Role of the Microbiome in the Formation and Development of Colorectal Cancer

Czech version

Authors: Barbora Zwinsová; Veronika Brychtová; Martina Hrivňáková; Lenka Zdražilová-Dubská; Beatrix Bencsiková; Roman Šefr; Rudolf Nenutil; Petra Vídeňská; Eva Budinská
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2019; 32(4): 261-269
Category: Review
doi: https://doi.org/10.14735/amko2019261

Overview

Background: The clinical, histopathological, and molecular characteristics of colorectal cancer vary considerably. Factors associated with the heterogeneity of this disease and with understanding the effects of heterogeneity on disease progression and response to therapy are critical for the better stratification of patients and the development of new therapeutic methods. Although studies have focused mainly on tumor molecular profiling, current molecular predictive and prognostic factors are relevant to specific groups of colorectal cancer patients and are mostly used to predict the applicability of targeted biological agents rather than to predict their benefits. Molecular profiling fails to capture aspects important for tumor growth and aggressiveness, including the tumor microenvironment. The gut microbiome, consisting of specific communities of all commensal, symbiotic, and pathogenic microorganisms, has been shown to have a significant impact on the development of many diseases, including Crohn’s disease, type II diabetes, and obesity. Recent studies have indicated that long-term dysbiosis of the intestinal microflora can influence the development and progression of colorectal cancer, as well as tumor aggressiveness and response to treatment.

Conclusion: This review article summarizes current knowledge of the gut microbiome in colorectal cancer, including the various mechanisms by which the gut microbiome affects the intestinal wall, thereby contributing to the development and progression of colorectal cancer.

This work was supported by Ministry of Health of the Czech Republic (project AZV 16-31966A), project of Ministry of Education, Youth and Sports of the Czech Republic – NPU I – LO1413 a Ministry of Health of the Czech Republic – RVO (MMCI, 00209805).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted: 15. 4. 2019

Accepted: 17. 6. 2019

Keywords:

dysbiosis

Sources

1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. CA Cancer J Clin 2018; 68 (1): 7–30. doi: 10.3322/caac.21442.

2. Novotvary 2015. Ústav zdravotnických informací a statistik ČR. [online]. Dostupné z: https: //www.uzis.cz/publikace/novotvary-2015.

3. Arnold M, Sierra MS, Laversanne M et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017; 66 (4): 683–691. doi: 10.1136/gutjnl-2015-310912.

4. Tan C, Du X. KRAS mutation testing in metastatic colorectal cancer. World J Gastroenterol 2012; 18 (37): 5171–5180. doi: 10.3748/wjg.v18.i37.5171.

5. Renfro LA, Zhang N, Lopatin M et al. Prospective evaluation of a 12-gene assay on patient treatment decisions and physician confidence in mismatch repair proficient stage IIA colon cancer. Clin Colorectal Cancer 2017; 16 (1): 23–30. doi: 10.1016/j.clcc.2016.07.016.

6. Kopetz S, Tabernero J, Rosenberg R et al. Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors. Oncologist 2015; 20 (2): 127–133. doi: 10.1634/theoncologist.2014-0325.

7. Sharif S, O’Connell MJ. Gene signatures in stage II colon cancer: a clinical review. Curr Colorectal Cancer Rep 2012; 8 (3): 225–231. doi: 10.1007/s11888-012-0132-7.

8. Galon J, Pagès F, Marincola FM et al. Cancer classification using the immunoscore: a worldwide task force. J Transl Med 2012; 10: 205. doi: 10.1186/1479-5876-10-205.

9. Budinska E, Popovici V, Tejpar S et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol 2013; 231 (1): 63–76. doi: 10.1002/path.4212.

10. Dienstmann R, Guinney J, Delorenzi M et al. Colorectal cancer subtyping consortium (CRCSC) identification of a consensus of molecular subtypes. J Clin Oncol 2014; 32 (Suppl 15): 3511–3511.

11. Marisa L, Reyniès A de, Duval A et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 2013; 10 (5): e1001453. doi: 10.1371/journal.pmed.1001453.

12. Sadanandam A, Lyssiotis CA, Homicsko K et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 2013; 19 (5): 619–625. doi: 10.1038/nm.3175.

13. Guinney J, Dienstmann R, Wang X et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015; 21 (11): 1350–1356. doi: 10.1038/nm.3967.

14. Isella C, Brundu F, Bellomo SE et al. Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer. Nat Commun 2017; 8: 15107. doi: 10.1038/ncomms15 107.

