Positive and Negative Effects of the Commensal Bacteria on Carcinogenesis
Background: Cancer is a lethal disease that results from a multifactorial process. Progression into carcinogenesis and an abnormal cell proliferation can occur due to the micro and macro environment as well as genetic mutations and modifications. In this review, cancer and the microbiota – mainly bacteria that inhabit the tumour tissue – have been discussed. The positive and negative impacts of the commensal bacteria on tumours being protective or carcinogenic agents, respectively, and their strategies have also been described.
Methods: Related published articles written in English language were searched from Google Scholar, PubMed, Mendeley suggestions, as well as Google search using a combination of the keywords ‘Microbiota, commensal bacteria, cancer, tumor’. Relevant literature published between the years 1979 and 2018 were included in this review.
Results: The complicated nature of cancer as well as the role that might be played by the commensal bacteria in affected tissues have been the focus of the recent studies. The symbiotic relationships between the microbiota and the host have been shown to confer benefits to the last. By contrast, the microbiota has been suggested to upgrade cancer by modifying the balance of host cell proliferation and death, by provoking chronic inflammation, and by eliciting uncontrolled innate and adaptive immunity. In this context, aerobic and anaerobic bacteria have been isolated from various tumor samples.
Conclusions: It can be concluded that commensal microbiota plays an important role in the prevention of diseases including cancer. Inversely, microbiota alterations (dysbiosis) have been found to interrupt that symbiotic correlation between the host and the inhabitant microbiota probably leading to cancer.
Recommendations: The correlation between the commensal microbiome, antibiotics uptake and cancer occurrence need to be investigated exclusively. Moreover, increased attention must be paid to evaluating the effects of these microorganisms on the currently used anticancer agents, and the role that might be played by commensal bacteria on tumor progression or tumor regression.
 Howlader, N., Noone, A., and Krapcho, M. (2014). SEER Cancer Statistics Review, 1975–2012. Bethesda, Md, USA: National Cancer Institute.
 Grivennikov, S. I., Greten, F. R., and Karin, M. (2010). Immunity, inflammation, and cancer. Cell, vol. 140, pp. 883–889.
 Hanahan, D. and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, vol. 144, pp. 646–674.
 Jain, R. K. (2001). New approaches for the treatment of the cancer. Advanced Drug Delivery Reviews, vol. 36, pp. 149–168.
 Felgner, S., Kocijancic, D., Frahm, M., et al. (2016). Bacteria in Cancer Therapy: Renaissance of an Old Concept. International Journal of Medical Microbiology, vol. 2016, p. 8451728.
 Nauts, H. C. and McLaren, J. R. (1990). Coley toxins-the first century. Advances in Experimental Medicine and Biology, vol. 267, pp. 483–500.
 Fernandez, M. F., Reina-Perez, I., Astorga, J. M., et al. (2018). Breast cancer and its relationship with the microbiota. International Journal of Environmental Research and Public Health, vol. 15, no. 8, pii: E1747.
 Patyar, S., Joshi, R., Byrav, D. S., et al. (2010). Bacteria in cancer therapy: a novel experimental strategy. Journal of Biomedical Science, vol. 17, no. 1, pp. 21.
 Toso, J. F., Gill, V. J., Hwu, P., et al. (2002). Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. Journal of Clinical Oncology, vol. 20, pp. 142–152.
 Nemunaitis, J., Cunningham, C., Senzer, N., et al. (2003). Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Therapy, vol. 10, pp. 737–744.
 Baban, C. K., Cronin, M., O’Hanlon, D., et al. (2010). Bacteria as vectors for gene therapy of cancer. Bioengineered Bugs, vol. 1, pp. 385–394.
 Liu, S., Xu, X., Zeng, X., et al. (2014). Tumor-targeting bacterial therapy: a potential treatment for oral cancer. Oncol Letters, vol. 8, pp. 2359–2366.
 Lavigne, M. D. and Gorecki, D. C. (2006). Emerging vectors and targeting methods for nonviral gene therapy. Expert Opinion on Emerging Drugs, vol. 11, pp. 541–557.
