Host–microbiota maladaptation in colorectal cancer

Abstract

Colorectal cancer (CRC) is a heterogeneous disease of the intestinal epithelium that is characterized by the accumulation of mutations and a dysregulated immune response. Up to 90% of disease risk is thought to be due to environmental factors such as diet, which is consistent with a growing body of literature that describes an ‘oncogenic’ CRC-associated microbiota. Whether this dysbiosis contributes to disease or merely represents a bystander effect remains unclear. To prove causation, it will be necessary to decipher which specific taxa or metabolites drive CRC biology and to fully characterize the underlying mechanisms. Here we discuss the host–microbiota interactions in CRC that have been reported so far, with particular focus on mechanisms that are linked to intestinal barrier disruption, genotoxicity and deleterious inflammation. We further comment on unknowns and on the outstanding challenges in the field, and how cutting-edge technological advances might help to overcome these. More detailed mechanistic insights into the complex CRC-associated microbiota would potentially reveal avenues that can be exploited for clinical benefit.

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Fig. 1: A schematic of the host–microbiota interactions in health and in colorectal cancer.
Fig. 2: Known inflammatory mechanisms by which the microbiota contributes to CRC.
Fig. 3: Approaches to advance the translation of microbiome-based therapeutics in CRC.

References

  1. 1.

    Keum, N. & Giovannucci, E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat. Rev. Gastroenterol. Hepatol. 16, 713–732 (2019).

    PubMed  Google Scholar 

  2. 2.

    GBD 2017 Colorectal Cancer Collaborators. The global, regional, and national burden of colorectal cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 4, 913–933 (2019).

    Google Scholar 

  3. 3.

    Lloyd-Price, J., Abu-Ali, G. & Huttenhower, C. The healthy human microbiome. Genome Med. 8, 51 (2016).

    PubMed Central  PubMed  Google Scholar 

  4. 4.

    Garrett, W. S., Gordon, J. I. & Glimcher, L. H. Homeostasis and inflammation in the intestine. Cell 140, 859–870 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  5. 5.

    Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  6. 6.

    Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

    CAS  PubMed  Google Scholar 

  7. 7.

    Gehart, H. & Clevers, H. Tales from the crypt: new insights into intestinal stem cells. Nat. Rev. Gastroenterol. Hepatol. 16, 19–34 (2019).

    PubMed  Google Scholar 

  8. 8.

    Zhou, L. & Sonnenberg, G. F. Essential immunologic orchestrators of intestinal homeostasis. Sci. Immunol. 3, eaao1605 (2018).

    PubMed Central  PubMed  Google Scholar 

  9. 9.

    Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  10. 10.

    Kinchen, J., et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell 175, 372–386.e17 (2018).

    CAS  PubMed Central  PubMed  Google Scholar 

  11. 11.

    Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    CAS  Google Scholar 

  12. 12.

    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. 10, 639–645 (2012).

    Google Scholar 

  13. 13.

    Bogaert, J. & Prenen, H. Molecular genetics of colorectal cancer. Ann. Gastroenterol. 27, 9–14 (2014).

    PubMed Central  PubMed  Google Scholar 

  14. 14.

    Wu, S., Powers, S., Zhu, W. & Hannun, Y. A. Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016).

    ADS  CAS  Google Scholar 

  15. 15.

    Nomura, A. et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N. Engl. J. Med. 325, 1132–1136 (1991).

    CAS  Google Scholar 

  16. 16.

    Parsonnet, J. et al. Helicobacter pylori infection and the risk of gastric carcinoma. N. Engl. J. Med. 325, 1127–1131 (1991).

    CAS  PubMed  Google Scholar 

  17. 17.

    Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    CAS  Google Scholar 

  18. 18.

    Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  19. 19.

    Punt, C. J., Koopman, M. & Vermeulen, L. From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat. Rev. Clin. Oncol. 14, 235–246 (2017).

    CAS  Google Scholar 

  20. 20.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. 21.

    Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).

    ADS  CAS  PubMed  Google Scholar 

  22. 22.

