Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The role of oral bacteria in inflammatory bowel disease

Nature Reviews Gastroenterology & Hepatology volume 18, pages 731–742 (2021)Cite this article

Subjects

Abstract

Over the past two decades, the importance of the microbiota in health and disease has become evident. Pathological changes to the oral bacterial microbiota, such as those occurring during periodontal disease, are associated with multiple inflammatory conditions, including inflammatory bowel disease. However, the degree to which this association is a consequence of elevated oral inflammation or because oral bacteria can directly drive inflammation at distal sites remains under debate. In this Perspective, we propose that in inflammatory bowel disease, oral disease-associated bacteria translocate to the intestine and directly exacerbate disease. We propose a multistage model that involves pathological changes to the microbial and immune compartments of both the oral cavity and intestine. The evidence to support this hypothesis is critically evaluated and the relevance to other diseases in which oral bacteria have been implicated (including colorectal cancer and liver disease) are discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Commonalities in the inflammatory pathology of the gingiva in periodontitis and the intestine in IBD.
Fig. 2: The multistage model describing the intestinal expansion of oral-associated bacteria in IBD.
Fig. 3: Mechanisms by which oral-associated bacteria might mediate intestinal inflammation.

Similar content being viewed by others

References

  1. Davenport, E. R. et al. The human microbiome in evolution. BMC Biol. 15, 1–12 (2017).

    Article  Google Scholar 

  2. Flint, H. J., Scott, K. P., Louis, P. & Duncan, S. H. The role of the gut microbiota in nutrition and health. Nat. Rev. Gastroenterol. Hepatol. 9, 577–589 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Ni, J., Wu, G. D., Albenberg, L. & Tomov, V. T. Gut microbiota and IBD: causation or correlation? Nat. Rev. Gastroenterol. Hepatol. 14, 573–584 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lamont, R. J., Koo, H. & Hajishengallis, G. The oral microbiota: dynamic communities and host interactions. Nat. Rev. Microbiol. 16, 745–759 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tilg, H., Cani, P. D. & Mayer, E. A. Gut microbiome and liver diseases. Gut 65, 2035–2044 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769–2778 (2018).

    Article  Google Scholar 

  8. de Souza, H. S. P. & Fiocchi, C. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 13, 13–27 (2016).

    Article  PubMed  CAS  Google Scholar 

  9. Hajishengallis, G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol. 15, 30–44 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chavakis, T., Mitroulis, I. & Hajishengallis, G. Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation. Nat. Immunol. 20, 802–811 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mark Welch, J. L., Dewhirst, F. E. & Borisy, G. G. Biogeography of the oral microbiome: the site-specialist hypothesis. Annu. Rev. Microbiol. 73, 335–358 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Donaldson, G. P., Lee, S. M. & Mazmanian, S. K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 14, 20–32 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Lloyd-Price, J. et al. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature 550, 61–66 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schirmer, M. et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat. Microbiol. 3, 337–346 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Halfvarson, J. et al. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat. Microbiol. 2, 17004 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vandeputte, D. et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature 551, 507–511 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Andoh, A. et al. Comparison of the fecal microbiota profiles between ulcerative colitis and Crohn’s disease using terminal restriction fragment length polymorphism analysis. J. Gastroenterol. 46, 479–486 (2011).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ohkusa, T. et al. Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody. J. Gastroenterol. Hepatol. 17, 849–53 (2002).

    Article  PubMed  Google Scholar 

  20. Sokol, H. et al. Fungal microbiota dysbiosis in IBD. Gut 66, 1039–1048 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Peters, B. A., Wu, J., Hayes, R. B. & Ahn, J. The oral fungal mycobiome: characteristics and relation to periodontitis in a pilot study. BMC Microbiol. 17, 157 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. She, Y. Y. et al. Periodontitis and inflammatory bowel disease: a meta-analysis. BMC Oral. Health 20, 67 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Singhal, S. et al. The role of oral hygiene in inflammatory bowel disease. Dig. Dis. Sci. 56, 170–175 (2011).

    Article  PubMed  Google Scholar 

  24. Vavricka, S. R. et al. Periodontitis and gingivitis in inflammatory bowel disease: a case-control study. Inflamm. Bowel Dis. 19, 2768–2777 (2013).

