Colorectal cancer is a so-called westernized disease and the second leading cause of cancer death worldwide; approximately half of those with the disease will die from it
Geographical variation, migration studies and experimental studies provide compelling evidence that environmental factors, rather than genetic dysfunction, are responsible for the development of colorectal cancer
Convincing evidence suggests that risk of colon cancer is increased by processed and unprocessed meat consumption but suppressed by fibre-rich foods
Dietary risk is mediated by the colonic microbiota; carbohydrate residues stimulate production of metabolites that maintain mucosal health, proteinaceous residues and fat-stimulated bile acids might result in pro-inflammatory and carcinogenic metabolites
A moderate intake of meat and fat is part of our omnivorous diet and the carcinogenic potential can be suppressed by the induction of butyrogenesis from fibre-rich foods
Current dietary fibre recommendations need to be reviewed as they are based on the maintenance of cardiovascular health and are below the levels associated with low colon cancer risk
Colorectal cancer is one of the so-called westernized diseases and the second leading cause of cancer death worldwide. On the basis of global epidemiological and scientific studies, evidence suggests that the risk of colorectal cancer is increased by processed and unprocessed meat consumption but suppressed by fibre, and that food composition affects colonic health and cancer risk via its effects on colonic microbial metabolism. The gut microbiota can ferment complex dietary residues that are resistant to digestion by enteric enzymes. This process provides energy for the microbiota but culminates in the release of short-chain fatty acids including butyrate, which are utilized for the metabolic needs of the colon and the body. Butyrate has a remarkable array of colonic health-promoting and antineoplastic properties: it is the preferred energy source for colonocytes, it maintains mucosal integrity and it suppresses inflammation and carcinogenesis through effects on immunity, gene expression and epigenetic modulation. Protein residues and fat-stimulated bile acids are also metabolized by the microbiota to inflammatory and/or carcinogenic metabolites, which increase the risk of neoplastic progression. This Review will discuss the mechanisms behind these microbial metabolite effects, which could be modified by diet to achieve the objective of preventing colorectal cancer in Western societies.
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Ferlay, J. et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11 [online]. Lyon, France: International Agency for Research on Cancer, http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=colorectal (2013).
Perdue, D. G., Haverkamp, D., Perkins, C., Daley, C. M. & Provost, E. Geographic variation in colorectal cancer incidence and mortality, age of onset, and stage at diagnosis among American Indian and Alaska Native people, 1990–2009. Am. J. Public Health 104, S404–S414 (2014).
Houlston, R. S. et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat. Genet. 42, 973–977 (2010).
Figueiredo, J. C. et al. Genome-wide diet–gene interaction analyses for risk of colorectal cancer. PLoS Genet. 10, e1004228 (2014).
Aune, D. et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 343, d6617 (2011).
Magalhães, B., Peleteiro, B. & Lunet, N. Dietary patterns and colorectal cancer: systematic review and meta-analysis. Eur. J. Cancer Prev. 21, 15–23 (2012).
World Cancer Research Fund & American Institute for Cancer Research. Colorectal cancer 2011 report. Food, nutrition, physical activity, and the prevention of colorectal cancer. WCRFhttp://www.wcrf.org/sites/default/files/Colorectal-Cancer-2011-Report.pdf (2011).
World Health Organization. IARC monographs evaluate consumption of red meat and processed meat. IARChttps://www.iarc.fr/en/media-centre/pr/2015/pdfs/pr240_E.pdf (2015).
Doll, R. & Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl Cancer Inst. 66, 1191–1308 (1981).
Blot, W. J. & Tarone, R. E. Doll and Peto's quantitative estimates of cancer risks: holding generally true for 35 years. J. Natl Cancer Inst. 107, djv044 (2015).
Le Marchand, L. & Kolonel, L. N. Cancer in Japanese migrants to Hawaii: interaction between genes and environment [French]. Rev. Épidémiol. Santé Publique 40, 425–430 (1992).
Nosho, K. et al. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. World J. Gastroenterol. 22, 557–566 (2016).
Tjalsma, H., Boleij, A., Marchesi, J. R. & Dutilh, B. E. A bacterial driver–passenger model for colorectal cancer: beyond the usual suspects. Nat. Rev. Microbiol. 10, 575–582 (2012).