    Galon, J. & Bruni, D. Tumor immunology and tumor evolution: intertwined histories. Immunity 52, 55–81 (2020).

    CAS  PubMed  Google Scholar 

  23. 23.

    Canli, O. et al. Myeloid cell-derived reactive oxygen species induce epithelial mutagenesis. Cancer Cell 32, 869–883.e5 (2017).

    ADS  CAS  Google Scholar 

  24. 24.

    Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  25. 25.

    West, N. R., McCuaig, S., Franchini, F. & Powrie, F. Emerging cytokine networks in colorectal cancer. Nat. Rev. Immunol. 15, 615–629 (2015).

    CAS  PubMed  Google Scholar 

  26. 26.

    Reddy, B. S., Weisburger, J. H., Narisawa, T. & Wynder, E. L. Colon carcinogenesis in germ-free rats with 1,2-dimethylhydrazine and N-methyl-N′-nitro-N-nitrosoguanidine. Cancer Res. 34, 2368–2372 (1974).

    CAS  PubMed  Google Scholar 

  27. 27.

    Wong, S. H. et al. Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice. Gastroenterology 153, 1621–1633.e6 (2017). Faecal transplantation of stools from patients with CRC into mice illustrates a carcinogenic role of CRC-associated microbiota.

    Google Scholar 

  28. 28.

    Olesen, S. W. & Alm, E. J. Dysbiosis is not an answer. Nat. Microbiol. 1, 16228 (2016).

    CAS  Google Scholar 

  29. 29.

    Saus, E., Iraola-Guzmán, S., Willis, J. R., Brunet-Vega, A. & Gabaldón, T. Microbiome and colorectal cancer: roles in carcinogenesis and clinical potential. Mol. Aspects Med. 69, 93–106 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  30. 30.

    Wong, S. H. & Yu, J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat. Rev. Gastroenterol. Hepatol. 16, 690–704 (2019).

    CAS  Google Scholar 

  31. 31.

    Tilg, H., Adolph, T. E., Gerner, R. R. & Moschen, A. R. The intestinal microbiota in colorectal cancer. Cancer Cell 33, 954–964 (2018).

    CAS  Google Scholar 

  32. 32.

    Garrett, W. S. The gut microbiota and colon cancer. Science 364, 1133–1135 (2019).

    ADS  CAS  Google Scholar 

  33. 33.

    Ternes, D. et al. Microbiome in colorectal cancer: how to get from meta-omics to mechanism? Trends Microbiol. 28, 401–423 (2020).

    CAS  Google Scholar 

  34. 34.

    Wirbel, J. et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat. Med. 25, 679–689 (2019).

    CAS  PubMed  Google Scholar 

  35. 35.

    Yan, Y. et al. Structure of the mucosal and stool microbiome in Lynch syndrome. Cell Host Microbe 27, 585–600.e4 (2020).

    CAS  Google Scholar 

  36. 36.

    Touati, E. et al. Chronic Helicobacter pylori infections induce gastric mutations in mice. Gastroenterology 124, 1408–1419 (2003).

    CAS  Google Scholar 

  37. 37.

    Cuevas-Ramos, G. et al. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc. Natl Acad. Sci. USA 107, 11537–11542 (2010).

    ADS  CAS  Google Scholar 

  38. 38.

    Nougayrède, J. P. et al. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313, 848–851 (2006).

    ADS  Google Scholar 

  39. 39.

    Cougnoux, A. et al. Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype. Gut 63, 1932–1942 (2014).

    CAS  Google Scholar 

  40. 40.

    Goodwin, A. C. et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl Acad. Sci. USA 108, 15354–15359 (2011).

    ADS  CAS  Google Scholar 

  41. 41.

    Wang, X. et al. Enterococcus faecalis induces aneuploidy and tetraploidy in colonic epithelial cells through a bystander effect. Cancer Res. 68, 9909–9917 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. 42.

    He, Z. et al. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut 68, 289–300 (2019).

    CAS  Google Scholar 

  43. 43.

