Korean J Gastroenterol.  2012 Nov;60(5):275-284. 10.4166/kjg.2012.60.5.275.

Gut Microbial Influence and Probiotics on Colorectal Cancer

• Myung DS
• Joo YE

• KMID: 1775792
• DOI: http://doi.org/10.4166/kjg.2012.60.5.275

Abstract

The human intestinal microbiota is a community of 10(13)-10(14) microorganisms that harbor in the intestine and normally participate in a symbiotic relationship with human. Technical and conceptual advances have enabled rapid progress in characterizing the taxonomic composition, metabolic capacity and immunomodulatory activity of the human intestinal microbiota. Their collective genome, defined as microbiome, is estimated to contain > or =150 times as many genes as 2.85 billion base pair human genome. The intestinal microbiota and its microbiome form a diverse and complex ecological community that profoundly impact intestinal homeostasis and disease states. It is becoming increasingly evident that the large and complex bacterial population of the large intestine plays an important role in colorectal carcinogenesis. Numerous studies show that gut immunity and inflammation have impact on the development of colorectal cancer. Additionally, bacteria have been linked to colorectal cancer by the production of toxic and genotoxic bacterial metabolite. In this review, we discuss the multifactorial role of intestinal microbiota in colorectal cancer and role for probiotics in the prevention of colorectal cancer.

Keyword

Colorectal cancer; Gut; Microbiota; Probiotics

MeSH Terms

Animals
Bacteroides/metabolism
Colorectal Neoplasms/immunology/*microbiology
Fatty Acids, Nonesterified/metabolism
Humans
Hydrogen Sulfide/metabolism
Intestinal Mucosa/immunology/microbiology
Metagenome
*Probiotics
Reactive Oxygen Species/metabolism
Toxins, Biological/metabolism
Fatty Acids, Nonesterified
Reactive Oxygen Species
Toxins, Biological
Hydrogen Sulfide

Figure

• 

  Fig. 1 The microbiota promotes inflammation and carcinogenesis in the colon. Recognition of microbiota by pattern recognition receptors trigger signaling pathways leading to the expression of various genes such as inflammatory mediators. Autocrine and paracrine signaling from these mediators amplifies inflammation and promotes neoplasia. Besides toxin, enzymes and reactive oxygen species (ROS) by bacterial metabolism plays a role as carcinogen (modified from Fig. 1 in the article of Arthur and Jobin [Inflamm Bowel Dis 2011;17:396-409] with the original author's permission). TLR, toll-like receptor; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor-κB; ERK, extracellular signal-regulated kinase; JNK, jun-N-terminal kinase.

Reference

1. McFall-Ngai M. Adaptive immunity: care for the community. Nature. 2007. 445:153.

2. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006. 124:837–848.

3. Xu J, Mahowald MA, Ley RE, et al. Evolution of symbiotic bacteria in the distal human intestine. PLoS Biol. 2007. 5:e156.

4. Gill SR, Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006. 312:1355–1359.

5. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005. 308:1635–1638.

6. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010. 464:59–65.

7. Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology. 2009. 136:65–80.

8. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005. 307:1915–1920.

9. Scupham AJ, Presley LL, Wei B, et al. Abundant and diverse fungal microbiota in the murine intestine. Appl Environ Microbiol. 2006. 72:793–801.

10. Orrhage K, Nord CE. Factors controlling the bacterial colonization of the intestine in breastfed infants. Acta Paediatr Suppl. 1999. 88:47–57.

11. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007. 449:804–810.

12. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol. 2007. 5:e177.

13. Rausch P, Rehman A, Künzel S, et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc Natl Acad Sci U S A. 2011. 108:19030–19035.

14. Tennyson CA, Friedman G. Microecology, obesity, and probiotics. Curr Opin Endocrinol Diabetes Obes. 2008. 15:422–427.

15. Moore WE, Moore LH. Intestinal floras of populations that have a high risk of colon cancer. Appl Environ Microbiol. 1995. 61:3202–3207.

16. Kanazawa K, Konishi F, Mitsuoka T, et al. Factors influencing the development of sigmoid colon cancer. Bacteriologic and biochemical studies. Cancer. 1996. 77:8 Suppl. 1701–1706.

17. Sobhani I, Tap J, Roudot-Thoraval F, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 2011. 6:e16393.

18. Shen XJ, Rawls JF, Randall T, et al. Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas. Gut Microbes. 2010. 1:138–147.

19. Dove WF, Clipson L, Gould KA, et al. Intestinal neoplasia in the ApcMin mouse: independence from the microbial and natural killer (beige locus) status. Cancer Res. 1997. 57:812–814.

20. Kanneganti TD, Lamkanfi M, Núñez G. Intracellular NOD-like receptors in host defense and disease. Immunity. 2007. 27:549–559.