Colnot, S. et al. Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab. Invest. 84, 1619–1630 (2004).
Bordonaro, M., Lazarova, D. L. & Sartorelli, A. C. Butyrate and Wnt signaling: a possible solution to the puzzle of dietary fiber and colon cancer risk? Cell Cycle 7, 1178–1183 (2008).
Beyer-Sehlmeyera, G. et al. Butyrate is only one of several growth inhibitors produced during gut flora-mediated fermentation of dietary fibre sources. Br. J. Nutr. 90, 1057–1070 (2003).
Bultman, S. J. Molecular pathways: gene–environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention. Clin. Cancer Res. 20, 799–803 (2014).
Verma, M. Cancer control and prevention: nutrition and epigenetics. Curr. Opin. Clin. Nutr. Metab. Care 16, 376–384 (2013).
Tarapore, R. S., Siddiqui, I. A. & Mukhtar, H. Modulation of Wnt/β-catenin signaling pathway by bioactive food components. Carcinogenesis 33, 483–491 (2012).
Fung, K. Y., Cosgrove, L., Lockett, T., Head, R. & Topping, D. L. A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate. Br. J. Nutr. 108, 820–831 (2012).
Matsuki, T. et al. Epithelial cell proliferation arrest induced by lactate and acetate from Lactobacillus casei and Bifidobacterium breve. PLoS ONE 8, e63053 (2013).
Hu, Y. et al. Manipulation of the gut microbiota using resistant starch is associated with protection against colitis-associated colorectal cancer in rats. Carcinogenesis 37, 366–375 (2016).
Cho, M., Carter, J., Harari, S. & Pei, Z. The interrelationships of the gut microbiome and inflammation in colorectal carcinogenesis. Clin. Lab. Med. 34, 699–710 (2014).
Greer, J. B. & O'Keefe, S. J. Microbial induction of immunity, inflammation and cancer. Front. Physiol. 1, 168 (2011).
Vipperla, K. & O'Keefe, S. J. Diet, microbiota, and dysbiosis: a 'recipe' for colorectal cancer. Food Funct. 7, 1731–1740 (2016).
Berg, D. J. et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4+ TH1-like responses. J. Clin. Invest. 98, 1010–1020 (1996).
Uronis, J. M. et al. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS ONE 4, e6026 (2009).
Borges-Canha, M., Portela-Cidade, J. P., Dinis Ribeiro, M., Leite-Moreira, A. F. & Pimentel-Nunes, P. Role of colonic microbiota in colorectal carcinogenesis: a systematic review. Rev. Esp. Enferm. Dig. 107, 659–671 (2015).
Baxter, N. T., Zackular, J. P., Chen, G. Y. & Schloss, P. D. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden. Microbiome 2, 20 (2014).
Zackular, J. P. et al. The gut microbiome modulates colon tumorigenesis. mBio 4, e00692–13 (2013).
Zeller, G. et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol. Syst. Biol. 10, 766 (2014).
Kostic, A. D. et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207–215 (2013).
Mima, K. et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 1, 653–661 (2015).
Tahara, T. et al. Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res. 74, 1311–1318 (2014).
Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022 (2009).
Toprak, N. U. et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect. 12, 782–786 (2006).
DeStefano Shields, C. E. et al. Reduction of murine colon tumorigenesis driven by enterotoxigenic Bacteroides fragilis using cefoxitin treatment. J. Infect. Dis. 214, 122–129 (2016).
Urbaniak, C. et al. Microbiota of human breast tissue. Appl. Environ. Microbiol. 80, 3007–3014 (2014).
Al-Asmakh, M. et al. The gut microbiota and developmental programming of the testis in mice. PLoS ONE 9, e103809 (2014).
Collado, M. C., Rautava, S., Aakko, J., Isolauri, E. & Salminen, S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 6, 23129 (2016).
Sheflin, A. M., Whitney, A. K. & Weir, T. L. Cancer-promoting effects of microbial dysbiosis. Curr. Oncol. Rep. 16, 406 (2014).
Xuan, C. et al. Microbial dysbiosis is associated with human breast cancer. PLoS ONE 9, e83744 (2014).