15. Li K, Bihan M, Yooseph S et al. Analyses of the microbial diversity across the human microbiome. PloS One 2012; 7 (6): e32118. doi: 10.1371/journal.pone.0032118.

16. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 2016; 14 (8): e1002533. doi: 10.1371/journal.pbio. 1002533.

17. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 2016; 164 (3): 337–340. doi: 10.1016/j.cell.2016.01.013.

18. Turnbaugh PJ, Ley RE, Hamady M et al. The human microbiome project: exploring the microbial part of ourselves in a changing world. Nature 2007; 449 (7164): 804–810. doi: 10.1038/nature06244.

19. Jandhyala SM, Talukdar R, Subramanyam C et al. Role of the normal gut microbiota. World J Gastroenterol 2015; 21 (29): 8787–8803. doi: 10.3748/wjg.v21.i29.8787.

20. Koeth RA, Wang Z, Levison BS et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19 (5): 576–585. doi: 10.1038/nm.3145.

21. LeBlanc JG, Chain F, Martín R et al. Beneficial effects on host energy metabolism of short-chain fatty acids and vitamins produced by commensal and probiotic bacteria. Microb Cell Factories 2017; 16 (1): 79. doi: 10.1186/s12934-017-0691-z.

22. Sommer F, Bäckhed F. The gut microbiota – masters of host development and physiology. Nat Rev Microbiol 2013; 11 (4): 227–238. doi: 10.1038/nrmicro2974.

23. Ho JT, Chan GC, Li JC. Systemic effects of gut microbiota and its relationship with disease and modulation. BMC Immunol 2015; 16: 21. doi: 10.1186/s12865-015-0083-2.

24. Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 2012; 3 (1): 4–14. doi: 10.4161/gmic.19320.

25. Hill CJ, Lynch DB, Murphy K et al. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET cohort. Microbiome 2017; 5 (1): 4. doi: 10.1186/s40168-016-0213-y.

26. Jurjus A, Eid A, Al Kattar S et al. Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: the links. BBA Clin 2015; 5: 16–24. doi: 10.1016/j.bbacli.2015.11.002.

27. Di Bella JM, Bao Y, Gloor GB et al. High throughput sequencing methods and analysis for microbiome research. J Microbiol Methods 2013; 95 (3): 401–414. doi: 10.1016/j.mimet.2013.08.011.

28. Eckburg PB. Diversity of the human intestinal microbial flora. Science 2005; 308 (5728): 1635–1638. doi: 10.1126/science.1110591.

29. Galperin MY. Genome diversity of spore-forming firmicutes. Microbiol Spectr 2013; 1 (2). doi: 10.1128/microbiolspectrum.TBS-0015-2012.

30. Qin J, Li R, Raes J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464 (7285): 59–65. doi: 10.1038/nature08821.

31. Kang M, Martin A. Microbiome and colorectal cancer: unraveling host-microbiota interactions in colitis-associated colorectal cancer development. Semin Immunol 2017; 32: 3–13. doi: 10.1016/j.smim.2017.04.003.

32. Serban DE. Gastrointestinal cancers: influence of gut microbiota, probiotics and prebiotics. Cancer Lett 2014; 345 (2): 258–270. doi: 10.1016/j.canlet.2013.08.013.

33. Ehrlich SD. MetaHIT: The European Union project on metagenomics of the human intestinal tract. In: Nelson KE (ed). Metagenomics of the human body. New York: Springer New York 2011: 307–316.

34. Arumugam M, Raes J, Pelletier E et al. Enterotypes of the human gut microbiome. Nature 2011; 473 (7346): 174–180. doi: 10.1038/nature09944.

35. Costea PI, Hildebrand F, Arumugam M et al. Enterotypes in the landscape of gut microbial community composition. Nat Microbiol 2018; 3 (1): 8–16. doi: 10.1038/s41564-017-0072-8.

36. Chen J, Pitmon E, Wang K. Microbiome, inflammation and colorectal cancer. Semin Immunol 2017; 32: 43–53. doi: 10.1016/j.smim.2017.09.006.

37. Dulal S, Keku TO. Gut microbiome and colorectal adenomas. Cancer J 2014; 20 (3): 225–231. doi: 10.1097/PPO.0000000000000050.

38. Goldszmid RS, Dzutsev A, Viaud S et al. Microbiota modulation of myeloid cells in cancer therapy. Cancer Immunol Res 2015; 3 (2): 103–109. doi: 10.1158/2326-6066.CIR-14-0225.