    Article  PubMed  Google Scholar 

  25. Habashneh, R. A., Khader, Y. S., Alhumouz, M. K., Jadallah, K. & Ajlouni, Y. The association between inflammatory bowel disease and periodontitis among Jordanians: a case-control study. J. Periodontal. Res. 47, 293–298 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Koutsochristou, V. et al. Dental caries and periodontal disease in children and adolescents with inflammatory bowel disease: a case-control study. Inflamm. Bowel Dis. 21, 1839–1846 (2015).

    Article  PubMed  Google Scholar 

  27. Xu, X. et al. Oral cavity contains distinct niches with dynamic microbial communities. Environ. Microbiol. 17, 699–710 (2015).

    Article  PubMed  Google Scholar 

  28. Caselli, E. et al. Defining the oral microbiome by whole-genome sequencing and resistome analysis: the complexity of the healthy picture. BMC Microbiol. 20, 120 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schmidt, T. S. et al. Extensive transmission of microbes along the gastrointestinal tract. eLife 8, e42693 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wilbert, S. A., Mark Welch, J. L. & Borisy, G. G. Spatial ecology of the human tongue dorsum microbiome. Cell Rep. 30, 4003–4015.e3 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Welch, J. L. M., 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).

    CAS  Google Scholar 

  32. Curtis, M. A., Diaz, P. I. & Van Dyke, T. E. The role of the microbiota in periodontal disease. Periodontology 2000 83, 14–25 (2020).

    Article  PubMed  Google Scholar 

  33. Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 14, e1002533 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Humphrey, S. P. & Williamson, R. T. A review of saliva: normal composition, flow, and function. J. Prosthet. Dent. 85, 162–169 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. van den Bogert, B. et al. Diversity of human small intestinal Streptococcus and Veillonella populations. FEMS Microbiol. Ecol. 85, 376–388 (2013).

    Article  PubMed  CAS  Google Scholar 

  36. Kirk, K. F. et al. Molecular epidemiology and comparative genomics of Campylobacter concisus strains from saliva, faeces and gut mucosal biopsies in inflammatory bowel disease. Sci. Rep. 8, 1902 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 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).

    Article  PubMed  Google Scholar 

  38. Giannella, R. A., Broitman, S. A. & Zamcheck, N. Gastric acid barrier to ingested microorganisms in man: studies in vivo and in vitro. Gut 13, 251–256 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lawley, T. D. & Walker, A. W. Intestinal colonization resistance. Immunology 138, 1–11 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Sequeira, R. P., McDonald, J. A. K., Marchesi, J. R. & Clarke, T. B. Commensal Bacteroidetes protect against Klebsiella pneumoniae colonization and transmission through IL-36 signalling. Nat. Microbiol. 5, 304–313 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li, B. et al. Oral bacteria colonize and compete with gut microbiota in gnotobiotic mice. Int. J. Oral. Sci. 11, 10 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Segata, N. et al. Composition of the adult digestive tract bacterial microbiome based on seven mouth surfaces, tonsils, throat and stool samples. Genome Biol. 13, R42 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Eren, A. M., Borisy, G. G., Huse, S. M. & Mark Welch, J. L. Oligotyping analysis of the human oral microbiome. Proc. Natl Acad. Sci. USA 111, E2875–2884 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tierney, B. T. et al. The landscape of genetic content in the gut and oral human microbiome. Cell Host Microbe 26, 283–295.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Carr, V. R. et al. Abundance and diversity of resistomes differ between healthy human oral cavities and gut. Nat. Commun. 11, 693 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Man, S. M. et al. Campylobacter concisus and other Campylobacter species in children with newly diagnosed Crohn’s disease. Inflamm. Bowel Dis. 16, 1008–1016 (2010).

