., Brown, J. M., Hazen, S. L., Mandard, S., et al. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m075713 · Cited by 121 · see citing works
Miles, J. P., Zou, J., Kumar, M.-V., Pellizzon, M., Ulman, E. A., Ricci, M. R., Gewirtz, A. T., & Chassaing, B. (2017) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000001155 · Cited by 110 · see citing works
Self-citationEtienne‐Mesmin, L., Vijay–Kumar, M., Gewirtz, A. T., & Chassaing, B. (2016) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.04.007 · Cited by 98 · see citing works
Self-citationZiegler, T. R., Luo, M., Estívariz, C. F., Moore, D. A., Sitaraman, S. V., Li, H., Bazargan, N., Klapproth, J. A., Tian, J. J., Galloway, J. R., et al. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00650.2007 · Cited by 96 · see citing works
Self-citationLetran, S. E., Lee, S., Atif, S. M., Flores‐Langarica, A., Uematsu, S., Akira, S., Cunningham, A. F., & McSorley, S. J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003576 · Cited by 75 · see citing works
Pajari, A., Rajakangas, J., Päivärinta, E., Kosma, V., Rafter, J. J., & Mutanen, M. L. (2003) · International Journal of Cancer · doi:10.1002/ijc.11270 · Cited by 56 · see citing works
Effects of hops (Humulus lupulus L.) extract on volatile fatty acid production by rumen bacteria
Flythe, M. D. D., & Aiken, G. E. (2010) · Journal of Applied Microbiology · doi:10.1111/j.1365-2672.2010.04739.x · Cited by 45 · see citing works
Self-citationCaviglia, J. M., & Schwabe, R. F. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2297-0_8 · Cited by 43 · see citing works
Lipocalin‐2 (NGAL/LCN2), a “help‐me” signal in organ inflammation
Asimakopoulou, A., Borkham‐Kamphorst, E., Tacke, F., & Weiskirchen, R. (2015) · Hepatology · doi:10.1002/hep.27930 · Cited by 43 · see citing works
Quantitative Proteomics Using Reductive Dimethylation for Stable Isotope Labeling
Tolonen, A. C., & Haas, W. (2014) · Journal of Visualized Experiments · doi:10.3791/51416 · Cited by 39 · see citing works
Harlow, B. E., LAWRENCE, L. M., Kagan, I. A., et al. (2014) · Journal of Applied Microbiology · doi:10.1111/jam.12532 · Cited by 22 · see citing works
Misikangas, M., Tanayama, H., Rajakangas, J., Lindén, J., Pajari, A., & Mutanen, M. L. (2007) · British Journal Of Nutrition · doi:10.1017/s0007114507853414 · Cited by 20 · see citing works
Detection of hippuric acid: A glue solvent metabolite, using a mobile test kit
Zinalibdin, M. R., & Yacob, A. R. (2010) · Arabian Journal of Chemistry · doi:10.1016/j.arabjc.2010.09.029 · Cited by 14 · see citing works
Build a better mouse model, and the world will beat a path to your door
Arteel, G. E. (2013) · Hepatology · doi:10.1002/hep.26596 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
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The gut–liver axis and gut microbiota in health and liver disease
Hsu, C. L., & Schnabl, B. (2023) · Nature Reviews Microbiology · doi:10.1038/s41579-023-00904-3 · Cited by 737 · see citing works
Matson, V., Chervin, C. S., & Gajewski, T. F. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.11.041 · Cited by 385 · see citing works
Metabolic reprogramming in the tumor microenvironment of liver cancer
Lin, J., Rao, D., Zhang, M., & Gao, Q. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01527-8 · Cited by 251 · see citing works
“In wild-type mice, a diet rich in inulin-enriched soluble fiber leads to microbiota-dependent cholestasis, hepatocyte death, and subsequent neutrophilic inflammation in the liver, culminating in HCC [231].”
BackgroundLeveraging diet to engineer the gut microbiome
Wolter, M., Grant, E. T., Boudaud, M., Steimle, A., Pereira, G. V., Martens, E. C., & Desai, M. S. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00512-7 · Cited by 211 · see citing works
High fat diet, gut microbiome and gastrointestinal cancer
Tong, Y., Gao, H., Qi, Q., Liu, X., Li, J., Gao, J., Li, P., Wang, Y., Du, L., & Wang, C. (2021) · Theranostics · doi:10.7150/thno.56157 · Cited by 205 · see citing works
Deciphering the Chemical Lexicon of Host–Gut Microbiota Interactions
Nicolas, G. R., & Chang, P. V. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.04.006 · Cited by 195 · see citing works
Simon, T. G., Roelstraete, B., Sharma, R., Khalili, H., Hagström, H., & Ludvigsson, J. F. (2021) · Hepatology · doi:10.1002/hep.31845 · Cited by 176 · see citing works
Melanoma and microbiota: Current understanding and future directions
Routy, B., Jackson, T., Mählmann, L., Baumgartner, C. K., Blaser, M., Byrd, A., Corvaia, N., Couts, K., Davar, D., Derosa, L., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2023.12.003 · Cited by 89 · see citing works
The gut microbial influence on cholestatic liver disease
Kummen, M., & Hov, J. R. (2019) · Liver International · doi:10.1111/liv.14153 · Cited by 74 · see citing works
Ostrem Loss, E., Thompson, J., Cheung, P. L. K., Qian, Y., & Venturelli, O. S. (2023) · Nature Ecology & Evolution · doi:10.1038/s41559-022-01930-9 · Cited by 38 · see citing works
Gut microbial metabolites in cancer therapy
Song, P., Peng, Z., & Guo, X. (2025) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2024.06.016 · Cited by 38 · see citing works
- Authors
- 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.
- Affiliations
- University of Toledo (US)
- Pennsylvania State University (US)
- University of California San Diego (US)
- United States Department of Agriculture (US)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Moffitt Cancer Center (US)
- Georgia State University (US)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 175
- Issue
- 3
- Pages
- 679-694.e22
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6232850
- OpenAlex
- W2898068898
- Cited by
- 532
- References
- 56
- Citations by year
- 2026: 44 · 2025: 68 · 2024: 58 · 2023: 74 · 2022: 64 · 2021: 94 · 2020: 68 · 2019: 59 · 2018: 1
- FWCI
- 19.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
- Funders
- Crohn’s and Colitis Foundation of America
- CCFA
- FRS-FNRS (WELBIO-CGR-2017-C2)
- Funds Baillet Latour
- ERC (336452-ENIGMO)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Nursing › Nutrition and Dietetics › Microbial Metabolites in Food Biotechnology
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- soluble dietary fiber, inulin, hepatocellular carcinoma, cholestasis, gut microbiota, short-chain fatty acids, microbial fermentation, dysbiosis, high-fat diet, neutrophilic inflammation, hepatocyte death, bile acid reabsorption, cholestyramine
- MeSH terms
- Gastrointestinal Microbiome, Animals, Cholestasis, Dietary Fiber, Fermentation, Carcinoma, Hepatocellular, Inulin, Liver Neoplasms, Male, Mice, Inbred C57BL, Cell Line, Tumor, Mice, Diet, High-Fat, Dysbiosis
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