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Fusobacterium nucleatum — symbiont, opportunist and oncobacterium

Abstract

Fusobacterium nucleatum has long been found to cause opportunistic infections and has recently been implicated in colorectal cancer; however, it is a common member of the oral microbiota and can have a symbiotic relationship with its hosts. To address this dissonance, we explore the diversity and niches of fusobacteria and reconsider historic fusobacterial taxonomy in the context of current technology. We also undertake a critical reappraisal of fusobacteria with a focus on F. nucleatum as a mutualist, infectious agent and oncogenic microorganism. In this Review, we delve into recent insights and future directions for fusobacterial research, including the current genetic toolkit, our evolving understanding of its mechanistic role in promoting colorectal cancer and the challenges of developing diagnostics and therapeutics for F. nucleatum.

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Fig. 1: The organizing role of Fusobacterium nucleatum in oral biofilms.
Fig. 2: Oral and extraoral diseases associated with Fusobacterium nucleatum.
Fig. 3: Mechanisms by which Fusobacterium nucleatum may contribute to colorectal carcinogenesis.

References

  1. 1.

    Hug, L. A. et al. A new view of the tree of life. Nat. Microbiol. 1, 16048 (2016).

    CAS  PubMed  Google Scholar 

  2. 2.

    Parks, D. H. et al. Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life. Nat. Microbiol. 2, 1533–1542 (2017).

    CAS  PubMed  Google Scholar 

  3. 3.

    Zhao, J.-S., Manno, D. & Hawari, J. Psychrilyobacter atlanticus gen. nov., sp. nov., a marine member of the phylum Fusobacteria that produces H2 and degrades nitramine explosives under low temperature conditions. Int. J. Syst. Evol. Microbiol. 59, 491–497 (2009).

    CAS  PubMed  Google Scholar 

  4. 4.

    Kolenbrander, P. E., Palmer, R. J., Periasamy, S. & Jakubovics, N. S. Oral multispecies biofilm development and the key role of cell-cell distance. Nat. Rev. Microbiol. 8, 471–480 (2010).

    CAS  PubMed  Google Scholar 

  5. 5.

    Lancy, P., Dirienzo, J. M., Appelbaum, B., Rosan, B. & Holt, S. C. Corncob formation between Fusobacterium nucleatum and Streptococcus sanguis. Infect. Immun. 40, 303–309 (1983).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Guo, L., Shokeen, B., He, X., Shi, W. & Lux, R. Streptococcus mutans SpaP binds to RadD of Fusobacterium nucleatum ssp. polymorphum. Mol. Oral Microbiol. 32, 355–364 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kaplan, C. W., Lux, R., Haake, S. K. & Shi, W. 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. 71, 35–47 (2009).

    CAS  PubMed  Google Scholar 

  8. 8.

    Wu, T. et al. Cellular components mediating coadherence of Candida albicans and Fusobacterium nucleatum. J. Dent. Res. 94, 1432–1438 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Manson McGuire, A. et al. Evolution of invasion in a diverse set of Fusobacterium species. MBio 5, e01864 (2014). This publication is a comparative genomic analysis of sequenced Fusobacterium species focused on potential mechanisms of molecular pathogenesis.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Zanzoni, A., Spinelli, L., Braham, S. & Brun, C. Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins. Microbiome 5, 89 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Tan, K. H. et al. Porphyromonas gingivalis and Treponema denticola exhibit metabolic symbioses. PLOS Pathog. 10, e1003955 (2014).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Sakanaka, A., Kuboniwa, M., Takeuchi, H., Hashino, E. & Amano, A. Arginine-ornithine antiporter ArcD controls arginine metabolism and interspecies biofilm development of Streptococcus gordonii. J. Biol. Chem. 290, 21185–21198 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Hendrickson, E. L. et al. Proteomics of Fusobacterium nucleatum within a model developing oral microbial community. Microbiologyopen 3, 729–751 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Mark Welch, J. L., Rossetti, B. J., Rieken, C. W., Dewhirst, F. E. & Borisy, G. G. Biogeography of a human oral microbiome at the micron scale. Proc. Natl Acad. Sci. USA 113, E791–E800 (2016). This publication is a technical re-exploration of the spatial organization of the microbiota in the oral cavity, revealing new layers of complexity.