    Article  PubMed  Google Scholar 

  47. Kirk, K. F., Nielsen, H. L., Thorlacius-Ussing, O. & Nielsen, H. Optimized cultivation of Campylobacter concisus from gut mucosal biopsies in inflammatory bowel disease. Gut Pathog. 8, 27 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Schirmer, M. et al. Compositional and temporal changes in the gut microbiome of pediatric ulcerative colitis patients are linked to disease course. Cell Host Microbe 24, 600–610.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dinakaran, V. et al. Identification of specific oral and gut pathogens in full thickness colon of colitis patients: implications for colon motility. Front. Microbiol. 10, 3220 (2019).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Atarashi, K. et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science 358, 359–365 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Baker, J. L. et al. Klebsiella and Providencia emerge as lone survivors following long-term starvation of oral microbiota. Proc. Natl Acad. Sci. USA 116, 8499–8504 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sayad, A. et al. Genetic susceptibility for periodontitis with special focus on immune-related genes: a concise review. Gene Rep. 21, 100814 (2020).

    Article  Google Scholar 

  54. Graham, D. B. & Xavier, R. J. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578, 527–539 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Xun, Z., Zhang, Q., Xu, T., Chen, N. & Chen, F. Dysbiosis and ecotypes of the salivary microbiome associated with inflammatory bowel diseases and the assistance in diagnosis of diseases using oral bacterial profiles. Front. Microbiol. 9, 1136 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Said, H. S. et al. Dysbiosis of salivary microbiota in inflammatory bowel disease and its association with oral immunological biomarkers. DNA Res. 21, 15–25 (2015).

    Article  CAS  Google Scholar 

  57. Szafrański, S. P. et al. Functional biomarkers for chronic periodontitis and insights into the roles of Prevotella nigrescens and Fusobacterium nucleatum; a metatranscriptome analysis. NPJ Biofilms Microbiomes 1, 15017 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kumar, P. S., Griffen, A. L., Moeschberger, M. L. & Leys, E. J. Identification of candidate periodontal pathogens and beneficial species by quantitative 16S clonal analysis. J. Clin. Microbiol. 43, 3944–3955 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kelsen, J. et al. Alterations of the subgingival microbiota in pediatric Crohn’s disease studied longitudinally in discovery and validation cohorts. Inflamm. Bowel Dis. 21, 2797–2805 (2015).

    Article  PubMed  Google Scholar 

  60. Moutsopoulos, N. M. & Konkel, J. E. Tissue-specific immunity at the oral mucosal barrier. Trends Immunol. 39, 276–287 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Dutzan, N., Konkel, J. E., Greenwell-Wild, T. & Moutsopoulos, N. M. Characterization of the human immune cell network at the gingival barrier. Mucosal Immunol. 9, 1163–1172 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pan, W., Wang, Q. & Chen, Q. The cytokine network involved in the host immune response to periodontitis. Int. J. Oral. Sci. 11, 30 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Herrero, E. R. et al. Dysbiotic biofilms deregulate the periodontal inflammatory response. J. Dent. Res. 97, 547–555 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Hajishengallis, G., Shakhatreh, M.-A. K., Wang, M. & Liang, S. Complement receptor 3 blockade promotes IL-12-mediated clearance of porphyromonas gingivalis and negates its virulence in vivo. J. Immunol. 179, 2359–2367 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Dutzan, N. et al. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans. Sci. Transl. Med. 10, eaat0797 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Suárez, L. J., Vargas, D. E., Rodríguez, A., Arce, R. M. & Roa, N. S. Systemic Th17 response in the presence of periodontal inflammation. J. Appl. Oral. Sci. 28, e20190490 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Aleksandra Nielsen, A., Nederby Nielsen, J., Schmedes, A., Brandslund, I. & Hey, H. Saliva Interleukin-6 in patients with inflammatory bowel disease. Scand. J. Gastroenterol. 40, 1444–1448 (2005).

    Article  PubMed  Google Scholar 

  68. Szczeklik, K., Owczarek, D., Pytko-Polończyk, J., Kȩsek, B. & Mach, T. H. Proinflammatory cytokines in the saliva of patients with active and nonactive Crohn’s disease. Pol. Arch. Med. Wewn. 122, 200–208 (2012).