Schulz, M. D. et al. High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity. Nature 514, 508–512 (2014).
Rook, G. A. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Darwinian medicine and the 'hygiene' or 'old friends' hypothesis. Clin. Exp. Immunol. 160, 70–79 (2010).
Cordain, L. et al. Origins and evolution of the Western diet: health implications for the 21st century. Am. J. Clin. Nutr. 81, 341–354 (2005).
Balter, V., Braga, J., Telouk, P. & Thackeray, J. F. Evidence for dietary change but not landscape use in South African early hominins. Nature 489, 558–560 (2012).
Richardson, E. U. Archaeological dig reveals causes — and possible cures — for diabetes epidemic. Indian Country Today Media Network [online] http://indiancountrytodaymedianetwork.com/2012/08/23/archaeological-dig-reveals-causes-and-possible-cures-diabetes-epidemic-130651 (2012)
Ungar, P. S. & Sponheimer, M. The diets of early hominins. Science 334, 190–193 (2011).
O'Keefe, S. J. et al. Why do African Americans get more colon cancer than Native Africans? J. Nutr. 137, 175S–182S (2007).
O'Keefe, S. J. et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat. Commun. 6, 6342 (2015).
Ou, J. et al. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am. J. Clin. Nutr. 98, 111–120 (2013).
Macfarlane, G. T. & Englyst, H. N. Starch utilization by the human large intestinal microflora. J. Appl. Bacteriol. 60, 195–201 (1986).
Macfarlane, G. T., Gibson, G. R. & Cummings, J. H. Comparison of fermentation reactions in different regions of the human colon. J. Appl. Bacteriol. 72, 57–64 (1992).
Cummings, J. H., Beatty, E. R., Kingman, S. M., Bingham, S. A. & Englyst, H. N. Digestion and physiological properties of resistant starch in the human large bowel. Br. J. Nutr. 75, 733–747 (1996).
Roediger, W. E. Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology 83, 424–429 (1982).
Flint, H. J., Duncan, S. H., Scott, K. P. & Louis, P. Links between diet, gut microbiota composition and gut metabolism. Proc. Nutr. Soc. 74, 13–22 (2015).
Macfarlane, S. & Macfarlane, G. T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62, 67–72 (2003).
Macfarlane, G. T. & Macfarlane, S. Bacteria, colonic fermentation, and gastrointestinal health. J. AOAC Int. 95, 50–60 (2012).
Duncan, S. H. et al. Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl. Environ. Microbiol. 73, 1073–1078 (2007).
Waldecker, M., Kautenburger, T., Daumann, H., Busch, C. & Schrenk, D. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J. Nutr. Biochem. 19, 587–593 (2008).
Macfarlane, G. T. & Macfarlane, S. Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J. Clin. Gastroenterol. 45, S120–S127 (2011).
Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).
Al-Lahham, S. H., Peppelenbosch, M. P., Roelofsen, H., Vonk, R. J. & Venema, K. Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim. Biophys. Acta 1801, 1175–1183 (2010).
Venter, C. S., Vorster, H. H. & Cummings, J. H. Effects of dietary propionate on carbohydrate and lipid metabolism in healthy volunteers. Am. J. Gastroenterol. 85, 549–553 (1990).
Canfora, E. E., Jocken, J. W. & Blaak, E. E. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577–591 (2015).
Nordgaard, I., Hansen, B. S. & Mortensen, P. B. Importance of colonic support for energy absorption as small-bowel failure proceeds. Am. J. Clin. Nutr. 64, 222–231 (1996).
Silvester, K. R. & Cummings, J. H. Does digestibility of meat protein help explain large bowel cancer risk? Nutr. Cancer 24, 279–288 (1995).
Windey, K., De Preter, V. & Verbeke, K. Relevance of protein fermentation to gut health. Mol. Nutr. Food Res. 56, 184–196 (2012).
Bui, T. P. et al. Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal. Nat. Commun. 6, 10062 (2015).
Visek, W. J. Diet and cell growth modulation by ammonia. Am. J. Clin. Nutr. 31, S216–S220 (1978).
