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The Microbiota: A New Player in the Etiology of Colorectal Cancer

  • Prevention and Early Detection (N Arber, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

Colorectal cancer is one of the commonest forms of cancer worldwide. Although the molecular pathogenesis of colorectal cancer shares many characteristics with that of other cancers, the tissue environment is unique in that the intestinal mucosal surface is continuously exposed to a vast community of microorganisms. It is increasingly recognized that the intestinal microbiota is a critical component of the tumor environment that contributes to the development of colorectal cancer, and certain members of the commensal microbiota have been identified as critical elements in intestinal carcinogenesis. As sensors of the presence of microbes at mucosal surfaces, pattern-recognition receptors of the innate immune system are equally involved in this process. This review summarizes our current knowledge of the role of the microbiota in colorectal cancer development and provides an overview of the mechanisms involved in the cross talk between intestinal microbial colonization and tumorigenesis.

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References

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  1. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. 2000;248:171–83.

    Article  CAS  PubMed  Google Scholar 

  2. Hu WY, Bushman FD, Siva AC. RNA interference against retroviruses. Virus Res. 2004;102:59–64.

    Article  CAS  PubMed  Google Scholar 

  3. Russell W. An address on a characteristic organism of cancer. Br Med J. 1890;2:1356–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Wuerthele-Caspe V et al. Cultural properties and pathogenicity of certain microorganisms obtained from various proliferative and neoplastic diseases. Am J Med Sci. 1950;220:638–46.

    Article  CAS  PubMed  Google Scholar 

  5. Livingston VW, Alexander-Jackson E. An experimental biologic approach to the treatment of neoplastic disease; determination of actinomycin in urine and cultures as an aid to diagnosis and prognosis. J Am Med Womens Assoc. 1965;20:858–66.

    CAS  PubMed  Google Scholar 

  6. Unproven methods of cancer management. Livingston-Wheeler therapy. CA Cancer J Clin. 1991;41:A7–12.

    Google Scholar 

  7. Polk DB, Peek Jr RM. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer. 2010;10:403–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Samaras V, Rafailidis PI, Mourtzoukou EG, Peppas G, Falagas ME. Chronic bacterial and parasitic infections and cancer: a review. J Infect Dev Ctries. 2010;4:267–81.

    PubMed  Google Scholar 

  9. Berg RD. The indigenous gastrointestinal microflora. Trends Microbiol. 1996;4:430–5.

    Article  CAS  PubMed  Google Scholar 

  10. Gordon JI. Honor thy gut symbionts redux. Science. 2012;336:1251–3.

    Article  CAS  PubMed  Google Scholar 

  11. Sonnenburg JL et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science. 2005;307:1955–9.

    Article  CAS  PubMed  Google Scholar 

  12. Candela M et al. Interaction of probiotic Lactobacillus and Bifidobacterium strains with human intestinal epithelial cells: adhesion properties, competition against enteropathogens and modulation of IL-8 production. Int J Food Microbiol. 2008;125:286–92.

    Article  CAS  PubMed  Google Scholar 

  13. Fukuda S et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature. 2011;469:543–7.

    Article  CAS  PubMed  Google Scholar 

  14. Hosokawa T, Kikuchi Y, Nikoh N, Shimada M, Fukatsu T. Strict host-symbiont cospeciation and reductive genome evolution in insect gut bacteria. PLoS Biol. 2006;4:e337.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336:1268–73.

    Article  CAS  PubMed  Google Scholar 

  16. Yatsunenko T et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Dominguez-Bello MG et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107:11971–5.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Eckburg PB et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–8.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Spor A, Koren O, Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol. 2011;9:279–90.

    Article  CAS  PubMed  Google Scholar 

  20. Lupp C et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe. 2007;2:204.

    Article  CAS  PubMed  Google Scholar 

  21. Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet. 2009;10:353–8.

    Article  CAS  PubMed  Google Scholar 

  22. Peek Jr RM, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2:28–37.

    Article  CAS  PubMed  Google Scholar 

  23. Gold JS, Bayar S, Salem RR. Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. Arch Surg. 2004;139:760–5.

    Article  PubMed  Google Scholar 

  24. Nakamura J et al. Comparison of four microbial enzymes in Clostridia and Bacteroides isolated from human feces. Microbiol Immunol. 2002;46:487–90.

    Article  CAS  PubMed  Google Scholar 

  25. Ellmerich S, Djouder N, Scholler M, Klein JP. Production of cytokines by monocytes, epithelial and endothelial cells activated by Streptococcus bovis. Cytokine. 2000;12:26–31.

