Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention
Open accessAbstract
Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression.
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Obesity might increase colorectal cancer risk by reducing the abundance of short-chain fatty acid-producing bacteria and short-chain fatty acid production in the intestine.
“Obesity might therefore increase risk of CRC by reducing the abundance of SCFA-producing bacteria and SCFA production in the intestine 94.”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [94]
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
Siegel, R., Naishadham, D., & Jemal, A. (2013) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21166 · Cited by 11,825 · see citing works
A human gut microbial gene catalogue established by metagenomic sequencing
MetaHIT Consortium, Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., et al. (2010) · Nature · doi:10.1038/nature08821 · Cited by 11,624 · 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
Why Do Cancers Have High Aerobic Glycolysis?
Gatenby, R. A., & Gillies, R. J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1478 · Cited by 4,784 · see citing works
Bacterial Community Variation in Human Body Habitats Across Space and Time
Costello, E. K., Lauber, C. L., Hamady, M., Fierer, N., Gordon, J. I., & Knight, R. (2009) · Science · doi:10.1126/science.1177486 · Cited by 3,231 · see citing works
Cancer epigenetics: from mechanism to therapy
Dawson, M. A., & Kouzarides, T. (2012) · Cell · doi:10.1016/j.cell.2012.06.013 · Cited by 3,203 · see citing works
Short chain fatty acids in human large intestine, portal, hepatic and venous blood
Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P., & Macfarlane, G. T. (1987) · Gut · doi:10.1136/gut.28.10.1221 · Cited by 3,119 · see citing works
Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation
Lunt, S. Y., & Vander Heiden, M. G. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154237 · Cited by 3,057 · see citing works
Review article: the role of butyrate on colonic function
HAMER, H. M., JONKERS, D., VENEMA, K., VANHOUTVIN, S., TROOST, F. J., & BRUMMER, R. ‐. (2008) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2007.03562.x · Cited by 2,721 · see citing works
A framework for human microbiome research
The Human Microbiome Project Consortium (2012) · Nature · doi:10.1038/nature11209 · Cited by 2,650 · see citing works
ATP-citrate lyase links cellular metabolism to histone acetylation
Wellen, K. E., Hatzivassiliou, G., Sachdeva, U. M., Bui, T. V., Cross, J. R., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1164097 · Cited by 2,298 · see citing works
The 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 · cited 2× · see citing works
“Because butyrate is a fatty acid and the preferred energy source of normal colonocytes, it undergoes β-oxidation in the mitochondria and relatively little accumulates in the nucleus (12, 20) (Figure 1).”
H OW H OST -M ICROBIAL I NTERACTIONS S HAPE THE N UTRIENT E NVIRONMENT OF THE M AMMALIAN I NTESTINE
Hooper, L. V., Midtvedt, T., & Gordon, J. I. (2002) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.22.011602.092259 · Cited by 1,623 · see citing works
Samuel, B. S., Shaito, A., Motoike, T., Rey, F. E., Backhed, F., Manchester, J. K., Hammer, R. E., Williams, S. C., Crowley, J., Yanagisawa, M., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808567105 · Cited by 1,564 · see citing works
Inhibition of Histone Deacetylase Activity by Butyrate
Davie, J. R. (2003) · The Journal of Nutrition · doi:10.1093/jn/133.7.2485s · Cited by 1,515 · see citing works
Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man.