 Ptak, C. and Petronis, A. (2008). Epigenetics and complex disease: from etiology to new therapeutics. Annual Review of Pharmacology and Toxicology, vol. 48, pp. 257–276.
 Lax, A. J. and Thomas, W. (2002). How bacteria could cause cancer: one step at a time. Trends in Microbiology, vol. 10, pp. 293–299.
 Vogelstein, B., Papadopoulos, N., Velculescu, V. E., et al. (2013). Cancer genome landscapes. Science, vol. 339, pp. 1546–1558.
 Trinchieri, G. (2012). Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annual Review of Immunology, vol. 30, pp. 677–706.
 Backhed, F., Ley, R. E., Sonnenburg, J. L., et al. (2005). Host-bacterial mutualism in the human intestine. Science, vol. 307, pp. 1915–1920.
 Human Microbiome Project Consortium. (2012). Structure, function and diversity of the healthy human microbiome. Nature, vol. 486, pp. 207–214.
 Schlaeppi, K. and Bulgarelli, D. (2015). The plant microbiome at work. Molecular Plant-Microbe Interactions, vol. 28, pp. 212–217.
 Eckburg, P. B., Bik, E. M., Bernstein, C. N., et al. (2005). Diversity of the human intestinal microbial flora. Science, vol. 308, pp. 1635–1638.
 Lax, A. J. (2005). Opinion: bacterial toxins and cancer-a case to answer? Nature Reviews Microbiology, vol. 3, pp. 343–349.
 Brook, I. (1990). Bacteria from solid tumours. Journal of Medical Microbiology, vol. 32, pp. 207–210.
 Urbaniak, C., Cummins, J., Brackstone, M., et al. (2014). Microbiota of human breast tissue. Applied and Environmental Microbiology, vol. 80, pp. 3007–3014.
 Hieken, T. J., Chen, J., Hoskin, T. L., et al. (2016). The microbiome of aseptically collected human breast tissue in benign and malignant disease. Scientific Reports, vol. 6, p. 30751.
 Shaker, D. A. and Lafta, I. J. (2018). Methicillin-resistant Staphylococcus epidermidis isolated from breast tumors of Iraqi patients. International Journal of Medical Research and Health Sciences, vol. 7, no. 7, pp. 54–62.
 Guidi, R., Guerra, L., Levi, L., et al. (2013). Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response. Cellular Microbiology, vol. 15, pp. 98–113.
 Kamada, N., Kim, Y. G., Sham, H. P., et al. (2012). Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science, vol. 336, pp. 1325–1329.
 Kamada, N., Chen, G. Y., Inohara, N., et al. (2013). Control of pathogens and pathobionts by the gut microbiota. Nature Immunology, vol. 14, pp. 685–690.
 Salcedo, R., Worschech, A., Cardone, M., et al. (2010). MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. Journal of Experimental Medicine, vol. 207, pp. 1625–1636.
 Ege, M. J., Mayer, M., Normand, A. C., et al. (2011). Exposure to environmental microorganisms and childhood asthma. The New England Journal of Medicine, vol. 364, pp. 701–709.
 Olszak, T., An, D., Zeissig, S., et al. (2012). Microbial exposure during early life has persistent effects on natural killer T cell function. Science, vol. 336, pp. 489–493.
 Serbina, N. V., Jia, T., Hohl, T. M., et al. (2008). Monocyte-mediated defense against microbial pathogens. Annual Review of Immunology, vol. 26, pp. 421–452.
 Avila, M., Ojcius, D. M., and Yilmaz, O. (2009). The oral microbiota: living with a permanent guest. DNA and Cell Biology, vol. 28, pp. 405–411.
 Hajishengallis, G., Liang, S., Payne, M. A., et al. (2011). Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host & Microbe, vol. 10, pp. 497–506.
 Hajishengallis, G. and Lamont, R. J. (2014). Breaking bad: manipulation of the host response by Porphyromonas gingivalis. European Journal of Immunology, vol. 44, pp. 328–338.
 Iwase, T., Uehara, Y., Shinji, H., et al. (2010). Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature, vol. 465, pp. 346–349.
 Zipperer, A., Konnerth, M. C., Laux, C., et al. (2016). Human commensals producing a novel antibiotic impair pathogen colonization. Nature, vol. 535, pp. 511–516.