Clinton, S. K., Bostwick, D. G., Olson, L. M., Mangian, H. J. & Visek, W. J. Effects of ammonium acetate and sodium cholate on N-methyl-N′-nitro-N-nitrosoguanidine-induced colon carcinogenesis of rats. Cancer Res. 48, 3035–3039 (1988).
Mirvish, S. S. Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett. 93, 17–48 (1995).
Cross, A. J. & Sinha, R. Meat-related mutagens/carcinogens in the etiology of colorectal cancer. Environ. Mol. Mutagen. 44, 44–55 (2004).
Bingham, S. A. et al. Does increased endogenous formation of N-nitroso compounds in the human colon explain the association between red meat and colon cancer? Carcinogenesis 17, 515–523 (1996).
Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature. 487, 104–108 (2012).
Attene-Ramos, M. S., Wagner, E. D., Plewa, M. J. & Gaskins, H. R. Evidence that hydrogen sulfide is a genotoxic agent. Mol. Cancer Res. 4, 9–14 (2006).
Wallace, J. L., Vong, L., McKnight, W., Dicay, M. & Martin, G. R. Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats. Gastroenterology 137, 569–578, (2009).
Ianaro, A., Cirino, G. & Wallace, J. L. Hydrogen sulfide-releasing anti-inflammatory drugs for chemoprevention and treatment of cancer. Pharmacol. Res. 111, 652–658 (2016).
Elsheikh, W., Blackler, R. W., Flannigan, K. L. & Wallace, J. L. Enhanced chemopreventive effects of a hydrogen sulfide-releasing anti-inflammatory drug (ATB-346) in experimental colorectal cancer. Nitric Oxide 41, 131–137 (2014).
De Preter, V. et al. Decreased mucosal sulfide detoxification is related to an impaired butyrate oxidation in ulcerative colitis. Inflamm. Bowel Dis. 18, 2371–2380 (2012).
McCall, I. C. et al. Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization. Toxicol. Appl. Pharmacol. 241, 61–70 (2009).
Birkett, A., Muir, J., Phillips, J., Jones, G. & O'Dea, K. Resistant starch lowers fecal concentrations of ammonia and phenols in humans. Am. J. Clin. Nutr. 63, 766–772 (1996).
De Preter, V. et al. The in vivo use of the stable isotope-labelled biomarkers lactose-[15N]ureide and [2H4]tyrosine to assess the effects of pro- and prebiotics on the intestinal flora of healthy human volunteers. Br. J. Nutr. 92, 439–446 (2004).
Rafter, J. et al. Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Am. J. Clin. Nutr. 85, 488–496 (2007).
Humphreys, K. J. et al. Dietary manipulation of oncogenic microRNA expression in human rectal mucosa: a randomized trial. Cancer Prev. Res. (Phila.) 7, 786–795 (2014).
Hu, S., Liu, L., Chang, E. B., Wang, J. Y. & Raufman, J. P. Butyrate inhibits pro-proliferative miR-92a by diminishing c-Myc-induced miR-17-92a cluster transcription in human colon cancer cells. Mol. Cancer 14, 180 (2015).
Chen, H. M. et al. Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma. Am. J. Clin. Nutr. 97, 1044–1052 (2013).
Wang, T. et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 6, 320–329 (2012).
Vipperla, K. & O'Keefe, S. J. The microbiota and its metabolites in colonic mucosal health and cancer risk. Nutr. Clin. Pract. 27, 624–635 (2012).
Rodriguez-Cabezas, M. E. et al. Dietary fiber down-regulates colonic tumor necrosis factor α and nitric oxide production in trinitrobenzenesulfonic acid-induced colitic rats. J. Nutr. 132, 3263–3271 (2002).
Inan, M. S. et al. The luminal short-chain fatty acid butyrate modulates NF-κB activity in a human colonic epithelial cell line. Gastroenterology 118, 724–734 (2000).
Chirakkal, H. et al. Upregulation of BAK by butyrate in the colon is associated with increased Sp3 binding. Oncogene 25, 7192–7200 (2006).
Hinnebusch, B. F., Meng, S., Wu, J. T., Archer, S. Y. & Hodin, R. A. The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J. Nutr. 132, 1012–1017 (2002).
Comalada, M. et al. The effects of short-chain fatty acids on colon epithelial proliferation and survival depend on the cellular phenotype. J. Cancer Res. Clin. Oncol. 132, 487–497 (2006).