    Tomkovich, S. et al. Locoregional effects of microbiota in a preclinical model of colon carcinogenesis. Cancer Res. 77, 2620–2632 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  44. 44.

    Cougnoux, A. et al. Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria. Gut 65, 278–285 (2016).

    CAS  Google Scholar 

  45. 45.

    Lucas, C. et al. Autophagy of intestinal epithelial cells inhibits colorectal carcinogenesis induced by colibactin-producing Escherichia coli in Apc Min/+ mice. Gastroenterology 158, 1373–1388 (2020).

    CAS  Google Scholar 

  46. 46.

    Pleguezuelos-Manzano, C. et al. Mutational signature in colorectal cancer caused by genotoxic pks + E. coli. Nature 580, 269–273 (2020). This pioneering study provides direct evidence of causality between pks + E. coli and established CRC driver mutations.

    ADS  CAS  Google Scholar 

  47. 47.

    Wang, X., Yang, Y. & Huycke, M. M. Commensal bacteria drive endogenous transformation and tumour stem cell marker expression through a bystander effect. Gut 64, 459–468 (2015).

    CAS  Google Scholar 

  48. 48.

    Irrazabal, T. et al. Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer. Nat. Commun. 11, 1802 (2020).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  49. 49.

    Veziant, J. et al. Association of colorectal cancer with pathogenic Escherichia coli: focus on mechanisms using optical imaging. World J. Clin. Oncol. 7, 293–301 (2016).

    PubMed Central  PubMed  Google Scholar 

  50. 50.

    Zhu, W. et al. Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer. J. Exp. Med. 216, 2378–2393 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  51. 51.

    Gaines, S. et al. Western diet promotes intestinal colonization by collagenolytic microbes and promotes tumor formation after colorectal surgery. Gastroenterology, 158, 958–970 (2020).

    CAS  PubMed  Google Scholar 

  52. 52.

    Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  53. 53.

    De Almeida, C. V., de Camargo, M. R., Russo, E. & Amedei, A. Role of diet and gut microbiota on colorectal cancer immunomodulation. World J. Gastroenterol. 25, 151–162 (2019).

    PubMed Central  PubMed  Google Scholar 

  54. 54.

    Nguyen, L. H. et al. Association between sulfur-metabolizing bacterial communities in stool and risk of distal colorectal cancer in men. Gastroenterology 158, 1313–1325 (2020).

    CAS  PubMed  Google Scholar 

  55. 55.

    Yachida, S. et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nat. Med. 25, 968–976 (2019).

    CAS  PubMed  Google Scholar 

  56. 56.

    Long, S. et al. Metaproteomics characterizes human gut microbiome function in colorectal cancer. NPJ Biofilms Microbiomes 6, 14 (2020).

    ADS  PubMed Central  PubMed  Google Scholar 

  57. 57.

    Kawalek, J. C., Hallmark, R. K. & Andrews, A. W. Effect of lithocholic acid on the mutagenicity of some substituted aromatic amines. J. Natl Cancer Inst. 71, 293–298 (1983).

    CAS  PubMed  Google Scholar 

  58. 58.

    Shibuya, N. et al. Co-mutagenicity of glyco- and tauro-deoxycholic acids in the Ames test. Mutat. Res. 395, 1–7 (1997).

    CAS  PubMed  Google Scholar 

  59. 59.

    Lavoie, S. et al. Expression of FFAR2 by dendritic cells prevents their expression of IL27 and is required for maintenance of mucosal barrier and immune response against colorectal tumors in mice. Gastroenterology 158, 1359–1372.e9 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  60. 60.

    Liu, T. et al. High-fat diet-induced dysbiosis mediates MCP-1/CCR2 axis-dependent M2 macrophage polarization and promotes intestinal adenoma-adenocarcinoma sequence. J. Cell. Mol. Med. 24, 2648–2662 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  61. 61.

    Denison, M. S. & Nagy, S. R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43, 309–334 (2003).

    CAS  PubMed  Google Scholar 

  62. 62.

    Metidji, A. et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 49, 353–362 (2018).

    CAS  PubMed Central  PubMed  Google Scholar 

  63. 63.