    CAS  PubMed  Google Scholar 

  69. Rezaie, A. et al. Alterations in salivary antioxidants, nitric oxide, and transforming growth factor-β1 in relation to disease activity in Crohn’s disease patients. Ann. N. Y. Acad. Sci. 1091, 110–122 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Rezaie, A. et al. Study on the correlations among disease activity index and salivary transforming growth factor-β1 and nitric oxide in ulcerative colitis patients. Ann. N. Y. Acad. Sci. 1095, 305–314 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Lamster, I. B., Rodrick, M. L., Sonis, S. T. & Falchuk, Z. M. An analysis of peripheral blood and salivary polymorphonuclear leukocyte function, circulating immune complex levels and oral status in patients with inflammatory bowel disease. J. Periodontol. 53, 231–238 (1982).

    Article  CAS  PubMed  Google Scholar 

  72. van Dyke, T. E., Dowell, V. R., Offenbacher, S., Snyder, W. & Hersh, T. Potential role of microorganisms isolated from periodontal lesions in the pathogenesis of inflammatory bowel disease. Infect. Immun. 53, 671–677 (1986).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Fournier, B. M. & Parkos, C. A. The role of neutrophils during intestinal inflammation. Mucosal Immunol. 5, 354–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Mowat, A. M. & Agace, W. W. Regional specialization within the intestinal immune system. Nat. Rev. Immunol. 14, 667–685 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Antoni, L., Nuding, S., Wehkamp, J. & Stange, E. F. Intestinal barrier in inflammatory bowel disease. World J. Gastroenterol. 20, 1165–1179 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Friedrich, M., Pohin, M. & Powrie, F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity 50, 992–1006 (2019).

    Article  CAS  PubMed  Google Scholar 

  77. Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nassar, M. et al. GAS6 is a key homeostatic immunological regulator of host-commensal interactions in the oral mucosa. Proc. Natl Acad. Sci. USA 114, E337–E346 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Duran-Pinedo, A. E. et al. Community-wide transcriptome of the oral microbiome in subjects with and without periodontitis. ISME J. 8, 1659–1672 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Goggins, M. G. et al. Increased urinary nitrite, a marker of nitric oxide, in active inflammatory bowel disease. Mediators Inflamm. 10, 69–73 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Avdagić, N. et al. Nitric oxide as a potential biomarker in inflammatory bowel disease. Bosn. J. Basic Med. Sci. 13, 5–9 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Ali, O. T. et al. Nitrite and nitrate levels of gingival crevicular fluid and saliva in subjects with gingivitis and chronic periodontitis. J. Oral Maxillofac. Res. 5, e5 (2014).

    Google Scholar 

  83. Hyde, E. R. et al. Metagenomic analysis of nitrate-reducing bacteria in the oral cavity: implications for nitric oxide homeostasis. PLoS One 9, e88645 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Kitamoto, S. et al. The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis. Cell 182, 447–462.e14 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bamias, G. & Cominelli, F. Role of type 2 immunity in intestinal inflammation. Curr. Opin. Gastroenterol. 31, 471–476 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Komiya, Y. et al. Patients with colorectal cancer have identical strains of Fusobacterium nucleatum in their colorectal cancer and oral cavity. Gut 68, 1335–1337 (2018).

    Article  PubMed  Google Scholar 

  88. Mahendran, V. et al. Delineation of genetic relatedness and population structure of oral and enteric Campylobacter concisus strains by analysis of housekeeping genes. Microbiology 161, 1600–1612 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Ismail, Y. et al. Investigation of the enteric pathogenic potential of oral Campylobacter concisus strains isolated from patients with inflammatory bowel disease. PLoS One 7, e38217 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chung, H. K. L. et al. Genome analysis of Campylobacter concisus strains from patients with inflammatory bowel disease and gastroenteritis provides new insights into pathogenicity. Sci. Rep. 6, 38442 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang, Y. et al. Campylobacter concisus genomospecies 2 is better adapted to the human gastrointestinal tract as compared with Campylobacter concisus genomospecies 1. Front. Physiol. 8, 543 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Liu, F. et al. Genomic analysis of oral Campylobacter concisus strains identified a potential bacterial molecular marker associated with active Crohn’s disease. Emerg. Microbes Infect. 7, 64 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zaura, E. et al. Same exposure but two radically different responses to antibiotics: resilience of the salivary microbiome versus long-term microbial shifts in feces. mBio 6, e01693-15 (2015).