    Article  CAS  PubMed  Google Scholar 

  26. Castellarin M et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012;22:299–306.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Arthur JC et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338:120–3. This article demonstrates the impact of intestinal inflammation on the outgrowth of a bacterial strain that exerts genotoxic effects on the host.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Sobhani I et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 2011;6:e16393.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Chiba T, Marusawa H, Ushijima T. Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology. 2012;143:550–63.

    Article  CAS  PubMed  Google Scholar 

  30. Scanlan PD et al. Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis. Environ Microbiol. 2008;10:789–98.

    Article  CAS  PubMed  Google Scholar 

  31. Wu N et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol. 2013;66:462–70.

    Article  CAS  PubMed  Google Scholar 

  32. Wang T et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 2012;6:320–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Pryde SE, Duncan SH, Hold GL, Stewart CS, Flint HJ. The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett. 2002;217:133–9.

    Article  CAS  PubMed  Google Scholar 

  34. Rose DJ, DeMeo MT, Keshavarzian A, Hamaker BR. Influence of dietary fiber on inflammatory bowel disease and colon cancer: importance of fermentation pattern. Nutr Rev. 2007;65:51–62.

    Article  PubMed  Google Scholar 

  35. Martin HM et al. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology. 2004;127:80–93.

    Article  CAS  PubMed  Google Scholar 

  36. Maddocks OD, Short AJ, Donnenberg MS, Bader S, Harrison DJ. Attaching and effacing Escherichia coli downregulate DNA mismatch repair protein in vitro and are associated with colorectal adenocarcinomas in humans. PLoS One. 2009;4:e5517.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Reddy BS, Mastromarino A, Wynder EL. Further leads on metabolic epidemiology of large bowel cancer. Cancer Res. 1975;35:3403–6.

    CAS  PubMed  Google Scholar 

  38. Kim SC et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128:891–906.

    Article  CAS  PubMed  Google Scholar 

  39. Fasano A. Cellular microbiology: can we learn cell physiology from microorganisms? Am J Physiol. 1999;276:C765–76.

    CAS  PubMed  Google Scholar 

  40. Rhee KJ et al. Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice. Infect Immun. 2009;77:1708–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Wu S et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009;15:1016–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Jess T, Rungoe C, Peyrin-Biroulet L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clin Gastroenterol Hepatol. 2012;10:639–45.

    Article  PubMed  Google Scholar 

  43. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011;140:1807–16.

    Article  CAS  PubMed  Google Scholar 

  45. Hu B et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc Natl Acad Sci U S A. 2013;110:9862–7. This report demonstrates that susceptibility to CRC development is transmissible through the transfer of dysbiotic microbiota.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Qin J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45.

    Article  CAS  PubMed  Google Scholar 

  48. Darfeuille-Michaud A et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology. 1998;115:1405–13.

    Article  CAS  PubMed  Google Scholar 

  49. Swidsinski A et al. Association between intraepithelial Escherichia coli and colorectal cancer. Gastroenterology. 1998;115:281–6.

    Article  CAS  PubMed  Google Scholar 

  50. Cuevas-Ramos G et al. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc Natl Acad Sci U S A. 2010;107:11537–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Nougayrede JP et al. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science. 2006;313:848–51.

    Article  CAS  PubMed  Google Scholar 

  52. Putze J et al. Genetic structure and distribution of the colibactin genomic island among members of the family Enterobacteriaceae. Infect Immun. 2009;77:4696–703.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Geijtenbeek TB, van Vliet SJ, Engering A, ’t Hart BA, van Kooyk Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol. 2004;22:33–54.

    Article  CAS  PubMed  Google Scholar 

  54. Medzhitov R, Janeway Jr CA. Decoding the patterns of self and nonself by the innate immune system. Science. 2002;296:298–300.

    Article  CAS  PubMed  Google Scholar 

  55. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.

    Article  CAS  PubMed  Google Scholar 

  56. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65.

    Article  CAS  PubMed  Google Scholar 

  57. Elinav E, Strowig T, Henao-Mejia J, Flavell RA. Regulation of the antimicrobial response by NLR proteins. Immunity. 2011;34:665–79.

    Article  CAS  PubMed  Google Scholar 

  58. Chen GY, Shaw MH, Redondo G, Nunez G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 2008;68:10060–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Rakoff-Nahoum S, Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science. 2007;317:124–7.

    Article  CAS  PubMed  Google Scholar 

  60. Salcedo R et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med. 2010;207:1625–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Fukata M et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology. 2007;133:1869–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Lowe EL et al. Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS One. 2010;5:e13027.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Dupaul-Chicoine J et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity. 2010;32:367–78.