    Chang, P. V., Hao, L., Offermanns, S. & Medzhitov, R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl Acad. Sci. USA 111, 2247–2252 (2014).

    ADS  CAS  PubMed  Google Scholar 

  64. 64.

    Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50, 432–445.e7 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  65. 65.

    Zagato, E. et al. Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth. Nat. Microbiol. 5, 511–524 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  66. 66.

    Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  67. 67.

    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).

    CAS  PubMed Central  PubMed  Google Scholar 

  68. 68.

    Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  69. 69.

    Belcheva, A. et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 158, 288–299 (2014).

    CAS  PubMed  Google Scholar 

  70. 70.

    Uronis, J. M. et al. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS ONE 4, e6026 (2009).

    ADS  PubMed Central  PubMed  Google Scholar 

  71. 71.

    Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. 72.

    Chen, G. Y., Shaw, M. H., Redondo, G. & Núñez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 68, 10060–10067 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. 73.

    Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  74. 74.

    Dejea, C. M. et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc. Natl Acad. Sci. USA 111, 18321–18326 (2014).

    ADS  CAS  PubMed  Google Scholar 

  75. 75.

    Drewes, J. L. et al. High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia. NPJ Biofilms Microbiomes 3, 34 (2017).

    PubMed Central  PubMed  Google Scholar 

  76. 76.

    Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  77. 77.

    Tomkovich, S. et al. Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic. J. Clin. Invest. 129, 1699–1712 (2019).

    PubMed Central  PubMed  Google Scholar 

  78. 78.

    Domingue, J. C., Drewes, J. L., Merlo, C. A., Housseau, F. & Sears, C. L. Host responses to mucosal biofilms in the lung and gut. Mucosal Immunol. 13, 413–422 (2020).

    CAS  PubMed  Google Scholar 

  79. 79.

    Hu, B. et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc. Natl Acad. Sci. USA 110, 9862–9867 (2013).

    ADS  CAS  PubMed  Google Scholar 

  80. 80.

    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).

    CAS  PubMed Central  PubMed  Google Scholar 

  81. 81.

    Wu, P. et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity 40, 785–800 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  82. 82.

    Zackular, J. P. et al. The gut microbiome modulates colon tumorigenesis. MBio 4, e00692-13 (2013).

    PubMed Central  PubMed  Google Scholar 

  83. 83.

    Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  84. 84.

    Dmitrieva-Posocco, O. et al. Cell-type-specific responses to interleukin-1 control microbial invasion and tumor-elicited inflammation in colorectal cancer. Immunity 50, 166–180.e7 (2019). Using mouse models, this study highlights how cell-type-specific cytokine responses differentially influence tumorigenesis.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 85.

    Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  86. 86.

    Busbee, P. B. et al. Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22-dependent manner. JCI Insight 5, e127551 (2020).

    PubMed Central  Google Scholar 

  87. 87.

    Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  88. 88.

    Hernandez, P., Gronke, K. & Diefenbach, A. A catch-22: interleukin-22 and cancer. Eur. J. Immunol. 48, 15–31 (2018).

    CAS  PubMed  Google Scholar 

  89. 89.

    Gronke, K. et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 566, 249–253 (2019). This study shows how dietary stimuli mediates IL-22 signalling, which can in turn protect stem cells from genotoxic stress.

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  90. 90.

    Perez, L. G. et al. TGF-β signaling in TH17 cells promotes IL-22 production and colitis-associated colon cancer. Nat. Commun. 11, 2608 (2020).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  91. 91.

    Lloyd-Price, J. et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569, 655–662 (2019).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  92. 92.

    Arthur, J. C. et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338, 120–123 (2012).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  93. 93.

    Arthur, J. C. et al. Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer. Nat. Commun. 5, 4724 (2014).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  94. 94.

    Dennis, K. L. et al. Adenomatous polyps are driven by microbe-instigated focal inflammation and are controlled by IL-10-producing T cells. Cancer Res. 73, 5905–5913 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  95. 95.