21. Beutler BA. TLRs and innate immunity. Blood. 2009. 113:1399–1407.

22. Mantovani A. Cancer: inflammation by remote control. Nature. 2005. 435:752–753.

23. Fukata M, Chen A, Vamadevan AS, et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology. 2007. 133:1869–1881.

24. Uronis JM, Mühlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One. 2009. 4:e6026.

25. Rakoff-Nahoum S, Hao L, Medzhitov R. Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity. 2006. 25:319–329.

26. Karrasch T, Kim JS, Muhlbauer M, Magness ST, Jobin C. Gnotobiotic IL-10-/-;NF-kappa B(EGFP) mice reveal the critical role of TLR/NF-kappa B signaling in commensal bacteria-induced colitis. J Immunol. 2007. 178:6522–6532.

27. Rakoff-Nahoum S, Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science. 2007. 317:124–127.

28. Chen GY, Shaw MH, Redondo G, Núñez G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 2008. 68:10060–10067.

29. Normand S, Delanoye-Crespin A, Bressenot A, et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc Natl Acad Sci U S A. 2011. 108:9601–9606.

30. Allen IC, TeKippe EM, Woodford RM, et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 2010. 207:1045–1056.

31. Wu S, Rhee KJ, Albesiano E, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009. 15:1016–1022.

32. Toprak NU, Yagci A, Gulluoglu BM, et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin Microbiol Infect. 2006. 12:782–786.

33. Housseau F, Sears CL. Enterotoxigenic Bacteroides fragilis (ETBF)-mediated colitis in Min (Apc+/-) mice: a human commensal-based murine model of colon carcinogenesis. Cell Cycle. 2010. 9:3–5.

34. Lara-Tejero M, Galán JE. Cytolethal distending toxin: limited damage as a strategy to modulate cellular functions. Trends Microbiol. 2002. 10:147–152.

35. Killeen SD, Wang JH, Andrews EJ, Redmond HP. Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system. Br J Cancer. 2009. 100:1589–1602.

36. Dabek M, McCrae SI, Stevens VJ, Duncan SH, Louis P. Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol Ecol. 2008. 66:487–495.

37. Takada H, Hirooka T, Hiramatsu Y, Yamamoto M. Effect of beta-glucuronidase inhibitor on azoxymethane-induced colonic carcinogenesis in rats. Cancer Res. 1982. 42:331–334.

38. Kim DH, Jin YH. Intestinal bacterial beta-glucuronidase activity of patients with colon cancer. Arch Pharm Res. 2001. 24:564–567.

39. Reddy BS, Mangat S, Weisburger JH, Wynder EL. Effect of high-risk diets for colon carcinogenesis on intestinal mucosal and bacterial beta-glucuronidase activity in F344 rats. Cancer Res. 1977. 37:3533–3536.

40. Gorbach SL, Goldin BR. The intestinal microflora and the colon cancer connection. Rev Infect Dis. 1990. 12:Suppl 2. S252–S261.

41. Wang RF, Chen H, Paine DD, Cerniglia CE. Microarray method to monitor 40 intestinal bacterial species in the study of azo dye reduction. Biosens Bioelectron. 2004. 20:699–705.

42. Nakamura J, Kubota Y, Miyaoka M, Saitoh T, Mizuno F, Benno Y. Comparison of four microbial enzymes in Clostridia and Bacteroides isolated from human feces. Microbiol Immunol. 2002. 46:487–490.

43. Hughes R, Cross AJ, Pollock JR, Bingham S. Dose-dependent effect of dietary meat on endogenous colonic N-nitrosation. Carcinogenesis. 2001. 22:199–202.

44. Roldán MD, Pérez-Reinado E, Castillo F, Moreno-Vivián C. Reduction of polynitroaromatic compounds: the bacterial nitroreductases. FEMS Microbiol Rev. 2008. 32:474–500.

45. Huycke MM, Gaskins HR. Commensal bacteria, redox stress, and colorectal cancer: mechanisms and models. Exp Biol Med (Maywood). 2004. 229:586–597.

46. Christl SU, Gibson GR, Cummings JH. Role of dietary sulphate in the regulation of methanogenesis in the human large intestine. Gut. 1992. 33:1234–1238.

47. Ramasamy S, Singh S, Taniere P, Langman MJ, Eggo MC. Sulfide-detoxifying enzymes in the human colon are decreased in cancer and upregulated in differentiation. Am J Physiol Gastrointest Liver Physiol. 2006. 291:G288–G296.

48. Boffetta P, Hashibe M. Alcohol and cancer. Lancet Oncol. 2006. 7:149–156.

49. Seitz HK, Becker P. Alcohol metabolism and cancer risk. Alcohol Res Health. 2007. 30:38–41. 44–47.

50. Seitz HK, Simanowski UA, Garzon FT, et al. Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat. Gastroenterology. 1990. 98:406–413.