    CAS  PubMed  Google Scholar 

  15. 15.

    Krisanaprakornkit, S. 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. 68, 2907–2915 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Ahn, S.-H. et al. Transcriptome profiling analysis of senescent gingival fibroblasts in response to Fusobacterium nucleatum infection. PLOS ONE 12, e0188755 (2017).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Bhattacharyya, S. et al. FAD-I, a Fusobacterium nucleatum cell wall-associated diacylated lipoprotein that mediates human beta defensin 2 induction through Toll-like receptor-1/2 (TLR-1/2) and TLR-2/6. Infect. Immun. 84, 1446–1456 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Gallimidi, A. B. et al. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget 6, 22613–22623 (2015).

    PubMed Central  Google Scholar 

  19. 19.

    Park, S.-R. et al. Diverse Toll-like receptors mediate cytokine production by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in macrophages. Infect. Immun. 82, 1914–1920 (2014).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Taxman, D. J. et al. Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis. J. Biol. Chem. 287, 32791–32799 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Saito, A. et al. Porphyromonas gingivalis entry into gingival epithelial cells modulated by Fusobacterium nucleatum is dependent on lipid rafts. Microb. Pathog. 53, 234–242 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Metzger, Z. et al. Synergistic pathogenicity of Porphyromonas gingivalis and Fusobacterium nucleatum in the mouse subcutaneous chamber model. J. Endod. 35, 86–94 (2009).

    PubMed  Google Scholar 

  23. 23.

    Swidsinski, A. et al. Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/necrophorum. Gut 60, 34–40 (2011).

    PubMed  Google Scholar 

  24. 24.

    Han, X. Y. et al. Fusobacterial brain abscess: a review of five cases and an analysis of possible pathogenesis. J. Neurosurg. 99, 693–700 (2003).

    PubMed  Google Scholar 

  25. 25.

    Gregory, S. W., Boyce, T. G., Larson, A. N., Patel, R. & Jackson, M. A. Fusobacterium nucleatum osteomyelitis in 3 previously healthy children: a case series and review of the literature. J. Pediatr. Infect. Dis. Soc. 4, e155–e159 (2015).

    Google Scholar 

  26. 26.

    Truant, A. L., Menge, S., Milliorn, K., Lairscey, R. & Kelly, M. T. Fusobacterium nucleatum pericarditis. J. Clin. Microbiol. 17, 349–351 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Altshuler, G. & Hyde, S. Clinicopathologic considerations of fusobacteria chorioamnionitis. Acta Obstet. Gynecol. Scand. 67, 513–517 (1988).

    CAS  PubMed  Google Scholar 

  28. 28.

    Tjalsma, H., Boleij, A., Marchesi, J. R. & Dutilh, B. E. A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects. Nat. Rev. Microbiol. 10, 575–582 (2012).

    CAS  PubMed  Google Scholar 

  29. 29.

    Strauss, J. et al. Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm. Bowel Dis. 17, 1971–1978 (2011).

    PubMed  Google Scholar 

  30. 30.

    Ikegami, A., Chung, P. & Han, Y. W. Complementation of the fadA mutation in Fusobacterium nucleatum demonstrates that the surface-exposed adhesin promotes cellular invasion and placental colonization. Infect. Immun. 77, 3075–3079 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Han, Y. W. et al. Interactions between periodontal bacteria and human oral epithelial cells: Fusobacterium nucleatum adheres to and invades epithelial cells. Infect. Immun. 68, 3140–3146 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kinder Haake, S. & Lindemann, R. A. Fusobacterium nucleatum T18 aggregates human mononuclear cells and inhibits their PHA-stimulated proliferation. J. Periodontol. 68, 39–44 (1997).