Andoh, A., Shimada, M., Araki, Y., Fujiyama, Y. & Bamba, T. Sodium butyrate enhances complement-mediated cell injury via down-regulation of decay-accelerating factor expression in colonic cancer cells. Cancer Immunol. Immunother. 50, 663–672 (2002).
Rodríguez-Salvador, J. et al. Effect of sodium butyrate on pro-matrix metalloproteinase-9 and -2 differential secretion in pediatric tumors and cell lines. J. Exp. Clin. Cancer Res. 24, 463–473 (2005).
Zeng, H. & Briske-Anderson, M. Prolonged butyrate treatment inhibits the migration and invasion potential of HT1080 tumor cells. J. Nutr. 135, 291–295 (2005).
Zgouras, D., Wachtershauser, A., Frings, D. & Stein, J. Butyrate impairs intestinal tumor cell-induced angiogenesis by inhibiting HIF-1α nuclear translocation. Biochem. Biophys. Res. Commun. 300, 832–838 (2003).
Willemsen, L. E., Koetsier, M. A., van Deventer, S. J. & van Tol, E. A. Short chain fatty acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E1 and E2 production by intestinal myofibroblasts. Gut 52, 1442–1447 (2003).
D'Argenio, G. et al. Butyrate enemas in experimental colitis and protection against large bowel cancer in a rat model. Gastroenterology 110, 1727–1734 (1996).
Schauber, J. et al. Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 52, 735–741 (2003).
Malago, J. J., Koninkx, J. F., Tooten, P. C., van Liere, E. A. & van Dijk, J. E. Anti-inflammatory properties of heat shock protein 70 and butyrate on Salmonella-induced interleukin-8 secretion in enterocyte-like Caco-2 cells. Clin. Exp. Immunol. 141, 62–71 (2005).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Hu, S. et al. The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer. PLoS ONE 6, e16221 (2011).
He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).
Li, C.-J., Li, R. W. & Elsasser, T. H. MicroRNA (miRNA) expression is regulated by butyrate-induced epigenetic modulation of gene expression in bovine cells. Genet. Epigenet. 3, 23–32 (2010).
Humphreys, K. J., Cobiac, L., Le Leu, R. K., Van der Hoek, M. B. & Michael, M. Z. Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster. Mol. Carcinog. 52, 459–474 (2013).
Sengupta, S., Muir, J. G. & Gibson, P. R. Does butyrate protect from colorectal cancer? J. Gastroenterol. Hepatol. 21, 209–218 (2006).
Donohoe, D. R. et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48, 612–626 (2012).
Donohoe, D. R. et al. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 4, 1387–1397 (2014).
Belcheva, A. et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 158, 288–299 (2014).
Ye, H., Liu, J., Feng, P., Zhu, W. & Mao, S. Grain-rich diets altered the colonic fermentation and mucosa-associated bacterial communities and induced mucosal injuries in goats. Sci. Rep. 6, 20329 (2016).
Gressley, T. F., Hall, M. B. & Armentano, L. E. Ruminant Nutrition Symposium: productivity, digestion, and health responses to hindgut acidosis in ruminants. J. Anim. Sci. 89, 1120–1130 (2011).
Kowlgi, N. G. & Chhabra, L. D-lactic acidosis: an underrecognized complication of short bowel syndrome. Gastroenterol. Res. Pract. 2015, 476215 (2015).
Winter, J. et al. Inhibition by resistant starch of red meat-induced promutagenic adducts in mouse colon. Cancer Prev. Res. (Phila.) 4, 1920–1928 (2011).
Toden, S., Bird, A. R., Topping, D. L. & Conlon, M. A. Resistant starch prevents colonic DNA damage induced by high dietary cooked red meat or casein in rats. Cancer Biol. Ther. 5, 267–272 (2006).
Toden, S., Bird, A. R., Topping, D. L. & Conlon, M. A. Differential effects of dietary whey, casein and soya on colonic DNA damage and large bowel SCFA in rats fed diets low and high in resistant starch. Br. J. Nutr. 97, 535–543 (2007).