    Moschen, A. R. et al. Lipocalin 2 protects from inflammation and tumorigenesis associated with gut microbiota alterations. Cell Host Microbe 19, 455–469 (2016).

    CAS  Google Scholar 

  96. 96.

    Feng, Q. et al. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat. Commun. 6, 6528 (2015).

    ADS  CAS  Google Scholar 

  97. 97.

    Chen, D. et al. Clostridium butyricum, a butyrate-producing probiotic, inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota. Cancer Lett. 469, 456–467 (2020).

    CAS  Google Scholar 

  98. 98.

    Malik, A. et al. IL-33 regulates the IgA-microbiota axis to restrain IL-1α-dependent colitis and tumorigenesis. J. Clin. Invest. 126, 4469–4481 (2016).

    PubMed Central  PubMed  Google Scholar 

  99. 99.

    Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726–1729 (2002).

    ADS  CAS  PubMed  Google Scholar 

  100. 100.

    Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353.e21 (2016). Using a gnotobiotic mouse model, this study correlates a low-fibre diet to the expansion of a mucus-degrading bacteria and aggressive colitis.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. 101.

    Seregin, S. S. et al. NLRP6 protects Il10 −/− mice from colitis by limiting colonization of Akkermansia muciniphila. Cell Rep. 19, 733–745 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. 102.

    Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  103. 103.

    Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625–1636 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  104. 104.

    Cremonesi, E. et al. Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut 67, 1984–1994 (2018).

    CAS  Google Scholar 

  105. 105.

    Lévy, J. et al. Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth. Nat. Cell Biol. 17, 1062–1073 (2015).

    Google Scholar 

  106. 106.

    Yu, A. I. et al. Gut microbiota modulate CD8 T cell responses to influence colitis-associated tumorigenesis. Cell Rep. 31, 107471 (2020).

    CAS  Google Scholar 

  107. 107.

    Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).

    CAS  Google Scholar 

  108. 108.

    Thiele Orberg, E. et al. The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis. Mucosal Immunol. 10, 421–433 (2017).

    CAS  Google Scholar 

  109. 109.

    Chung, L. et al. Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe 23, 203–214.e5 (2018). In this study, it is shown that enterotoxic B. fragilis creates a pro-tumorigenic environment in the distal colon by driving locally restricted chemokine expression in mice.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. 110.

    James, K. R. et al. Distinct microbial and immune niches of the human colon. Nat. Immunol. 21, 343–353 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  111. 111.

    Kim, J. M., Oh, Y. K., Kim, Y. J., Oh, H. B. & Cho, Y. J. Polarized secretion of CXC chemokines by human intestinal epithelial cells in response to Bacteroides fragilis enterotoxin: NF-κB plays a major role in the regulation of IL-8 expression. Clin. Exp. Immunol. 123, 421–427 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  112. 112.

    Sanfilippo, L. et al. Bacteroides fragilis enterotoxin induces the expression of IL-8 and transforming growth factor-beta (TGF-β) by human colonic epithelial cells. Clin. Exp. Immunol. 119, 456–463 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  113. 113.

    Zhang, Y., Weng, Y., Gan, H., Zhao, X. & Zhi, F. Streptococcus gallolyticus conspires myeloid cells to promote tumorigenesis of inflammatory bowel disease. Biochem. Biophys. Res. Commun. 506, 907–911 (2018).

    CAS  PubMed  Google Scholar 

  114. 114.

    Kostic, A. D. et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14, 207–215 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  115. 115.

    Long, X. et al. Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity. Nat. Microbiol. 4, 2319–2330 (2019).

    PubMed  Google Scholar 

  116. 116.

    Gur, C. et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42, 344–355 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  117. 117.

    Tuveson, D. & Clevers, H. Cancer modeling meets human organoid technology. Science 364, 952–955 (2019).

    ADS  CAS  PubMed  Google Scholar 

  118. 118.

    Co, J. Y. et al. Controlling epithelial polarity: a human enteroid model for host–pathogen interactions. Cell Rep26, 2509–2520.e4 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  119. 119.