    CAS  PubMed  Google Scholar 

  33. 33.

    Gursoy, U. K., Könönen, E. & Uitto, V.-J. Intracellular replication of fusobacteria requires new actin filament formation of epithelial cells. APMIS 116, 1063–1070 (2008).

    PubMed  Google Scholar 

  34. 34.

    Weiss, E. I. et al. Attachment of Fusobacterium nucleatum PK1594 to mammalian cells and its coaggregation with periodontopathogenic bacteria are mediated by the same galactose-binding adhesin. Oral Microbiol. Immunol. 15, 371–377 (2000).

    CAS  PubMed  Google Scholar 

  35. 35.

    Han, Y. W. et al. Fusobacterium nucleatum induces premature and term stillbirths in pregnant mice: implication of oral bacteria in preterm birth. Infect. Immun. 72, 2272–2279 (2004). This publication provides evidence in a preclinical model to support the association of fusobacteria with adverse pregnancy outcomes in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Xu, M. et al. FadA from Fusobacterium nucleatum utilizes both secreted and nonsecreted forms for functional oligomerization for attachment and invasion of host cells. J. Biol. Chem. 282, 25000–25009 (2007).

    CAS  PubMed  Google Scholar 

  37. 37.

    Fardini, Y. et al. Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity. Mol. Microbiol. 82, 1468–1480 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl Med. 6, 237ra65 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Hatakeyama, M. Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis. Cell Host Microbe 15, 306–316 (2014).

    CAS  PubMed  Google Scholar 

  40. 40.

    Kostic, A. D. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Castellarin, M. et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 22, 299–306 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Pascal, V. et al. A microbial signature for Crohn’s disease. Gut 66, 813–822 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    McCoy, A. N. et al. Fusobacterium is associated with colorectal adenomas. PLOS ONE 8, e53653 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    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  PubMed Central  Google Scholar 

  46. 46.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

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

    CAS  PubMed  Google Scholar 

  48. 48.

    Yu, J. et al. Invasive Fusobacterium nucleatum may play a role in the carcinogenesis of proximal colon cancer through the serrated neoplasia pathway. Int. J. Cancer 139, 1318–1326 (2016).

    CAS  PubMed  Google Scholar 

  49. 49.

    Li, Y.-Y. et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J. Gastroenterol. 22, 3227–3233 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Al-Hebshi, N. N. et al. Inflammatory bacteriome featuring Fusobacterium nucleatum and Pseudomonas aeruginosa identified in association with oral squamous cell carcinoma. Sci. Rep. 7, 1834 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zhao, H. et al. Variations in oral microbiota associated with oral cancer. Sci. Rep. 7, 11773 (2017).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Audirac-Chalifour, A. et al. Cervical microbiome and cytokine profile at various stages of cervical cancer: a pilot study. PLOS ONE 11, e0153274 (2016).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Hsieh, Y.-Y. et al. Increased abundance of Clostridium and Fusobacterium in gastric microbiota of patients with gastric cancer in Taiwan. Sci. Rep. 8, 158 (2018).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Yamamura, K. et al. Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin. Cancer Res. 22, 5574–5581 (2016).

    CAS  PubMed  Google Scholar 

  55. 55.

    Warren, R. L. et al. Co-occurrence of anaerobic bacteria in colorectal carcinomas. Microbiome 1, 16 (2013).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

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

    CAS  PubMed  Google Scholar 

  57. 57.

    Guo, S. et al. A simple and novel fecal biomarker for colorectal cancer: ratio of Fusobacterium nucleatum to probiotics populations, based on their antagonistic effect. Clin. Chem. 64, 1327–1337 (2018).

    PubMed  Google Scholar 

  58. 58.