Hylla, S. et al. Effects of resistant starch on the colon in healthy volunteers: possible implications for cancer prevention. Am. J. Clin. Nutr. 67, 136–142 (1998).
van Munster, I. P., Tangerman, A. & Nagengast, F. M. Effect of resistant starch on colonic fermentation, bile acid metabolism, and mucosal proliferation. Dig. Dis. Sci. 39, 834–842 (1994).
Scharlau, D. et al. Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutat. Res. 682, 39–53 (2009).
Cardona, F., Andres-Lacueva, C., Tulipani, S., Tinahones, F. J. & Queipo-Ortuno, M. I. Benefits of polyphenols on gut microbiota and implications in human health. J. Nutr. Biochem. 24, 1415–1422 (2013).
Russell, W. R. et al. High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. Am. J. Clin. Nutr. 93, 1062–1072 (2011).
Dueñas, M. et al. A survey of modulation of gut microbiota by dietary polyphenols. Biomed. Res. Int. 2015, 850902 (2015).
Kemperman, R. A., Bolca, S., Roger, L. C. & Vaughan, E. E. Novel approaches for analysing gut microbes and dietary polyphenols: challenges and opportunities. Microbiology 156, 3224–3231 (2010).
Sirk, T. W., Friedman, M. & Brown, E. F. Molecular binding of black tea theaflavins to biological membranes: relationship to bioactivities. J. Agric. Food Chem. 59, 3780–3787 (2011).
Martin, C., Zhang, Y., Tonelli, C. & Petroni, K. Plants, diet, and health. Annu. Rev. Plant Biol. 64, 19–46 (2013).
Eid, N. et al. Impact of palm date consumption on microbiota growth and large intestinal health: a randomised, controlled, cross-over, human intervention study. Br. J. Nutr. 114, 1226–1236 (2015).
Nuñez-Sánchez, M. A. et al. In vivo relevant mixed urolithins and ellagic acid inhibit phenotypic and molecular colon cancer stem cell features: a new potentiality for ellagitannin metabolites against cancer. Food Chem. Toxicol. 92, 8–16 (2016).
Giménez-Bastida, J. A. et al. Intestinal ellagitannin metabolites ameliorate cytokine-induced inflammation and associated molecular markers in human colon fibroblasts. J. Agric. Food Chem. 60, 8866–8876 (2012).
González-Sarrías, A., Nuñez-Sánchez, M. A., García-Villalba, R., Tomás-Barberán, F. A. & Espín, J. C. Antiproliferative activity of the ellagic acid-derived gut microbiota isourolithin A and comparison with its urolithin A isomer: the role of cell metabolism. Eur. J. Nutr. http://dx.doi.org/10.1007/s00394-015-1131-7 (2015).
Wang, L. S. et al. A phase Ib study of the effects of black raspberries on rectal polyps in patients with familial adenomatous polyposis. Cancer Prev. Res. (Phila.) 7, 666–674 (2014).
Stoner, G. D. et al. Cancer prevention with freeze-dried berries and berry components. Semin. Cancer Biol. 17, 403–410 (2007).
Queipo-Ortuno, M. I. et al. Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers. Am. J. Clin. Nutr. 95, 1323–1334 (2012).
Yamada, H. et al. Coffee consumption and risk of colorectal cancer: the Japan Collaborative Cohort Study. J. Epidemiol. 24, 370–378 (2014).
Guercio, B. J. et al. Coffee intake, recurrence, and mortality in stage III colon cancer: results from CALGB 89803 (Alliance). J. Clin. Oncol. 33, 3598–3607 (2015).
Wang, Z. J. et al. Dietary polyphenols and colorectal cancer risk: the Fukuoka colorectal cancer study. World J. Gastroenterol. 19, 2683–2690 (2013).
Schmit, S. L., Rennert, H. S., Rennert, G. & Gruber, S. B. Coffee consumption and the risk of colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 25, 634–639 (2016).
Guertin, K. A. et al. Serum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancer. Am. J. Clin. Nutr. 101, 1000–1011 (2015).
Willett, W. C., Stampfer, M. J., Colditz, G. A., Rosner, B. A. & Speizer, F. E. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N. Engl. J. Med. 323, 1664–1672 (1990).