 Xuan, C., Shamonki, J. M., Chung, A., et al. (2014). Microbial dysbiosis is associated with human breast cancer. PLOS One, vol. 9, e83744.
 Belkaid, Y. and Naik, S. (2013) Compartmentalized and systemic control of tissue immunity by commensals. Nature Immunology, vol. 14, pp. 646–653.
 Naik, S., Bouladoux, N., Wilhelm, C., et al. (2012). Compartmentalized control of skin immunity by resident commensals. Science, vol. 337, pp. 1115–1119.
 Chu, H. and Mazmanian, S. K. (2013). Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nature Immunology, vol. 14, pp. 668–675.
 Lai, Y., Di Nardo, A., Nakatsuji, T., et al. (2009). Commensal bacteria regulate Tolllike receptor 3-dependent inflammation after skin injury. Nature Medicine, vol. 15, pp. 1377–1382.
 Lai, Y., Cogen, A. L., Radek, K. A., et al. (2010). Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. Journal of Investigative Dermatology, vol. 130, pp. 2211– 2221.
 Wanke, I., Steffen, H., Christ, C., et al. (2011). Skin commensals amplify the innate immune response to pathogens by activation of distinct signaling pathways. Journal of Investigative Dermatology, vol. 131, pp. 382–390.
 Li, D., Lei, H., Li, Z., et al. (2013). A novel lipopeptide from skin commensal activates TLR2/CD36-p38 MAPK signaling to increase antibacterial defense against bacterial infection. PLOS ONE, vol. 8, e58288.
 Naik, S., Bouladoux, N., Linehan, J. L., et al. (2015). Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature, vol. 520, pp. 104–108.
 Cogen, A. L., Yamasaki, K., Sanchez, K. M., et al. (2010). Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis, a normal resident of the skin. Journal of Investigative Dermatology, vol. 130, pp.192–200.
 Nakatsuji, T., Chen, T. H., Narala, S., et al. (2017). Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Science Translational Medicine, vol. 9.
 Cogen, A. L., Yamasaki, K., Muto, J., et al. (2010). Staphylococcus epidermidis antimicrobial delta-toxin (phenol-soluble modulin-gamma) cooperates with host antimicrobial peptides to kill group A Streptococcus. PLOS ONE, vol. 5, e8557.
 Nakatsuji, T., Chen, T. H., Butcher, A. M., et al. (2018). A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Science Advances, vol. 4, no. 3, eaao4502.
 Kalina, U., Koyama, N., Hosoda, T., et al. (2002). Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region. European Journal of Immunology, vol. 32, pp. 2635–2643.
 Singh, N., Gurav, A., Sivaprakasam, S., et al. (2014). Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity, vol. 40, pp. 128–139.
 Huber, S., Gagliani, N., Zenewicz, L. A., et al. (2012). IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature, vol. 491, pp. 259–263.
 Saleh, M. and Trinchieri, G. (2011). Innate immune mechanisms of colitis and colitisassociated colorectal cancer. Nature Reviews Immunology, vol. 11, pp. 9–20.
 Kirchberger, S., Royston, D. J., Boulard, O., et al. (2013). Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. Journal of Experimental Medicine, vol. 210, pp. 917–931.
 Smith, P. M., Howitt, M. R., Panikov, N., et al. (2013). The microbial metabolites, shortchain fatty acids,regulate colonic Treg cell homeostasis. Science, vol. 341, pp. 569– 573.
 Round, J. L. and Mazmanian, S. K. (2010). Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proceedings of the National Academy of Sciences of the United States of America, vol. 107, pp. 12204–12209.
 Mazmanian, S. K., Round, J. L., and Kasper, D. L. (2008). A microbial symbiosis factor prevents intestinal inflammatory disease. Nature, vol. 453, pp. 620–625.
 Plottel, C. S. and Blaser, M. J. (2011). Microbiome and malignancy. Cell Host & Microbe, vol. 10, pp. 324–335.
 Velicer, C. M., Lampe, J. W., Heckbert, S. R., et al. (2003). Hypothesis: is antibiotic use associated with breast cancer? Cancer Causes & Control, vol. 14, pp. 739–747.