    Mima, K. et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 65, 1973–1980 (2015). This molecular epidemiology study highlights the association of tumoural fusobacterial levels with worse prognosis in colorectal cancer.

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Yu, T. et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170, 548–563 (2017). This work explores the links between fusobacteria, colon cancer and autophagy, suggesting that fusobacteria may confer chemoresistance in colon cancers.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Tahara, T. et al. Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res. 74, 1311–1318 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ito, M. et al. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. Int. J. Cancer 137, 1258–1268 (2015).

    CAS  PubMed  Google Scholar 

  62. 62.

    Mima, K. et al. Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location. Clin. Transl Gastroenterol. 7, e200 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Mima, K. et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 1, 653–661 (2015).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Mehta, R. S. et al. Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol. 3, 921–927 (2017).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Liu, L. et al. Diets that promote colon inflammation associate with risk of colorectal carcinomas that contain Fusobacterium nucleatum. Clin. Gastroenterol. Hepatol. 16, 1622–1631 (2018).

    PubMed  Google Scholar 

  66. 66.

    Komiya, Y. et al. Patients with colorectal cancer have identical strains of Fusobacterium nucleatum in their colorectal cancer and oral cavity. Gut https://doi.org/10.1136/gutjnl-2018-316661 (2018).

    Article  PubMed  Google Scholar 

  67. 67.

    Yang, G. Y. & Shamsuddin, A. M. Gal-GalNAc: a biomarker of colon carcinogenesis. Histol. Histopathol. 11, 801–806 (1996).

    CAS  PubMed  Google Scholar 

  68. 68.

    Coppenhagen-Glazer, S. et al. Fap2 of Fusobacterium nucleatum is a galactose-inhibitable adhesin involved in coaggregation, cell adhesion, and preterm birth. Infect. Immun. 83, 1104–1113 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Abed, J. et al. Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe 20, 215–225 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Carroll, G. C. & Sebor, R. J. Dental flossing and its relationship to transient bacteremia. J. Periodontol. 51, 691–692 (1980).

    CAS  PubMed  Google Scholar 

  71. 71.

    Lockhart, P. B. et al. Bacteremia associated with toothbrushing and dental extraction. Circulation 117, 3118–3125 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992).

    CAS  PubMed  Google Scholar 

  73. 73.

    Moser, A. R., Pitot, H. C. & Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324 (1990).

    CAS  Google Scholar 

  74. 74.

    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  PubMed Central  Google Scholar 

  75. 75.

    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  PubMed Central  Google Scholar 

  76. 76.

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

    CAS  Google Scholar 

  77. 77.

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

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Sanders, B. E., Umana, A., Lemkul, J. A. & Slade, D. J. FusoPortal: an interactive repository of hybrid MinION-sequenced fusobacterium genomes improves gene identification and characterization. mSphere 3, 284 (2018).

    Google Scholar 

  79. 79.

    Rubinstein, M. R. et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 14, 195–206 (2013). This publication and reference 74 are seminal papers supporting that fusobacteria potentiate colonic tumorigenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    White, B. D., Chien, A. J. & Dawson, D. W. Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. Gastroenterology 142, 219–232 (2012).

    CAS  PubMed  Google Scholar 

  81. 81.

    Dougall, W. C., Kurtulus, S., Smyth, M. J. & Anderson, A. C. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol. Rev. 276, 112–120 (2017).

    CAS  PubMed  Google Scholar 

  82. 82.

    Wang, H.-F. et al. Evaluation of antibody level against Fusobacterium nucleatum in the serological diagnosis of colorectal cancer. Sci. Rep. 6, 33440 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Wu, Y. et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis in mice via a Toll-like receptor 4/p21-activated kinase 1 cascade. Dig. Dis. Sci. 63, 1210–1218 (2018).

    CAS  PubMed  Google Scholar 

  85. 85.

    Routy, B. et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 15, 382–396 (2018).