51. Homann N, Tillonen J, Salaspuro M. Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency. Int J Cancer. 2000. 86:169–173.

52. Acharya A, Das I, Chandhok D, Saha T. Redox regulation in cancer: a double-edged sword with therapeutic potential. Oxid Med Cell Longev. 2010. 3:23–34.

53. Brozovic A, Ambriović-Ristov A, Osmak M. The relationship between cisplatin-induced reactive oxygen species, glutathione, and BCL-2 and resistance to cisplatin. Crit Rev Toxicol. 2010. 40:347–359.

54. Landriscina M, Maddalena F, Laudiero G, Esposito F. Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid Redox Signal. 2009. 11:2701–2716.

55. Zheng CL, Che XF, Akiyama S, Miyazawa K, Tomoda A. 2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells. Int J Oncol. 2010. 36:641–650.

56. Kumar A, Wu H, Collier-Hyams LS, et al. Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species. EMBO J. 2007. 26:4457–4466.

57. Roessner A, Kuester D, Malfertheiner P, Schneider-Stock R. Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol Res Pract. 2008. 204:511–524.

58. Nishikawa M, Tamada A, Hyoudou K, et al. Inhibition of experimental hepatic metastasis by targeted delivery of catalase in mice. Clin Exp Metastasis. 2004. 21:213–221.

59. Laqueur GL, McDaniel EG, Matsumoto H. Tumor induction in germfree rats with methylazoxymethanol (MAM) and synthetic MAM acetate. J Natl Cancer Inst. 1967. 39:355–371.

60. Rowland IR. The role of the gastrointestinal microbiota in colorectal cancer. Curr Pharm Des. 2009. 15:1524–1527.

61. McGarr SE, Ridlon JM, Hylemon PB. Diet, anaerobic bacterial metabolism, and colon cancer: a review of the literature. J Clin Gastroenterol. 2005. 39:98–109.

62. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res. 2005. 589:47–65.

63. Booth LA, Gilmore IT, Bilton RF. Secondary bile acid induced DNA damage in HT29 cells: are free radicals involved? Free Radic Res. 1997. 26:135–144.

64. Chang CL, Marra G, Chauhan DP, et al. Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol. 2002. 283:C148–C154.

65. Arthur JC, Jobin C. The struggle within: microbial influences on colorectal cancer. Inflamm Bowel Dis. 2011. 17:396–409.

66. Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009. 294:1–8.

67. Barnard JA, Warwick G. Butyrate rapidly induces growth inhibition and differentiation in HT-29 cells. Cell Growth Differ. 1993. 4:495–501.

68. Tsao D, Shi ZR, Wong A, Kim YS. Effect of sodium butyrate on carcinoembryonic antigen production by human colonic adenocarcinoma cells in culture. Cancer Res. 1983. 43:1217–1222.

69. Hague A, Manning AM, Hanlon KA, Huschtscha LI, Hart D, Paraskeva C. Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53-independent pathway: implications for the possible role of dietary fibre in the prevention of large-bowel cancer. Int J Cancer. 1993. 55:498–505.

70. Berry RD, Paraskeva C. Expression of carcinoembryonic antigen by adenoma and carcinoma derived epithelial cell lines: possible marker of tumour progression and modulation of expression by sodium butyrate. Carcinogenesis. 1988. 9:447–450.

71. Heerdt BG, Houston MA, Augenlicht LH. Short-chain fatty acid-initiated cell cycle arrest and apoptosis of colonic epithelial cells is linked to mitochondrial function. Cell Growth Differ. 1997. 8:523–532.

72. Hague A, Elder DJ, Hicks DJ, Paraskeva C. Apoptosis in colorectal tumour cells: induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate. Int J Cancer. 1995. 60:400–406.

73. Bordonaro M, Lazarova DL, Sartorelli AC. Hyperinduction of Wnt activity: a new paradigm for the treatment of colorectal cancer? Oncol Res. 2008. 17:1–9.

74. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006. 5:769–784.

75. Ruemmele FM, Schwartz S, Seidman EG, Dionne S, Levy E, Lentze MJ. Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway. Gut. 2003. 52:94–100.

76. Bonnotte B, Favre N, Reveneau S, et al. Cancer cell sensitization to fas-mediated apoptosis by sodium butyrate. Cell Death Differ. 1998. 5:480–487.

77. Park JY, Helm JF, Zheng W, et al. Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. Pancreas. 2008. 36:e32–e39.

78. Bennett KL, Karpenko M, Lin MT, et al. Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res. 2008. 68:4494–4499.

79. Whitman SP, Hackanson B, Liyanarachchi S, et al. DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication. Blood. 2008. 112:2013–2016.