 Shapiro, T. A., Fahey, J. W., Wade, K. L., et al. (1998). Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiology, Biomarkers & Prevention, vol. 7, pp.1091–1100.
 Kilkkinen, A., Pietinen, P., Klaukka, T., et al. (2002). Use of oral antimicrobials decreases serum enterolactone concentration. American Journal of Epidemiology, vol. 155, pp. 472–477.
 Reed, M. J. and Purohit, A. (2001). Aromatase regulation and breast cancer. Clinical Endocrinology, vol. 54, pp. 563–571.
 de Martel, C., Ferlay, J., Franceschi, S., et al. (2012). Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. The Lancet Oncology, vol. 13, pp. 607–615.
 Dzutsev, A., Goldszmid, R. S., Viaud, S., et al. (2015). The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. European Journal of Immunology, vol. 45, pp. 17–31.
 Underwood, M. A. (2014). Intestinal dysbiosis: novel mechanisms by which gut microbes trigger and prevent disease. Preventive Medicine, vol. 65, pp. 133–137.
 Frank, D. N., St Amand, A. L., Feldman, R. A., et al. (2007). Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proceedings of the National Academy of Sciences of the United States of America, vol. 104, pp. 13780–13785.
 Backhed, F., Ley, R. E., Sonnenburg, J. L., et al. (2005). Host-bacterial mutualism in the human intestine. Science, vol. 307, pp. 1915–1920.
 Rosadi, F., Fiorentini, C., and Fabbri, A. (2016). Bacterial protein toxins in human cancers. Pathogens and Disease, vol. 74, ftv105.
 Allen, I. C., TeKippe, E. M., Woodford, R. M., et al. (2010). The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. Journal of Experimental Medicine, vol. 207, pp. 1045–1056.
 Elinav, E., Strowig, T., Kau, A. L., et al. (2011). NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell, vol. 145, pp. 745–757.
 Kuper, H., Adami, H. O., and Trichopoulos, D. (2000). Infections as a major preventable cause of human cancer. Journal of Internal Medicine, vol. 248, pp. 171–183.
 Correa, P. and Miller, M. J. (1998). Carcinogenesis, apoptosis and cell proliferation. British Medical Bulletin, vol. 54, pp. 151–162.
 Cover, T. L., Glupczynski, Y., Lage, A. P., et al. (1995). Serologic detection of infection with cagA+ Helicobacter pylori strains. Journal of Clinical Microbiology, vol. 33, pp. 1496–1500.
 Correa, P., Fox, J., Fontham, E., et al. (1990). Helicobacter pylori and gastric carcinoma. Serum antibody prevalence in populations with contrasting cancer risks. Cancer, vol. 66, pp. 2569–2574.
 Montalban, C., Santon, A., Boixeda, D., et al. (2001). Regression of gastric high grade mucosa associated lymphoid tissue (MALT) lymphoma after Helicobacter pylori eradication. Gut, vol. 49, pp. 584–587.
 Crowe, S. E. (2005). Helicobacter infection, chronic inflammation, and the development of malignancy. Current Opinion in Gastroenterology, vol. 21, pp. 32–38.
 Caygill, C. P., Braddick, M., Hill, M. J., et al. (1995). The association between typhoid carriage, typhoid infection and subsequent cancer at a number of sites. European Journal of Cancer Prevention, vol. 4: 187–193.
 Dutta, U., Garg, P. K., Kumar, R., et al. (2000). Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gallbladder. The American Journal of Gastroenterology, vol. 95, pp. 784–787.
 Shukla, V. K., Singh, H., Pandey, M., et al. (2000). Carcinoma of the gallbladder-is it a sequel of typhoid? Digestive Diseases and Sciences, vol. 45, pp. 900–903.
 Mesnard, B., De Vroey, B., Maunoury, V., et al. (2012). Immunoproliferative small intestinal disease associated with Campylobacter jejuni. Digestive and Liver Disease, vol. 44, pp. 799–800.
 Zarkin, B. A., Lillemoe, K. D., Cameron, J. L., et al. (1990). The triad of Streptococcus bovis bacteremia, colonic pathology, and liver disease. Annals of Surgery, vol. 211, pp. 786–791.