Kato, I., Majumdar, A. P., Land, S. J., Barnholtz-Sloan, J. S. & Severson, R. K. Dietary fatty acids, luminal modifiers, and risk of colorectal cancer. Int. J. Cancer 127, 942–951 (2010).
Enos, R. T. et al. High-fat diets rich in dietary saturated fat protect against azoxymethane/dextran sulfate sodium induced colon cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G906–G919 (2016).
Hodge, A. M. et al. Dietary and biomarker estimates of fatty acids and risk of colorectal cancer. Int. J. Cancer 137, 1224–1234 (2015).
Viggiano, E. et al. Effects of an high-fat diet enriched in lard or in fish oil on the hypothalamic amp-activated protein kinase and inflammatory mediators. Front. Cell. Neurosci. 10, 150 (2016).
Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).
Wang, D. & Dubois, R. N. Eicosanoids and cancer. Nat. Rev. Cancer 10, 181–193 (2010).
Wells, J. E. & Hylemon, P. B. Identification and characterization of a bile acid 7α-dehydroxylation operon in Clostridium sp. strain TO-931, a highly active 7α-dehydroxylating strain isolated from human feces. Appl. Environ. Microbiol. 66, 1107–1113 (2000).
Bernstein, C. et al. Carcinogenicity of deoxycholate, a secondary bile acid. Arch. Toxicol. 85, 863–871 (2011).
Burnat, G., Majka, J. & Konturek, P. C. Bile acids are multifunctional modulators of the Barrett's carcinogenesis. J. Physiol. Pharmacol. 61, 185–192 (2010).
Sharma, V., Chauhan, V. S., Nath, G., Kumar, A. & Shukla, V. K. Role of bile bacteria in gallbladder carcinoma. Hepatogastroenterology 54, 1622–1625 (2007).
Alberts, D. S. et al. Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps. J. Natl Cancer Inst. 88, 81–92 (1996).
De Boever, P. et al. Protective effect of the bile salt hydrolase-active Lactobacillus reuteri against bile salt cytotoxicity. Appl. Microbiol. Biotechnol. 53, 709–714 (2000).
Taira, T. et al. Dietary polyphenols increase fecal mucin and immunoglobulin A and ameliorate the disturbance in gut microbiota caused by a high fat diet. J. Clin. Biochem. Nutr. 57, 212–216 (2015).
Higashimura, Y. et al. Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed mice. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G367–G375 (2016).
Reddy, B. S., Simi, B., Patel, N., Aliaga, C. & Rao, C. V. Effect of amount and types of dietary fat on intestinal bacterial 7 α-dehydroxylase and phosphatidylinositol-specific phospholipase C and colonic mucosal diacylglycerol kinase and PKC activities during stages of colon tumor promotion. Cancer Res. 56, 2314–2320 (1996).
Bersamin, A., Luick, B. R., King, I. B., Stern, J. S. & Zidenberg-Cherr, S. Westernizing diets influence fat intake, red blood cell fatty acid composition, and health in remote Alaskan Native communities in the Center for Alaska Native Health Study. J. Am. Diet. Assoc. 108, 266–273 (2008).
Simopoulos, A. P. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed. Pharmacother. 60, 502–507 (2006).
Kim, S., Sandler, D. P., Galanko, J., Martin, C. & Sandler, R. S. Intake of polyunsaturated fatty acids and distal large bowel cancer risk in whites and African Americans. Am. J. Epidemiol. 171, 969–979 (2010).
Woodworth, H. L. et al. Dietary fish oil alters T lymphocyte cell populations and exacerbates disease in a mouse model of inflammatory colitis. Cancer Res. 70, 7960–7969 (2010).
Moreira, A. P. B. et al. Fish oil ingestion reduces the number of aberrant crypt foci and adenoma in 1,2-dimethylhydrazine-induced colon cancer in rats. Braz. J. Med. Biol. Res. 42, 1167–1172 (2009).
Young, T. K., Kelly, J. J., Friborg, J., Soininen, L. & Wong, K. O. Cancer among circumpolar populations: an emerging public health concern. Int. J. Circumpolar Health 75, 29787 (2016).
Hofmanová, J., Vaculová, A., Lojek, A. & Kozubík, A. Interaction of polyunsaturated fatty acids and sodium butyrate during apoptosis in HT-29 human colon adenocarcinoma cells. Eur. J. Nutr. 44, 40–51 (2005).