    Article  CAS  PubMed  Google Scholar 

  64. Elinav E et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145:745–57. This article shows the involvement of the NLRP6 inflammasome in the prevention of dysbiosis development. Absence of NLRP6 leads to the outgrowth of colitogenic microbiota.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Allen IC et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 2010;207:1045–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Zaki MH et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity. 2010;32:379–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Bauer C et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut. 2010;59:1192–9.

    Article  CAS  PubMed  Google Scholar 

  68. Hu B et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci U S A. 2010;107:21635–40.

    Article  PubMed Central  PubMed  Google Scholar 

  69. Chen GY, Liu M, Wang F, Bertin J, Nunez G. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J Immunol. 2011;186:7187–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Allen IC et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling. Immunity. 2012;36:742–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Zaki MH et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell. 2011;20:649–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Zhu Y, Michelle Luo T, Jobin C, Young HA. Gut microbiota and probiotics in colon tumorigenesis. Cancer Lett. 2011;309:119–27.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Pala V et al. Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort. Int J Cancer. 2011;129:2712–9.

    Article  CAS  PubMed  Google Scholar 

  74. Goncharova GI, Dorofeichuk VG, Smolianskaia AZ, Sokolova K. [Microbial ecology of the intestines in health and in pathology]. Antibiot Khimioter. 1989;34:462–6.

    CAS  PubMed  Google Scholar 

  75. Arumugam M et al. Enterotypes of the human gut microbiome. Nature. 2011;473:174–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Corthesy B, Gaskins HR, Mercenier A. Cross-talk between probiotic bacteria and the host immune system. J Nutr. 2007;137:781S–90.

    CAS  PubMed  Google Scholar 

  77. Orlando A, Messa C, Linsalata M, Cavallini A, Russo F. Effects of Lactobacillus rhamnosus GG on proliferation and polyamine metabolism in HGC-27 human gastric and DLD-1 colonic cancer cell lines. Immunopharmacol Immunotoxicol. 2009;31:108–16.

    Article  CAS  PubMed  Google Scholar 

  78. Lee NK, Park JS, Park E, Paik HD. Adherence and anticarcinogenic effects of Bacillus polyfermenticus SCD in the large intestine. Lett Appl Microbiol. 2007;44:274–8.

    Article  PubMed  Google Scholar 

  79. Kim Y et al. Inhibition of proliferation in colon cancer cell lines and harmful enzyme activity of colon bacteria by Bifidobacterium adolescentis SPM0212. Arch Pharm Res. 2008;31:468–73.

    Article  CAS  PubMed  Google Scholar 

  80. Le Leu RK et al. A synbiotic combination of resistant starch and Bifidobacterium lactis facilitates apoptotic deletion of carcinogen-damaged cells in rat colon. J Nutr. 2005;135:996–1001.

    PubMed  Google Scholar 

  81. Pool-Zobel BL et al. Lactobacillus- and bifidobacterium-mediated antigenotoxicity in the colon of rats. Nutr Cancer. 1996;26:365–80.

    Article  CAS  PubMed  Google Scholar 

  82. Borody TJ, Paramsothy S, Agrawal G. Fecal microbiota transplantation: indications, methods, evidence, and future directions. Curr Gastroenterol Rep. 2013;15:337.

    Article  PubMed Central  PubMed  Google Scholar 

  83. van Nood E et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–15. This study presents the successful use of fecal transplantation to cure disease.

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank the members of the Elinav laboratory for fruitful discussions. We apologize to authors whose relevant work was not included in this review owing to space constraints. Eran Elinav is supported by grants provided by the Abisch-Frenkel Foundation, the Kenneth Rainin Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the Israel Science Foundation, and the German-Israel Foundation, and a Marie Curie Career Integration Grant Christoph Thaiss is funded by a Boehringer Ingelheim Fonds PhD Fellowship. We thank A. Levy and Z. Levy for excellent support.

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Maayan Levy, Christoph A. Thaiss, and Eran Elinav declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Department of Immunology, Weizmann Institute of Science, 100 Herzl Street, 76100, Rehovot, Israel

    Maayan Levy, Christoph A. Thaiss & Eran Elinav

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  1. Maayan Levy
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  2. Christoph A. Thaiss
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Correspondence to Eran Elinav.

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Maayan Levy and Christoph A. Thaiss are equal contributors.

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Levy, M., Thaiss, C.A. & Elinav, E. The Microbiota: A New Player in the Etiology of Colorectal Cancer. Curr Colorectal Cancer Rep 10, 1–8 (2014). https://doi.org/10.1007/s11888-013-0196-z

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