 Ellmerich, S., Scholler, M., Duranton, B., et al. (2000). Promotion of intestinal carcinogenesis by Streptococcus bovis. Carcinogenesis, vol. 21, pp. 753–756.
 Gold, J. S., Bayar, S., and Salem, R. R. (2004). Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy. The Archives of Surgery, vol. 139, pp. 760–765.
 Luperchio, S. A., Newman, J. V., Dangler, C. A., et al. (2000). Citrobacter rodentium, the causative agent of transmissible murine colonic hyperplasia, exhibits clonality: synonymy of C. rodentium and mouse-pathogenic Escherichia coli. Journal of Clinical Microbiology, vol. 38, pp. 4343–4350.
 Kostic, A. D., Chun, E., Robertson, L., et al. (2013). Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host & Microbe, vol. 14, pp. 207–215.
 McCoy, A. N., Araujo-Perez, F., Azcarate-Peril, A., et al. (2013). Fusobacterium is associated with colorectal adenomas. PLOS ONE, vol. 8, e53653.
 Koyi, H., Branden, E., Gnarpe, J., et al. (2001). An association between chronic infection with Chlamydia pneumoniae and lung cancer. a prospective 2-year study. APMIS, vol. 109, pp. 572–580.
 Anttila, T., Koskela, P., Leinonen, M., et al. (2003). Chlamydia pneumoniae infection and the risk of female early-onset lung cancer. International Journal of Cancer, vol. 107, pp. 681–682.
 Littman, A. J., White, E., Jackson, L. A., et al. (2004). Chlamydia pneumoniae infection and risk of lung cancer. Cancer Epidemiology, Biomarkers & Prevention, vol. 13, pp. 1624–1630.
 Gupta, P. K., Tripathi, D., Kulkarni, S., et al. (2016). Mycobacterium tuberculosis H37Rv infected THP-1 cells induce epithelial mesenchymal transition (EMT) in lung adenocarcinoma epithelial cell line (A549). Cellular Immunology, vol. 300, pp. 33–40.
 Ferreri, A. J., Guidoboni, M., Ponzoni, M., et al. (2004). Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. Journal of the National cancer Institute, vol. 96, pp. 586–594.
 De Spiegeleer, B., Verbeke, F., D’Hondt, M., et al. (2015). The quorum sensing peptides PhrG, CSP and EDF promote angiogenesis and invasion of breast cancer cells in vitro. PLOS ONE, vol. 10, e0119471.
 Jacob, J. A. (2016). Study links periodontal disease bacteria to pancreatic cancer risk. JAMA, vol. 315, pp. 2653–2654.
 Iida, N., Dzutsev, A., Stewart, C. A., et al. (2013). Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science, vol. 342,pp. 967–970.
 Mukherji, A., Kobiita, A., Ye, T., et al. (2013). Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell, vol. 153, pp. 812–827.
 Khosravi, A., Yanez, A., Price, J. G., et al. (2014). Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host & Microbe, vol. 15, pp. 374–381.
 Rubinstein, M. R., Wang, X., Liu, W., et al. (2013). Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host & Microbe, vol. 14, pp. 195–206.
 Sears, C. L. and Garrett, W. S. (2014). Microbes, microbiota, and colon cancer. Cell Host & Microbe, vol. 15, pp. 317–328.
 Mackowiak, P. A. (1987). Microbial oncogenesis. The American Journal of Medicine, vol. 82, pp. 79–97.
 Hussain, S. P., Hofseth, L. J., and Harris, C. C. (2003). Radical causes of cancer. Nature Reviews Cancer, vol. 3, pp. 276–285.
 Schetter, A. J., Heegaard, N. H., and Harris, C. C. (2010). Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis, vol. 31, pp. 37–49.
 Poutahidis, T., Cappelle, K., Levkovich, T., et al. (2013). Pathogenic intestinal bacteria enhance prostate cancer development via systemic activation of immune cells in mice. PLOS ONE, vol. 8, e73933.
 Yamamoto, M. L., Maier, I., Dang, A. T., et al. (2013). Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity. Cancer Research, vol. 73, pp. 4222–4232.