    CAS  PubMed  Google Scholar 

  86. 86.

    Bennett, J. E., Dolin, R. & Blaser, M. J. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Disease (Elsevier Health Sciences, 2014).

  87. 87.

    Liu, P.-F., Huang, I.-F., Shu, C.-W. & Huang, C.-M. Halitosis vaccines targeting FomA, a biofilm-bridging protein of fusobacteria nucleatum. Curr. Mol. Med. 13, 1358–1367 (2013).

    CAS  PubMed  Google Scholar 

  88. 88.

    Guo, S.-H. et al. Immunization with alkyl hydroperoxide reductase subunit C reduces Fusobacterium nucleatum load in the intestinal tract. Sci. Rep. 7, 10566 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Petrof, E. O., Claud, E. C., Gloor, G. B. & Allen-Vercoe, E. Microbial ecosystems therapeutics: a new paradigm in medicine? Benef. Microbes 4, 53–65 (2013).

    CAS  PubMed  Google Scholar 

  90. 90.

    Blaser, M. J. Helicobacter pylori and esophageal disease: wake-up call? Gastroenterology 139, 1819–1822 (2010).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Blaser, M. J. Helicobacter pylori eradication and its implications for the future. Aliment. Pharmacol. Ther. 11 (Suppl. 1), 103–107 (1997).

    PubMed  Google Scholar 

  92. 92.

    O’Keefe, S. J. D. et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat. Commun. 6, 6342 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Duncan, S. H., Hold, G. L., Harmsen, H. J. M., Stewart, C. S. & Flint, H. J. Growth requirements and fermentation products of Fusobacterium prausnitzii, and a proposal to reclassify it as Faecalibacterium prausnitzii gen. nov., comb. nov. Int. J. Syst. Evol. Microbiol. 52, 2141–2146 (2002).

    CAS  PubMed  Google Scholar 

  94. 94.

    Jalava, J. & Eerola, E. Phylogenetic analysis of Fusobacterium alocis and Fusobacterium sulci based on 16S rRNA gene sequences: proposal of Filifactor alocis (Cato, Moore and Moore) comb. nov. and Eubacterium sulci (Cato, Moore and Moore) comb. nov. Int. J. Syst. Bacteriol. 49, 1375–1379 (1999).

    CAS  PubMed  Google Scholar 

  95. 95.

    Todd, S. M., Settlage, R. E., Lahmers, K. K. & Slade, D. J. Fusobacterium genomics using MinION and illumina sequencing enables genome completion and correction. mSphere 3, 284 (2018).

    Google Scholar 

  96. 96.

    Gupta, R. S. & Sethi, M. Phylogeny and molecular signatures for the phylum Fusobacteria and its distinct subclades. Anaerobe 28, 182–198 (2014).

    CAS  PubMed  Google Scholar 

  97. 97.

    Nie, S. et al. Fusobacterium nucleatum subspecies identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry. J. Clin. Microbiol. 53, 1399–1402 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kook, J.-K. et al. Genome-based reclassification of Fusobacterium nucleatum subspecies at the species level. Curr. Microbiol. 74, 1137–1147 (2017).

    CAS  PubMed  Google Scholar 

  99. 99.

    Repass, J., Maherali, N. & Owen, K. Reproducibility project: cancer biology. Registered report: Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. eL ife 5, 427 (2016).

    Google Scholar 

  100. 100.

    Repass, J. et al. Replication study: Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. eLife 7, e64900 (2018).

    Google Scholar 

  101. 101.

    Errington, T. M. et al. An open investigation of the reproducibility of cancer biology research. eLife 3, 5773 (2014).

    Google Scholar 

  102. 102.

    Boleij, A. et al. The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. Clin. Infect. Dis. 60, 208–215 (2015).