80. Thangaraju M, Cresci GA, Liu K, et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res. 2009. 69:2826–2832.

81. Geier MS, Butler RN, Howarth GS. Probiotics, prebiotics and synbiotics: a role in chemoprevention for colorectal cancer? Cancer Biol Ther. 2006. 5:1265–1269.

82. Goldin BR, Gorbach SL. Alterations of the intestinal microflora by diet, oral antibiotics, and Lactobacillus: decreased production of free amines from aromatic nitro compounds, azo dyes, and glucuronides. J Natl Cancer Inst. 1984. 73:689–695.

83. Goldin BR, Swenson L, Dwyer J, Sexton M, Gorbach SL. Effect of diet and Lactobacillus acidophilus supplements on human fecal bacterial enzymes. J Natl Cancer Inst. 1980. 64:255–261.

84. Rowland IR, Rumney CJ, Coutts JT, Lievense LC. Effect of Bifidobacterium longum and inulin on gut bacterial metabolism and carcinogen-induced aberrant crypt foci in rats. Carcinogenesis. 1998. 19:281–285.

85. An H, Zhai Z, Yin S, Luo Y, Han B, Hao Y. Coexpression of the superoxide dismutase and the catalase provides remarkable oxidative stress resistance in Lactobacillus rhamnosus. J Agric Food Chem. 2011. 59:3851–3856.

86. Archibald FS, Fridovich I. Manganese and defenses against oxygen toxicity in Lactobacillus plantarum. J Bacteriol. 1981. 145:442–451.

87. Archibald FS, Fridovich I. Manganese, superoxide dismutase, and oxygen tolerance in some lactic acid bacteria. J Bacteriol. 1981. 146:928–936.

88. Goffin P, Muscariello L, Lorquet F, et al. Involvement of pyruvate oxidase activity and acetate production in the survival of Lactobacillus plantarum during the stationary phase of aerobic growth. Appl Environ Microbiol. 2006. 72:7933–7940.

89. Talwalkar A, Kailasapathy K. The role of oxygen in the viability of probiotic bacteria with reference to L. acidophilus and Bifidobacterium spp. Curr Issues Intest Microbiol. 2004. 5:1–8.

90. Azcárate-Peril MA, Sikes M, Bruno-Bárcena JM. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol. 2011. 301:G401–G424.

91. Candela M, Perna F, Carnevali P, 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. 125:286–292.

92. Candela M, Guidotti M, Fabbri A, Brigidi P, Franceschi C, Fiorentini C. Human intestinal microbiota: cross-talk with the host and its potential role in colorectal cancer. Crit Rev Microbiol. 2011. 37:1–14.

93. Food and Agriculture Organization of the United Nations, World Health Organization. Report of a Joint FAO/WHO Expert Consultation on health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria; 2001 Oct 1-4; Córdoba, Argentina [Internet]. 2001. cited 2012 Oct 15. FAO/WHO;Available from: ftp://ftp.fao.org/es/esn/food/probio_report_en.pdf.

94. Zhu Y, Michelle Luo T, Jobin C, Young HA. Gut microbiota and probiotics in colon tumorigenesis. Cancer Lett. 2011. 309:119–127.

95. Capurso G, Marignani M, Delle Fave G. Probiotics and the incidence of colorectal cancer: when evidence is not evident. Dig Liver Dis. 2006. 38:Suppl 2. S277–S282.

96. Preidis GA, Versalovic J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology. 2009. 136:2015–2031.

97. Kim Y, Lee D, Kim D, 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. 31:468–473.

98. Lee NK, Park JS, Park E, Paik HD. Adherence and anticarcinogenic effects of Bacillus polyfermenticus SCD in the large intestine. Lett Appl Microbiol. 2007. 44:274–278.

99. Urbanska AM, Bhathena J, Martoni C, Prakash S. Estimation of the potential antitumor activity of microencapsulated Lactobacillus acidophilus yogurt formulation in the attenuation of tumorigenesis in Apc(Min/+) mice. Dig Dis Sci. 2009. 54:264–273.

100. Le Leu RK, Hu Y, Brown IL, Woodman RJ, Young GP. Synbiotic intervention of Bifidobacterium lactis and resistant starch protects against colorectal cancer development in rats. Carcinogenesis. 2010. 31:246–251.

101. de Moreno de Leblanc A, Perdigón G. Yogurt feeding inhibits promotion and progression of experimental colorectal cancer. Med Sci Monit. 2004. 10:BR96–BR104.

102. Ishikawa H, Akedo I, Otani T, et al. Randomized trial of dietary fiber and Lactobacillus casei administration for prevention of colorectal tumors. Int J Cancer. 2005. 116:762–767.

103. Rafter J, Bennett M, Caderni G, et al. Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Am J Clin Nutr. 2007. 85:488–496.

104. Pala V, Sieri S, Berrino F, et al. Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort. Int J Cancer. 2011. 129:2712–2719.