Roediger, W. E. (1980) · Gut · doi:10.1136/gut.21.9.793 · Cited by 1,310 · see citing works
Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers
Wang, T., Cai, G., Qiu, Y., Fei, N., Zhang, M., Pang, X., Jia, W., Cai, S., & Zhao, L. (2012) · The ISME Journal · doi:10.1038/ismej.2011.109 · Cited by 1,287 · see citing works
Bingham, S. A., Day, N., Luben, R., Ferrari, P., Slimani, N., Norat, T., Clavel‐Chapelon, F., Kesse‐Guyot, E., Nieters, A., Boeing, H., et al. (2003) · The Lancet · doi:10.1016/s0140-6736(03)13174-1 · Cited by 1,109 · 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
Self-citationInternational Trends in Colorectal Cancer Incidence Rates
Jemal, A., & Ward, E. (2009) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-09-0090 · Cited by 837 · see citing works
Thangaraju, M., Cresci, G. A., Liu, K., Ananth, S., Gnanaprakasam, J. P., Browning, D. D., Mellinger, J. D., Smith, S. B., Digby, G. J., Lambert, N. A., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4466 · Cited by 789 · see citing works
Dietary Fiber and the Risk of Colorectal Cancer and Adenoma in Women
Fuchs, C. S., Giovannucci, E. L., Colditz, G. A., Hunter, D. J., Stampfer, M. J., ROSNER, B. A., Speizer, F. E., & Willett, W. C. (1999) · New England Journal of Medicine · doi:10.1056/nejm199901213400301 · Cited by 668 · see citing works
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · see citing works
Genomic approaches to studying the human microbiota
Weinstock, G. M. (2012) · Nature · doi:10.1038/nature11553 · Cited by 539 · see citing works
Dietary Fiber Intake and Risk of Colorectal Cancer
Park, Y., Hunter, D. J., Spiegelman, D. L., Bergkvist, L., Berrino, F., van den Brandt, P. A., Buring, J. E., Colditz, G. A., Freudenheim, J. L., Fuchs, C. S., et al. (2005) · JAMA · doi:10.1001/jama.294.22.2849 · Cited by 489 · see citing works
Diagnosis and management of dysplasia in patients with inflammatory bowel diseases
Itzkowitz, S. H., & Harpaz, N. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.03.025 · Cited by 424 · see citing works
A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate
Fung, K. Y. C., Cosgrove, L. J., Lockett, T. J., Head, R. J., & Topping, D. L. (2012) · British Journal Of Nutrition · doi:10.1017/s0007114512001948 · Cited by 357 · see citing works
Microbial Degradation Products Influence Colon Cancer Risk: the Butyrate Controversy
Lupton, J. R. (2004) · Journal of Nutrition · doi:10.1093/jn/134.2.479 · Cited by 343 · see citing works
Aerobic glycolysis during lymphocyte proliferation
Wang, T., Marquardt, C. A., & Foker, J. E. (1976) · Nature · doi:10.1038/261702a0 · Cited by 333 · see citing works
Ramadass, B., Rajendiran, E., George, S., Samuel, G. V., & Ramakrishna, B. (2008) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2008.05490.x · Cited by 307 · see citing works
G‐protein‐coupled receptor for short‐chain fatty acids suppresses colon cancer
Tang, Y., Chen, Y., Jiang, H., Robbins, G. T., & Nie, D. (2010) · International Journal of Cancer · doi:10.1002/ijc.25638 · Cited by 282 · see citing works
Does butyrate protect from colorectal cancer?
Sengupta, S., Muir, J. G., & Gibson, P. R. (2006) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04213.x · Cited by 219 · see citing works
Dietary fibres as “prebiotics”: Implications for colorectal cancer
Lim, C. C., Ferguson, L. R., & Tannock, G. W. (2005) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200500015 · Cited by 160 · see citing works
Efflux transporters in ulcerative colitis
Englund, G., Jacobson, A., Rorsman, F., et al. (2006) · Inflammatory Bowel Diseases · doi:10.1002/ibd.20030 · Cited by 156 · see citing works
Microbial Regulation of Glucose Metabolism and Cell-Cycle Progression in Mammalian Colonocytes
Donohoe, D. R., Wali, A., Brylawski, B. P., & Bultman, S. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046589 · Cited by 143 · see citing works
Self-citationPouillart, P. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00279-3 · Cited by 116 · see citing works
Activated lymphocytes as a metabolic model for carcinogenesis
Macintyre, A. N., & Rathmell, J. C. (2013) · Cancer & Metabolism · doi:10.1186/2049-3002-1-5 · Cited by 87 · see citing works
The dietary fibre debate: more food for thought
Ferguson, L. R., & Harris, P. J. (2003) · The Lancet · doi:10.1016/s0140-6736(03)13219-9 · Cited by 77 · see citing works
Andriamihaja, M., Chaumontet, C., Tomé, D., & Blachier, F. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21556 · Cited by 69 · see citing works
Bollrath, J., & Powrie, F. M. (2013) · Science · doi:10.1126/science.1242674 · Cited by 60 · see citing works
Dietary fibre and the risk of colorectal cancer
Goodlad, R. A. (2001) · Gut · doi:10.1136/gut.48.5.587 · Cited by 53 · see citing works
Why Cancer & Metabolism? Why now?