Kolar, S. S. N. et al. Synergy between docosahexaenoic acid and butyrate elicits p53-independent apoptosis via mitochondrial Ca2+ accumulation in colonocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G935–G943 (2007).
Ogden, C. L., Carroll, M. D., Kit, B. K. & Flegal, K. M. Prevalence of obesity among adults: United States, 2011–2012. NCHS Data Brief https://www.cdc.gov/nchs/data/databriefs/db131.pdf (2013).
Pischon, T., Nöthlings, U. & Boeing, H. Obesity and cancer. Proc. Nutr. Soc. 67, 128–145 (2008).
Goday, A. et al. Obesity as a risk factor in cancer: a national consensus of the Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology. Clin. Transl Oncol. 17, 763–771 (2015).
Bell, D. S. Changes seen in gut bacteria content and distribution with obesity: causation or association? Postgrad. Med. 127, 863–868 (2015).
Turnbaugh, P. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity 18, 190–195 (2009).
John, G. K. & Mullin, G. E. The gut microbiome and obesity. Curr. Oncol. Rep. 18, 45 (2016).
Ou, J. et al. Sa1465 Obesity and colon cancer risk: is it the fat? Gastroenterology 142, S-313 (2012).
Asano, T. K. & McLeod, R. S. Dietary fibre for the prevention of colorectal adenomas and carcinomas. Cochrane Database Syst. Rev. 2, CD003430 (2002).
Schatzkin, A. et al. Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. N. Engl. J. Med. 342, 1149–1155 (2000).
Burkitt, D. P. Diseases of the alimentary tract and western diets. Pathol. Microbiol. (Basel) 39, 177–186 (1971).
Lanza, E. et al. High dry bean intake and reduced risk of advanced colorectal adenoma recurrence among participants in the polyp prevention trial. J. Nutr. 136, 1896–1903 (2006).
Slavin, J. L. Position of the American Dietetic Association: health implications of dietary fiber. J. Am. Diet Assoc. 108, 1716–1731 (2008).
U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 Dietary Guidelines for Americans. 8th Edition. http://health.gov/dietaryguidelines/2015/guidelines/ (2015)
Scientific Advisory Committee on Nutrition. SACN Carbohydrates and Health Report. https://www.gov.uk/government/publications/sacn-carbohydrates-and-health-report (2015)
Australian National Health and Medical Research Council and the New Zealand Ministry of Health. Nutrient Reference Values for Australia and New Zealand Including Recommended Dietary Intakes. https://www.nrv.gov.au/nutrients/dietary-fibre (2006)
EFSA Panel on Dietetic Products, Nutrition, and Allergies. Scientific opinion on dietary reference values for carbohydrates and dietary fibre. EFSA Journal 8, 1462 (2010).
O'Keefe, S. J. The colon as a metabolic organ. S. Afr. Med. J. 84, 376–377 (1994).
O'Keefe, S. J. A.R.P. Walker Lecture. Food and the gut. S. Afr. Med. J. 85, 261–268 (1995).
O'Keefe, S. J. The African way of life and colon cancer risk. Am. J. Gastroenterol. 96, 3220–3221 (2001).
O'Keefe, S. J. Nutrition and colonic health: the critical role of the microbiota. Curr. Opin. Gastroenterol. 24, 51–58 (2008).
O'Keefe, S. J., Kidd, M., Espitalier-Noel, G. & Owira, P. Rarity of colon cancer in Africans is associated with low animal product consumption, not fiber. Am. J. Gastroenterol. 94, 1373–1380 (1999).
O'Keefe, S. J. et al. Products of the colonic microbiota mediate the effects of diet on colon cancer risk. J. Nutr. 139, 2044–2048 (2009).
Park, H. et al. A high-fat diet increases angiogenesis, solid tumor growth, and lung metastasis of CT26 colon cancer cells in obesity-resistant BALB/c mice. Mol. Carcinog. 51, 869–880 (2012).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
The author declares no competing financial interests.
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O'Keefe, S. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol 13, 691–706 (2016). https://doi.org/10.1038/nrgastro.2016.165
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