39. Dzutsev A, Goldszmid RS, Viaud S et al. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur J Immunol 2015; 45 (1): 17–3. doi: 10.1002/eji.201444972.

40. Lax AJ. Opinion: Bacterial toxins and cancer – a case to answer? Nat Rev Microbiol 2005; 3 (4): 343–349. doi: 10.1038/nrmicro1130.

41. Song M, Garrett WS, Chan AT. Nutrients, foods, and colorectal cancer prevention. Gastroenterology 2015; 148 (6): 1244–1260. doi: 10.1053/j.gastro.2014.12.035.

42. Bonnet M, Buc E, Sauvanet P et al. Colonization of the human gut by E. coli and colorectal cancer risk. Clin Cancer Res 2014; 20 (4): 859–867. doi: 10.1158/1078-0432.CCR-13-1343.

43. Arthur JC, Perez-Chanona E, Mühlbauer M et al. Intestinal inflammation targets cance – inducing activity of the microbiota. Science 2012; 338 (6103): 120–123. doi: 10.1126/science.1224820.

44. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140 (6): 883–899. doi: 10.1016/j.cell.2010.01.025.

45. Sun J, Kato I. Gut microbiota, inflammation and colorectal cancer. Genes Dis 2016; 3 (2): 130–143. doi: 10.1016/j.gendis.2016.03.004.

46. Kim M, Ashida H, Ogawa M et al. Bacterial interactions with the host epithelium. Cell Host Microbe 2010; 8 (1): 20–35. doi: 10.1016/j.chom.2010.06.006.

47. De Rycke J, Oswald E. Cytolethal distending toxin (CDT): a bacterial weapon to control host cell proliferation? FEMS Microbiol Lett 2001; 203 (2): 141–148. doi: 10.1111/j.1574-6968.2001.tb10832.x.

48. Wu S, Lim KC, Huang J et al. Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc Natl Acad Sci USA 1998; 95 (25): 14979–14984. doi: 10.1073/pnas.95.25.14979.

49. Wu S, Morin PJ, Maouyo D et al. Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology 2003; 124 (2): 392–400. doi: 10.1053/gast.2003.50047.

50. Sears CL, Geis AL, Housseau F. Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. J Clin Invest 2014; 124 (10): 4166–4172. doi: 10.1172/JCI72334.

51. Maddocks ODK, Short AJ, Donnenberg MS et al. Attaching and effacing Escherichia coli downregulate DNA mismatch repair protein in vitro and are associated with colorectal adenocarcinomas in humans. PLoS One 2009; 4 (5): e5517. doi: 10.1371/journal.pone.0005517.

52. Cougnoux A, Dalmasso G, Martinez R et al. Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype. Gut 2014; 63 (12): 1932–1942. doi: 10.1136/gutjnl-2013-305257.

53. Wang X, Huycke MM. Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells. Gastroenterology 2007; 132 (2): 551–561. doi: 10.1053/j.gastro.2006.11. 040.

54. Wang X, Allen TD, May RJ et al. Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect. Cancer Res 2008; 68 (23): 9909–9917. doi: 10.1158/0008-5472.CAN-08-1551.

55. Attene-Ramos MS, Wagner ED, Plewa MJ et al. Evidence that hydrogen sulfide is a genotoxic agent. Mol Cancer Res 2006; 4 (1): 9–14. doi: 10.1158/1541-7786.MCR-05-0126.

56. Dejea CM, Fathi P, Craig JM et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 2018; 359 (6375): 592–597. doi: 10.1126/science.aah3648.

57. Dickson I. Colorectal cancer: Bacterial biofilms and toxins prompt a perfect storm for colon cancer. Nat Rev Gastroenterol Hepatol 2018; 15 (3): 129. doi: 10.1038/nrgastro.2018.16.

58. Kaplan CW, Lux R, Haake SK et al. The Fusobacterium nucleatum outer membrane protein RadD is an arginine-inhibitable adhesin required for inter-species adherence and the structured architecture of multispecies biofilm. Mol Microbiol 2009; 71 (1): 35–47. doi: 10.1111/j.1365-2958.2008.06503.x.

59. Li S, Konstantinov SR, Smits R et al. Bacterial biofilms in colorectal cancer initiation and progression. Trends Mol Med 2017; 23 (1): 18–30. doi: 10.1016/j.molmed.2016.11.004.

60. Johnson CH, Dejea CM, Edler D et al. Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab 2015; 21 (6): 891–897. doi: 10.1016/j.cmet.2015.04.011.

61. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61 (5): 759–767. doi: 10.1016/0092-8674 (90) 90186-i.

62. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993; 9 (4): 138–141.

63. Tjalsma H, Boleij A, Marchesi JR et al. A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects. Nat Rev Microbiol 2012; 10 (8): 575–582. doi: 10.1038/nrmicro2819.

64. Zackular JP, Rogers MA, Ruffin MT et al. The human gut microbiome as a screening tool for colorectal cancer. Cancer Prev Res 2014; 7 (11): 1112–1121. doi: 10.1158/1940-6207.CAPR-14-0129.

65. Zeller G, Tap J, Voigt AY et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol 2014; 10: 766. doi: 10.15252/msb.20145645.

66. Richman S, Adlard J. Left and right sided large bowel cancer. BMJ 2002; 324 (7343): 931–932. doi: 10.1136/bmj. 324.7343.931.

67. Hagland HR, Søreide K. Cellular metabolism in colorectal carcinogenesis: influence of lifestyle, gut microbiome and metabolic pathways. Cancer Lett 2015; 356 (2PtA): 273–280. doi: 10.1016/j.canlet.2014.02.026.

68. Gao Z, Guo B, Gao R et al. Microbiota disbiosis is associated with colorectal cancer. Front Microbiol 2015; 6: 20. doi: 10.3389/fmicb.2015.00020.

69. Richard ML, Liguori G, Lamas B et al. Mucosa-associated microbiota dysbiosis in colitis associated cancer. Gut Microbes 2018; 9 (2): 131–142. doi: 10.1080/19490976.2017.1379637.

70. Gagnière J, Bonnin V, Jarrousse AS et al. Interactions between microsatellite instability and human gut colonization by Escherichia coli in colorectal cancer. Clin Sci (Lond) 2017; 131 (6): 471–485. doi: 10.1042/CS20160876.

71. Viljoen KS, Dakshinamurthy A, Goldberg P et al. Quantitative profiling of colorectal cancer-associated bacteria reveals associations between fusobacterium spp., enterotoxigenic bacteroides fragilis (ETBF) and clinicopathological features of colorectal cancer. PLoS One 2015; 10 (3): e0119462. doi: 10.1371/journal.pone.0119462.

72. Mima K, Nishihara R, Qian ZR et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 2016; 65 (12): 1973–1980. doi: 10.1136/gutjnl-2015-310101.

73. Purcell RV, Visnovska M, Biggs PJ et al. Distinct gut microbiome patterns associate with consensus molecular subtypes of colorectal cancer. Sci Rep 2017; 7 (1): 11590. doi: 10.1038/s41598-017-11237-6.

74. Grenier D. Demonstration of a bimodal coaggregation reaction between Porphyromonas gingivalis and Treponema denticola. Oral Microbiol Immunol 1992; 7 (5): 280–284.

75. Meuric V, Martin B, Guyodo H et al. Treponema denticola improves adhesive capacities of Porphyromonas gingivalis. Mol Oral Microbiol 2013; 28 (1): 40–53. doi: 10.1111/omi.12004.

76. Han YW. Fusobacterium nucleatum: a commensal-turned pathogen. Curr Opin Microbiol 2015; 0: 141–147. doi: 10.1016/j.mib.2014.11.013.

77. Rubinstein MR, Wang X, Liu W et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/b-catenin signaling via its FadA adhesin. Cell Host Microbe 2013; 14 (2): 195–206. doi: 10.1016/j.chom.2013.07.012.

78. Allen-Vercoe E, Strauss J, Chadee K. Fusobacterium nucleatum: an emerging gut pathogen? Gut Microbes 2011; 2 (5): 294–298. doi: 10.4161/gmic.2.5.18603.

79. Krisanaprakornkit S, Kimball JR, Weinberg A et al. Inducible expression of human beta-defensin 2 by Fusobacterium nucleatum in oral epithelial cells: multiple signaling pathways and role of commensal bacteria in innate immunity and the epithelial barrier. Infect Immun 2000; 68 (5): 2907–2915. doi: 10.1128/iai.68.5.2907-2915.2000.

80. Moore RA, Warren RL, Freeman JD et al. The sensitivity of massively parallel sequencing for detecting candidate infectious agents associated with human tissue. PLoS One 2011; 6 (5): e19838. doi: 10.1371/journal.pone.0019838.

81. Strauss J, Kaplan GG, Beck PL et al. Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm Bowel Dis 2011; 17 (9): 1971–1978. doi: 10.1002/ibd.21606.