  95. Shaw, L. P. et al. Modelling microbiome recovery after antibiotics using a stability landscape framework. ISME J. 13, 1845–1856 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Oswal, S., Ravindra, S., Sinha, A. & Manjunath, S. Antibiotics in periodontal surgeries: A prospective randomised cross over clinical trial. J. Indian. Soc. Periodontol. 18, 570–574 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Bernstein, C. N. Is antibiotic use a cause of IBD worldwide? Inflamm. Bowel Dis. 26, 448–449 (2020).

    PubMed  Google Scholar 

  98. Horliana, A. C. R. T. et al. Dissemination of periodontal pathogens in the bloodstream after periodontal procedures: a systematic review. PLoS One 9, e98271 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Kojima, A. et al. Aggravation of inflammatory bowel diseases by oral streptococci. Oral. Dis. 20, 359–366 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Goren, I. et al. Risk of bacteremia in hospitalised patients with inflammatory bowel disease: a 9-year cohort study. United European Gastroenterol. J. 8, 195–203 (2020).

    Article  PubMed  Google Scholar 

  101. Xue, Y. et al. Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages. Cell Death Dis. 9, 355 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Parhi, L. et al. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nat. Commun. 11, 3295 (2020).

    Article  CAS  Google Scholar 

  103. Seedorf, H. et al. Bacteria from diverse habitats colonize and compete in the mouse gut. Cell 159, 253–266 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Imhann, F. et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. Jackson, M. A. et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 65, 749–756 (2016).

    Article  PubMed  CAS  Google Scholar 

  107. Vich Vila, A. et al. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 11, 362 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hojo, M. et al. Gut microbiota composition before and after use of proton pump inhibitors. Dig. Dis. Sci. 63, 2940–2949 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mishiro, T. et al. Oral microbiome alterations of healthy volunteers with proton pump inhibitor. J. Gastroenterol. Hepatol. 33, 1059–1066 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Schwartz, N. R. M. et al. Proton pump inhibitors, H2 blocker use, and risk of inflammatory bowel disease in children. J. Pediatr. Pharmacol. Ther. 24, 489–496 (2019).

    PubMed  PubMed Central  Google Scholar 

  111. Juillerat, P. et al. Drugs that inhibit gastric acid secretion may alter the course of inflammatory bowel disease. Aliment. Pharmacol. Ther. 36, 239–247 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Shah, R., Richardson, P., Yu, H., Kramer, J. & Hou, J. K. Gastric acid suppression is associated with an increased risk of adverse outcomes in inflammatory bowel disease. Digestion 95, 188–193 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Liu, H. et al. Fusobacterium nucleatum exacerbates colitis by damaging epithelial barrier and inducing aberrant inflammation. J. Dig. Dis. 21, 385–398 (2020).