    Dutta, D. & Clevers, H. Organoid culture systems to study host–pathogen interactions. Curr. Opin. Immunol. 48, 15–22 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  120. 120.

    Qin, X. et al. Cell-type-specific signaling networks in heterocellular organoids. Nat. Methods 17, 335–342 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. 121.

    Zhang, B. et al. Advances in organ-on-a-chip engineering. Nat. Rev. Mater. 3, 257–278 (2018).

    ADS  Google Scholar 

  122. 122.

    Greenhalgh, K. et al. Integrated in vitro and in silico modeling delineates the molecular effects of a synbiotic regimen on colorectal-cancer-derived cells. Cell Rep. 27, 1621–1632 (2019).

    CAS  PubMed  Google Scholar 

  123. 123.

    Jalili-Firoozinezhad, S. et al. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat. Biomed. Eng. 3, 520–531 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  124. 124.

    Romano, G., Chagani, S. & Kwong, L. N. The path to metastatic mouse models of colorectal cancer. Oncogene 37, 2481–2489 (2018).

    CAS  PubMed  Google Scholar 

  125. 125.

    Fumagalli, A. et al. A surgical orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression. Nat. Protoc. 13, 235–247 (2018).

    CAS  PubMed  Google Scholar 

  126. 126.

    Rosshart, S. P. et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell 171, 1015–1028.e13 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  127. 127.

    Rosshart, S. P. et al. Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science 365, eaaw4361 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  128. 128.

    Jackstadt, R. et al. Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell 36, 319–336.e7 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. 129.

    Bullman, S. et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 358, 1443–1448 (2017).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  130. 130.

    Laukens, D., Brinkman, B. M., Raes, J., De Vos, M. & Vandenabeele, P. Heterogeneity of the gut microbiome in mice: guidelines for optimizing experimental design. FEMS Microbiol. Rev. 40, 117–132 (2016).

    CAS  PubMed  Google Scholar 

  131. 131.

    Zhan, Y. et al. Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. Cancer Res. 73, 7199–7210 (2013).

    CAS  PubMed  Google Scholar 

  132. 132.

    Kennedy, E. A., King, K. Y. & Baldridge, M. T. Mouse microbiota models: comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria. Front. Physiol. 9, 1534 (2018).

    PubMed Central  PubMed  Google Scholar 

  133. 133.

    Coker, O. O. et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut 68, 654–662 (2019).

    CAS  PubMed  Google Scholar 

  134. 134.

    Coker, O. O., Wu, W. K. K., Wong, S. H., Sung, J. J. & Yu, J. Altered gut archaea composition and interaction with bacteria are associated with colorectal cancer. Gastroenterology https://doi.org/10.1053/j.gastro.2020.06.042 (2020).

  135. 135.

    Nakatsu, G. et al. Alterations in enteric virome are associated with colorectal cancer and survival outcomes. Gastroenterology 155, 529–541.e5 (2018).

    PubMed  Google Scholar 

  136. 136.

    Malik, A. et al. SYK–CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer. Immunity 49, 515–530.e5 (2018). This study shows that fungal signalling via the Syk–CARD9 pathway promotes IL-18 maturation and CRC protection.

    CAS  PubMed Central  PubMed  Google Scholar 

  137. 137.

    Allen-Vercoe, E., Strauss, J. & Chadee, K. Fusobacterium nucleatum: an emerging gut pathogen? Gut Microbes 2, 294–298 (2011).

    PubMed  Google Scholar 

  138. 138.

    McGuire, A. M. et al. Evolution of invasion in a diverse set of Fusobacterium species. MBio 5, e01864-14 (2014).

    CAS  Google Scholar 

  139. 139.

    Kasper, S. H. et al. Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment. Sci. Rep. 10, 5321 (2020). This study shows that viable and heat-inactivated F. nucleatum induce different gene-expression profiles in three-dimensional tumour spheroids.

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  140. 140.

    Ridlon, J. M., Kang, D. J., Hylemon, P. B. & Bajaj, J. S. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30, 332–338 (2014).

    PubMed Central  PubMed  Google Scholar 

  141. 141.

    Narayanasamy, S. et al. IMP: a pipeline for reproducible reference-independent integrated metagenomic and metatranscriptomic analyses. Genome Biol. 17, 260 (2016).

    PubMed Central  PubMed  Google Scholar 

  142. 142.

    Yimagou, E. K. et al. Full-repertoire comparison of the microscopic objects composing the human gut microbiome with sequenced and cultured communities. J. Microbiol. 58, 377–386 (2020).

    CAS  PubMed  Google Scholar 

  143. 143.

    Bauer, E. & Thiele, I. From metagenomic data to personalized in silico microbiotas: predicting dietary supplements for Crohn’s disease. NPJ Syst. Biol. Appl. 4, 27 (2018).

    PubMed Central  PubMed  Google Scholar 

  144. 144.

    Tropini, C., Earle, K. A., Huang, K. C. & Sonnenburg, J. L. The gut microbiome: connecting spatial organization to function. Cell Host Microbe 21, 433–442 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  145. 145.

    Pacheco, M. P. & Sauter, T. The FASTCORE family: for the fast reconstruction of compact context-specific metabolic networks models. Methods Mol. Biol. 1716, 101–110 (2018).

    CAS  PubMed  Google Scholar 

  146. 146.

    Sobhani, I. et al. Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proc. Natl Acad. Sci. USA 116, 24285–24295 (2019).

    CAS  PubMed  Google Scholar 

  147. 147.

    Wang, Q. et al. Multi-omic profiling reveals associations between the gut mucosal microbiome, the metabolome, and host DNA methylation associated gene expression in patients with colorectal cancer. BMC Microbiol. 20, 83 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  148. 148.

    Kim, D. J. et al. Colorectal cancer diagnostic model utilizing metagenomic and metabolomic data of stool microbial extracellular vesicles. Sci. Rep. 10, 2860 (2020).

    ADS  CAS  PubMed Central  PubMed  Google Scholar 

  149. 149.

    Zheng, D. W. et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat. Biomed. Eng. 3, 717–728 (2019).

    ADS  CAS  PubMed  Google Scholar 

  150. 150.

    Fong, W., Li, Q. & Yu, J. Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene 39, 4925–4943 (2020).

    CAS  PubMed Central  PubMed  Google Scholar 

  151. 151.

    McCuaig, S. et al. The interleukin 22 pathway interacts with mutant KRAS to promote poor prognosis in colon cancer. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-1086 (2020).

  152. 152.

    Heintz-Buschart, A. & Wilmes, P. Human gut microbiome: function matters. Trends Microbiol. 26, 563–574 (2018).

    CAS  PubMed  Google Scholar 

  153. 153.

    Schirmer, M., Garner, A., Vlamakis, H. & Xavier, R. J. Microbial genes and pathways in inflammatory bowel disease. Nat. Rev. Microbiol. 17, 497–511 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

We thanks N. Ilott for conceiving and generating Fig. 1, as well as M. Friedrich, T. Griseri, S. Leedham, C. Pearson and M. Pohin for their input after reading the manuscript. This work was supported by the Cancer Research UK (CRUK) grant OPTIMISTICC (C10674/A27140). A.J. has received support from the Oxford–Medical Research Council Doctoral Training Partnership (MRC DTP) and the Kennedy Trust for Rheumatology Research. E.H.M. is supported by an MRC Experimental Medicine Grant (MR/N02690X/1).

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A.J. reviewed the literature and designed Figs. 2 and 3. A.J. and E.H.M. contributed equally to the writing of this manuscript. A.J., F.P. and E.H.M. discussed the content and edited the manuscript.

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Correspondence to Fiona Powrie.

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F.P. discloses the receipt of grants and research support from Roche and Janssen, and consulting fees from GSK, Genentech and Kintai Therapeutics.

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Janney, A., Powrie, F. & Mann, E.H. Host–microbiota maladaptation in colorectal cancer. Nature 585, 509–517 (2020). https://doi.org/10.1038/s41586-020-2729-3

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