    CAS  PubMed  Google Scholar 

  103. 103.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Kinder-Haake, S., Yoder, S. & Hunt Gerardo, S. Efficient gene transfer and targeted mutagenesis in Fusobacterium nucleatum. Plasmid 55, 27–38 (2006). This foundational paper establishes techniques for genetic manipulation of fusobacteria.

    CAS  PubMed  Google Scholar 

  105. 105.

    Nakagaki, H. et al. Fusobacterium nucleatum envelope protein FomA is immunogenic and binds to the salivary statherin-derived peptide. Infect. Immun. 78, 1185–1192 (2010).

    CAS  PubMed  Google Scholar 

  106. 106.

    Han, Y. W. et al. Identification and characterization of a novel adhesin unique to oral fusobacteria. J. Bacteriol. 187, 5330–5340 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Casasanta, M. A. et al. A chemical and biological toolbox for Type Vd secretion: characterization of the phospholipase A1 autotransporter FplA from Fusobacterium nucleatum. J. Biol. Chem. 292, 20240–20254 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Ma, L., Ding, Q., Feng, X. & Li, F. The protective effect of recombinant FomA-expressing Lactobacillus acidophilus against periodontal infection. Inflammation 36, 1160–1170 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Wu, C. et al. Forward genetic dissection of biofilm development by Fusobacterium nucleatum: novel functions of cell division proteins FtsX and EnvC. MBio 9, 101 (2018). This recent publication expands the fusobacterial genetic toolkit.

    Google Scholar 

  110. 110.

    Han, Y. W., Ikegami, A., Chung, P., Zhang, L. & Deng, C. X. Sonoporation is an efficient tool for intracellular fluorescent dextran delivery and one-step double-crossover mutant construction in Fusobacterium nucleatum. Appl. Environ. Microbiol. 73, 3677–3683 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Yang, Y. et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating Toll-like receptor 4 signaling to nuclear factor-κB, and up-regulating expression of MicroRNA-21. Gastroenterology 152, 851–866 (2017).

    CAS  PubMed  Google Scholar 

  112. 112.

    Kolenbrander, P. E., Andersen, R. N. & Moore, L. V. Coaggregation of Fusobacterium nucleatum, Selenomonas flueggei, Selenomonas infelix, Selenomonas noxia, and Selenomonas sputigena with strains from 11 genera of oral bacteria. Infect. Immun. 57, 3194–3203 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Kokes, M. et al. Integrating chemical mutagenesis and whole-genome sequencing as a platform for forward and reverse genetic analysis of Chlamydia. Cell Host Microbe 17, 716–725 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Zarkavelis, G. et al. Current and future biomarkers in colorectal cancer. Ann. Gastroenterol. 30, 613–621 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Imperiale, T. F., Ransohoff, D. F. & Itzkowitz, S. H. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 371, 187–188 (2014).

    CAS  PubMed  Google Scholar 

  117. 117.

    Nakatsu, G. et al. Gut mucosal microbiome across stages of colorectal carcinogenesis. Nat. Commun. 6, 8727 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Peng, B.-J. et al. Diagnostic performance of intestinal Fusobacterium nucleatum in colorectal cancer: a meta-analysis. Chin. Med. J. 131, 1349–1356 (2018).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Huang, Q., Peng, Y. & Xie, F. Fecal fusobacterium nucleatum for detecting colorectal cancer: a systematic review and meta-analysis. Int. J. Biol. Markers https://doi.org/10.1177/1724600818781301 (2018).

    Google Scholar 

  120. 120.

    Sze, M. A. & Schloss, P. D. Leveraging existing 16S rRNA gene surveys to identify reproducible biomarkers in individuals with colorectal tumors. MBio 9, 7 (2018).

    Google Scholar 

  121. 121.

    Kaplan, A. et al. Characterization of aid1, a novel gene involved in Fusobacterium nucleatum interspecies interactions. Microb. Ecol. 68, 379–387 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Lima, B. P., Shi, W. & Lux, R. Identification and characterization of a novel Fusobacterium nucleatum adhesin involved in physical interaction and biofilm formation with Streptococcus gordonii. Microbiologyopen 6, e00444 (2017).