Dang, C. V., & Pollak, M. (2013) · Cancer & Metabolism · doi:10.1186/2049-3002-1-1 · Cited by 41 · see citing works
The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein
Gonçalves, P., Gregório, I., & Martel, F. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00146.2011 · Cited by 39 · see citing works
Dietary Fiber and Colorectal Cancer
Baron, J. A. (2005) · JAMA · doi:10.1001/jama.294.22.2904 · Cited by 36 · see citing works
Experimental demonstration of human weight homeostasis: implications for understanding obesity
Macías, A. E. (2004) · British Journal Of Nutrition · doi:10.1079/bjn20031051 · Cited by 32 · see citing works
Microbial Oncotarget: Bacterial-Produced Butyrate, Chemoprevention and Warburg Effect
Donohoe, D. R., Curry, K. P., & Bultman, S. J. (2013) · Oncotarget · doi:10.18632/oncotarget.915 · Cited by 23 · see citing works
Self-citationHolzer, H. (2009) · Gastroenterologia · doi:10.1159/000202081 · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [14]Hooper LV Midtvedt T Gordon JI How host-microbial interactions shape the nutrient environment of the mammalian intestine Annu Rev Nutr 2002 22 283 307 12055347
- [37]Smith PM Howitt MR Panikov N Michaud M Gallini CA Bohlooly YM The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis Science 2013 341 569 573 23828891 PMC3807819
- [38]Bollrath J Powrie F Immunology. Feed your Tregs more fiber Science 2013 341 463 464 23908210
Cited by
Sorted by citations
Diet, microorganisms and their metabolites, and colon cancer
O'Keefe, S. J. D. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.165 · Cited by 1,100 · see citing works
Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer
Song, M., Chan, A. T., & Sun, J. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.06.048 · Cited by 752 · see citing works
Zeng, H., Umar, S., Rust, B., Lazarova, D., & Bordonaro, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20051214 · Cited by 480 · see citing works
Dietary patterns and cancer risk
Steck, S. E., & Murphy, E. A. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0227-4 · Cited by 292 · see citing works
Fiber Intake and Survival After Colorectal Cancer Diagnosis
Song, M., Wu, K., Meyerhardt, J. A., Ogino, S., Wang, M., Fuchs, C. S., Giovannucci, E. L., & Chan, A. T. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2017.3684 · Cited by 197 · see citing works
The microbiome and its potential as a cancer preventive intervention
Bultman, S. J. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2015.09.001 · Cited by 134 · see citing works
Self-citationButyrate production from high-fiber diet protects against lymphoma tumor
Wei, W., Sun, W., Yu, S., Yang, Y., & Ai, L. (2016) · Leukemia & Lymphoma · doi:10.3109/10428194.2016.1144879 · Cited by 102 · see citing works
- Authors
- Bultman, S. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Bultman, Scott J.
- Venue
- Clinical Cancer Research
- Published
- 2014-02-15
- Volume
- 20
- Issue
- 4
- Pages
- 799-803
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3944646
- OpenAlex
- W2117881676
- Cited by
- 157
- References
- 49
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 14 · 2023: 17 · 2022: 11 · 2021: 15 · 2020: 14 · 2019: 16 · 2018: 12 · 2017: 8 · 2016: 12 · 2015: 10 · 2014: 5
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Cancer Institute (R01CA125237)
- National Institute of Environmental Health Sciences (P30ES010126)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- dietary fiber, butyrate, gene-environment interaction, colorectal cancer prevention, short-chain fatty acids, colonic fermentation, histone deacetylase inhibition, epigenetic regulation, cell proliferation, apoptosis, Warburg effect, tumor suppression
- MeSH terms
- Animals, Butyrates, Colon, Dietary Fiber, Humans, Colorectal Neoplasms, Apoptosis, Receptors, G-Protein-Coupled, Epigenesis, Genetic, Cell Proliferation, Histone Deacetylase Inhibitors, Gene-Environment Interaction
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