82. Mima K, Sukawa Y, Nishihara R et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol 2015; 1 (5): 653–661. doi: 10.1001/jamaoncol.2015. 1377.

83. Anand S, Kaur H, Mande SS. Comparative in silico analysis of butyrate production pathways in gut commensals and pathogens. Front Microbiol 2016; 7: 1945. doi: 10.3389/fmicb.2016.01945.

84. Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov 2015; 5 (1): 16–18. doi: 10.1158/2159-8290.CD-14-1397.

85. Bullman S, Pedamallu CS, Sicinska E et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 2017; 358 (6369): 1443–1448. doi: 10.1126/science.aal5240.

86. Cho E, Park SN, Lim YK et al. Fusobacterium hwasookii sp. nov., isolated from a human periodontitis lesion. Curr Microbiol 2015; 70 (2): 169–175. doi: 10.1007/s00284-014-0692-7.

87. Zwielehner J, Lassl C, Hippe B et al. Changes in human fecal microbiota due to chemotherapy analyzed by TaqMan-PCR, 454 sequencing and PCR-DGGE fingerprinting. PloS One 2011; 6 (12): e28654. doi: 10.1371/journal.pone.0028654.

88. Guarner F, Malagelada JR. Gut flora in health and disease. The Lancet 2003; 361 (9356): 512–519. doi: 10.1016/S0140-6736 (03) 12489-0.

89. van Vliet MJ, Tissing WJ, Dun CA et al. Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis 2009; 49 (2): 262–270. doi: 10.1086/599346.

90. Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22 (47): 7265–7279. doi: 10.1038/sj.onc.1206933.

91. Kroemer G, Galluzzi L, Kepp O et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013; 31: 51–72. doi: 10.1146/annurev-immunol-032712-100008.

92. Tedjo DI, Jonkers DM, Savelkoul PH et al. The effect of sampling and storage on the fecal microbiota composition in healthy and diseased subjects. PloS One 2015; 10 (5): e0126685. doi: 10.1371/journal.pone.0126685.

93. Mathay C, Hamot G, Henry E et al. Method optimization for fecal sample collection and fecal DNA extraction. Biopreservation Biobanking 2015; 13 (2): 79–93. doi: 10.1089/bio.2014.0031.

94. Panek M, Čipčić Paljetak H, Barešić A et al. Methodology challenges in studying human gut microbiota – effects of collection, storage, DNA extraction and next generation sequencing technologies. Sci Rep 2018; 8 (1): 5143. doi: 10.1038/s41598-018-23296-4.

95. Balamurugan R, Rajendiran E, George S et al. Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer. J Gastroenterol Hepatol 2008; 23 (8 Pt 1): 1298–1303. doi: 10.1111/j.1440-1746.2008.05490.x.

96. Sobhani I, Tap J, Roudot-Thoraval F et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PloS One 2011; 6 (1): e16393. doi: 10.1371/journal.pone.0016393.

97. Wang T, Cai G, Qiu Y et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J 2012; 6 (2): 320–329. doi: 10.1038/ismej.2011.109.

98. Chen W, Liu F, Ling Z et al. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PloS One 2012; 7 (6): e39743. doi: 10.1371/journal.pone.0039743.

99. Ahn J, Sinha R, Pei Z et al. Human gut microbiome and risk for colorectal cancer. J Natl Cancer Inst 2013; 105 (24): 1907–1911. doi: 10.1093/jnci/djt300.

100. Wu N, Yang X, Zhang R et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol 2013; 66 (2): 462–470. doi: 10.1007/s00248-013-0245-9.

101. Feng Q, Liang S, Jia H et al. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat Commun 2015; 6: 6528. doi: 10.1038/ncomms7528.

102. Yu J, Feng Q, Wong SH et al. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut 2017; 66 (1): 70–78. doi: 10.1136/gutjnl-2015-309800.

103. Marchesi JR, Dutilh BE, Hall N et al. Towards the human colorectal cancer microbiome. PloS One 2011; 6 (5): e20447. doi: 10.1371/journal.pone.0020447.

104. Nakatsu G, Li X, Zhou H et al. Gut mucosal microbiome across stages of colorectal carcinogenesis. Nat Commun 2015; 6: 8727. doi: 10.1038/ncomms9727.

105. Lu Y, Chen J, Zheng J et al. Mucosal adherent bacterial dysbiosis in patients with colorectal adenomas. Sci Rep 2016; 6: 26337. doi: 10.1038/srep26337.