 Mulvey, M. A., Schilling, J. D., and Hultgren, S. J. (2001). Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infection and Immunity, vol. 69, pp. 4572–4579.
 Shurin, S. B., Socransky, S. S., Sweeney, E., et al. (1979). A neutrophil disorder induced by capnocytophaga, a dental microorganism. The New England Journal of Medicine, vol. 301, pp. 849–854.
 Kilian, M. (1981). Degradation of immunoglobulins A2, A2, and G by suspected principal periodontal pathogens. Infection and Immunity, vol. 34, pp. 757–765.
 Nougayrede, J. P., Taieb, F., De Rycke, J., et al. (2005). Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle. Trends in Microbiology, vol. 13, pp. 103–110.
 Lax, A. J. (2005). Opinion: bacterial toxins and cancer–a case to answer? Nature Reviews Microbiology, vol. 3, pp. 343–349.
 Urbaniak, C., Gloor, G. B., Brackstone, M., et al. (2016). The microbiota of breast tissue and its association with breast cancer. Applied and Environmental Microbiology, vol. 82, pp. 5039–5048.
 Koller, V. J., Marian, B., Stidl, R., et al. (2008). Impact of lactic acid bacteria on oxidative DNA damage in human derived colon cells. Food and Chemical Toxicology, vol. 46, pp. 1221–1229.
 Putze, J., Hennequin, C., Nougayrede, J. P., et al. (2009). Genetic structure and distribution of the colibactin genomic island among members of the family Enterobacteriaceae. Infection and Immunity, 77, pp. 4696–4703.
 Buc, E., Dubois, D., Sauvanet, P., et al. (2013). High prevalence of mucosa-associated E. coli producing cyclomodulin and genotoxin in colon cancer. PLOS ONE, vol. 8, e56964.
 Oswald, E., Sugai, M., Labigne, A., et al. (1994). Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. Proceedings of the National Academy of Sciences of the United States of America, vol. 91, pp. 3814–3818.
 Smith, J. L. and Bayles, D. O. (2006). The contribution of cytolethal distending toxin to bacterial pathogenesis. Critical Reviews in Microbiology, vol. 32, pp. 227–248.
 Marches, O., Ledger, T. N., Boury, M., et al. (2003). Enteropathogenic and enterohaemorrhagic Escherichia coli deliver a novel effector called Cif, which blocks cell cycle G2/M transition. Molecular Microbiology, vol. 50, pp. 1553–1567.
 Thelestam, M. and Frisan, T. (2006). Cytolethal distending toxins, in Alouf J, Popoff M (ed.) The comprehensive sourcebook of bacterial protein toxins, pp. 448–467. San Diego, USA: Elsevier, Academic Press.
 Haghjoo, E. and Galan, J. E. (2004). Salmonella typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway. Proceedings of the National Academy of Sciences of the United States of America, vol. 101, pp. 4614–4619.
 Winter, J. A., Letley, D. P., Cook, K. W., et al. (2014). A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. The Journal of Infectious Diseases, vol. 210, pp. 954–963.
 Neal, J. T., Peterson, T. S., Kent, M. L., et al. (2013). Pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model. Disease Models & Mechanisms, vol. 6, pp. 802–810.
 Lu, R., Wu, S., Zhang, Y. G., et al. (2014). Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway. Oncogenesis, vol. 3, e105.
 Rhee, K. J., Wu, S., Wu, X., et al. (2009). Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice. Infection and Immunity, vol. 77, pp. 1708–1718.
 Dabek, M., McCrae, S. I., Stevens, V. J., et al. (2008). Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiology Ecology, vol., 66, pp. 487–495.
 DeLuca, J. A., Allred, K. F., Menon, R., et al. (2018). Bisphenol-A alters microbiota metabolites derived from aromatic amino acids and worsens disease activity during colitis. Experimental Biology and Medicine, vol. 243, pp. 864–875.
 Wynendaele, E., Verbeke, F., D’Hondt, M., et al. (2015). Crosstalk between the microbiome and cancer cells by quorum sensing peptides. Peptides, vol. 64, pp.40–48.