    PubMed Central  Google Scholar 

  123. 123.

    Park, J., Shokeen, B., Haake, S. K. & Lux, R. Characterization of Fusobacterium nucleatum ATCC 23726 adhesins involved in strain-specific attachment to Porphyromonas gingivalis. Int. J. Oral Sci. 8, 138–144 (2016).

    PubMed Central  Google Scholar 

  124. 124.

    Kinder, S. A. & Holt, S. C. Localization of the Fusobacterium nucleatum T18 adhesin activity mediating coaggregation with Porphyromonas gingivalis T22. J. Bacteriol. 175, 840–850 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Liu, P.-F. et al. Vaccination targeting surface FomA of Fusobacterium nucleatum against bacterial co-aggregation: implication for treatment of periodontal infection and halitosis. Vaccine 28, 3496–3505 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Bolstad, A. I., Jensen, H. B. & Bakken, V. Taxonomy, biology, and periodontal aspects of Fusobacterium nucleatum. Clin. Microbiol. Rev. 9, 55–71 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Riordan, T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre’s syndrome. Clin. Microbiol. Rev. 20, 622–659 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is supported by US National Institutes of Health (NIH) grant R01CA154426. C.A.B. is the Dennis and Marsha Dammerman fellow of the Damon Runyon Cancer Research Foundation (DRG-2205-14).

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Both authors researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Wendy S. Garrett.

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W.S.G. serves on the Scientific Advisory Boards of Evelo Biosciences, Kintai Therapeutics and uBiome. W.S.G. is a consultant for BioMx and has been a consultant for Janssen, Pfizer and Merck. W.S.G. is a senior editor at eLife, which publishes the ‘Reproducibility Project: Cancer Biology’ experimental designs and methods as registered reports and results as replication studies.

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Supplementary Information

Glossary

Combinatorial labelling and spectral imaging–fluorescence in situ hybridization

(CLASI-FISH). This technique enables detection of ten to several hundred distinct microbial taxa by using combinations of fluorophores coupled to different oligonucleotide probes that target unique regions of the 16S ribosomal RNA (rRNA) gene.

Osteomyelitis

Infectious or non-infectious inflammation of the bone.

Pericarditis

Infectious or non-infectious inflammation of the sac-like tissue that surrounds the heart.

Chorioamnionitis

Infectious or non-infectious inflammation of the chorion and amnion (the fetal membranes) and the amniotic fluid, which can occur before or during labour.

Lemierre syndrome

Infectious thrombophlebitis of the internal jugular vein, which is often caused by F. necrophorum. It can occur in the setting of a fusobacterial throat infection with peritonsillar abscess formation, but in the modern antibiotic era it remains fairly rare. The syndrome is named after Andrew Lemierre, who published a case report in the 1930s that identified throat infections as the cause of several anaerobic sepsis cases.

CpG island methylator phenotype

(CIMP). A state of epigenetic instability in which promoter CpG island sites become hypermethylated, which results in turning off of genes, including tumour suppressor genes.

Microsatellite instability

A condition in which impaired DNA mismatch repair leads to genetic hypermutation. Colorectal tumours can be described as microsatellite instable-high (MSI-high) or microsatellite stable (MSS).

Familial adenomatous polyposis

A genetic disorder that is caused by mutation of the APC gene and results in numerous tumours of the large bowel. Classically, these colon tumours form during the teenage years and the number of tumours increases with age, but there are also attenuated variants.

Colorectal adenomas

Non-malignant tumours occurring in the colon and rectum that can develop into cancer.

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Brennan, C.A., Garrett, W.S. Fusobacterium nucleatum — symbiont, opportunist and oncobacterium. Nat Rev Microbiol 17, 156–166 (2019). https://doi.org/10.1038/s41579-018-0129-6

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