    Article  CAS  PubMed  Google Scholar 

  114. Caballero, S. et al. Distinct but spatially overlapping intestinal niches for vancomycin-resistant enterococcus faecium and carbapenem-resistant Klebsiella pneumoniae. PLoS Pathog. 11, e1005132 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rubinstein, M. R. et al. Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β-catenin modulator Annexin A1. EMBO Rep. 20, e47638 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Maroncle, N., Balestrino, D., Rich, C. & Forestier, C. Identification of Klebsiella pneumoniae genes involved in intestinal colonization and adhesion using signature-tagged mutagenesis. Infect. Immun. 70, 4729–4734 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hsu, C. R. et al. Klebsiella pneumoniae translocates across the intestinal epithelium via rho GTPase-and phosphatidylinositol 3-kinase/Akt-dependent cell invasion. Infect. Immun. 83, 769–779 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Lee, I. A. & Kim, D. H. Klebsiella pneumoniae increases the risk of inflammation and colitis in a murine model of intestinal bowel disease. Scand. J. Gastroenterol. 46, 684–693 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Deshpande, N. P. et al. Campylobacter concisus pathotypes induce distinct global responses in intestinal epithelial cells. Sci. Rep. 6, 34288 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kaakoush, N. O. et al. The pathogenic potential of Campylobacter concisus strains associated with chronic intestinal diseases. PLoS One 6, e29045 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tang, B. et al. Fusobacterium nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 cells. PLoS One 11, e0165701 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Dharmani, P., Strauss, J., Ambrose, C., Allen-Vercoe, E. & Chadee, K. Fusobacterium nucleatum infection of colonic cells stimulates MUC2 mucin and tumor necrosis factor alpha. Infect. Immun. 79, 2597–2607 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pope, J. L. et al. Microbial colonization coordinates the pathogenesis of a Klebsiella pneumoniae infant isolate. Sci. Rep. 9, 3380 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Mahendran, V. et al. Examination of the effects of Campylobacter concisus zonula occludens toxin on intestinal epithelial cells and macrophages. Gut Pathog. 8, 18 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hajishengallis, G., Darveau, R. P. & Curtis, M. A. The keystone-pathogen hypothesis. Nat. Rev. Microbiol. 10, 717–725 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gupta, V. K. et al. A predictive index for health status using species-level gut microbiome profiling. Nat. Commun. 11, 4635 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Vieira-Silva, S. et al. Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses. Nat. Microbiol. 4, 1826–1831 (2019).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ryan, F. J. et al. Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease. Nat. Commun. 11, 1512 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tang, Q. et al. Current sampling methods for gut microbiota: a call for more precise devices. Front. Cell Infect. Microbiol. 10, 151 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Man, S. M. et al. Host attachment, invasion, and stimulation of proinflammatory cytokines by Campylobacter concisus and other non-Campylobacter jejuni Campylobacter species. J. Infect. Dis. 202, 1855–1865 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Brennan, C. A. & Garrett, W. S. Fusobacterium nucleatum — symbiont, opportunist and oncobacterium. Nat. Rev. Microbiol. 17, 156–166 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mohammed, H. et al. Oral dysbiosis in pancreatic cancer and liver cirrhosis: a review of the literature. Biomedicines 6, 115 (2018).

    Article  CAS  PubMed Central  Google Scholar 

  136. Karlsen, T. H., Folseraas, T., Thorburn, D. & Vesterhus, M. Primary sclerosing cholangitis – a comprehensive review. J. Hepatol. 67, 1298–1323 (2017).

    Article  PubMed  Google Scholar 

  137. De Vries, A. B., Janse, M., Blokzijl, H. & Weersma, R. K. Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis. World J. Gastroenterol. 21, 1956–1971 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Iwasawa, K. et al. Dysbiosis of the salivary microbiota in pediatric-onset primary sclerosing cholangitis and its potential as a biomarker. Sci. Rep. 8, 5480 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Bajer, L. et al. Distinct gut microbiota profiles in patients with primary sclerosing cholangitis and ulcerative colitis. World J. Gastroenterol. 23, 4548–4558 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Sebastian, S. et al. Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). J. Crohns Colitis 8, 5–18 (2014).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  142. Kim, G. W. et al. Periodontitis is associated with an increased risk for proximal colorectal neoplasms. Sci. Rep. 9, 7528 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Flemer, B. et al. The oral microbiota in colorectal cancer is distinctive and predictive. Gut 67, 1454–1463 (2018).

    Article  CAS  PubMed  Google Scholar 

  144. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Luke Roberts, William Wade, Susan Joseph, Maggie Flak and Geraldine Jowett for their critical reading of the manuscript. We apologize to authors whose papers we could not cite due to space limitations. E.R. acknowledges a PhD fellowship from the Wellcome Trust (215027/Z/18/Z). J.F.N. acknowledges a RCUK/UKRI Rutherford Fund fellowship (MR/R024812/1). M.A.C. acknowledges an MRC grant (MR/P012175/2).

Author information

Authors and Affiliations

  1. Centre for Host-Microbiome Interactions, King’s College London, London, UK

    Emily Read, Michael A. Curtis & Joana F. Neves

  2. Wellcome Trust Cell Therapies and Regenerative Medicine PhD Programme, King’s College London, London, UK

    Emily Read

Authors
  1. Emily Read
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael A. Curtis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joana F. Neves
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.R. researched data for the article, made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission. J.F.N. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. M.A.C. made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Joana F. Neves.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks G. Hajishengallis, N. Kamada and H. Sokol for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Read, E., Curtis, M.A. & Neves, J.F. The role of oral bacteria in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 18, 731–742 (2021). https://doi.org/10.1038/s41575-021-00488-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-021-00488-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology