The impact of gut microbiota manipulation with antibiotics on colon tumorigenesis in a murine model

Autoři: Jae Gon Lee aff001;  Chang Soo Eun aff001;  Su Vin Jo aff001;  A-reum Lee aff001;  Chan Hyuk Park aff001;  Dong Soo Han aff001
Působiště autorů: Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea aff001
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


It has been suggested that manipulation of gut microbiota using antibiotics can inhibit colitis-associated colorectal cancer (CAC) in a mouse model. We investigated whether timing of gut microbial manipulation using antibiotics affects colon tumorigenesis in the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model. CAC was induced in C57BL/6 mice by injection of 12.5 mg/kg AOM followed by three rounds of 1.7% DSS exposure. There were six groups based on timing of antibiotic administration. Colonic inflammation, proliferation, and tumorigenesis were evaluated after animal sacrifice. High-throughput sequencing of the mice feces was performed to characterize changes in gut microbiota. Full-time antibiotic treatment significantly decreased the number and size of tumors, histological scores, and expression of pro-inflammatory cytokines compared to the AOM/DSS group without antibiotic treatment. The early and late antibiotic groups, antibiotic administration from the first and second rounds of DSS to the end of the study, showed significantly lower histological scores and tumor burden. In contrast, the pretreatment antibiotic group, antibiotic administration from 3 weeks prior to AOM to the first round of DSS, did not exhibit decreased tumorigenesis. Principal coordinate analysis showed similar gut microbial community structures among the full-time, early, and late antibiotic groups, whereas other groups showed distinct gut microbial profiles. There was a positive correlation between number of tumors and number of operational taxonomic units. Colonic tumorigenesis was attenuated by antibiotic administration, except for that only prior to DSS administration, suggesting that gut microbial changes should be maintained throughout the entire period of inflammation to suppress tumorigenesis.

Klíčová slova:

Antibiotics – Cancer treatment – Carcinogenesis – Colon – Dextran – Gut bacteria – Histology – Inflammation


1. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390(10114):2769–78. Epub 2017/10/21. doi: 10.1016/S0140-6736(17)32448-0 29050646.

2. Francescone R, Hou V, Grivennikov SI. Cytokines, IBD, and colitis-associated cancer. Inflamm Bowel Dis. 2015;21(2):409–18. Epub 2015/01/08. doi: 10.1097/MIB.0000000000000236 25563695; PubMed Central PMCID: PMC4481731.

3. Kang M, Martin A. Microbiome and colorectal cancer: Unraveling host-microbiota interactions in colitis-associated colorectal cancer development. Semin Immunol. 2017;32:3–13. Epub 2017/05/04. doi: 10.1016/j.smim.2017.04.003 28465070.

4. Klimesova K, Kverka M, Zakostelska Z, Hudcovic T, Hrncir T, Stepankova R, et al. Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice. Inflamm Bowel Dis. 2013;19(6):1266–77. Epub 2013/04/10. doi: 10.1097/MIB.0b013e318281330a 23567778; PubMed Central PMCID: PMC3744230.

5. Lasry A, Zinger A, Ben-Neriah Y. Inflammatory networks underlying colorectal cancer. Nat Immunol. 2016;17(3):230–40. Epub 2016/02/18. doi: 10.1038/ni.3384 26882261.

6. Brennan CA, Garrett WS. Gut Microbiota, Inflammation, and Colorectal Cancer. Annu Rev Microbiol. 2016;70:395–411. Epub 2016/09/09. doi: 10.1146/annurev-micro-102215-095513 27607555; PubMed Central PMCID: PMC5541233.

7. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80. Epub 2011/04/22. doi: 10.1038/nature09944 21508958; PubMed Central PMCID: PMC3728647.

8. Zackular JP, Baxter NT, Chen GY, Schloss PD. Manipulation of the Gut Microbiota Reveals Role in Colon Tumorigenesis. mSphere. 2016;1(1). Epub 2016/06/16. doi: 10.1128/mSphere.00001-15 27303681; PubMed Central PMCID: PMC4863627.

9. Zackular JP, Baxter NT, Iverson KD, Sadler WD, Petrosino JF, Chen GY, et al. The gut microbiome modulates colon tumorigenesis. MBio. 2013;4(6):e00692–13. Epub 2013/11/07. doi: 10.1128/mBio.00692-13 24194538; PubMed Central PMCID: PMC3892781.

10. Meira LB, Bugni JM, Green SL, Lee CW, Pang B, Borenshtein D, et al. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest. 2008;118(7):2516–25. Epub 2008/06/04. doi: 10.1172/JCI35073 18521188; PubMed Central PMCID: PMC2423313.

11. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011;140(6):1807–16. Epub 2011/05/03. doi: 10.1053/j.gastro.2011.01.057 21530747.

12. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117(5):1175–83. Epub 2007/05/04. doi: 10.1172/JCI31537 17476347; PubMed Central PMCID: PMC1857251.

13. Liu DP, Song H, Xu Y. A common gain of function of p53 cancer mutants in inducing genetic instability. Oncogene. 2010;29(7):949–56. Epub 2009/11/03. doi: 10.1038/onc.2009.376 19881536; PubMed Central PMCID: PMC2837937.

14. Arthur JC, Perez-Chanona E, Muhlbauer M, Tomkovich S, Uronis JM, Fan TJ, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338(6103):120–3. Epub 2012/08/21. doi: 10.1126/science.1224820 22903521; PubMed Central PMCID: PMC3645302.

15. Ponziani FR, Zocco MA, D'Aversa F, Pompili M, Gasbarrini A. Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation. World J Gastroenterol. 2017;23(25):4491–9. Epub 2017/07/26. doi: 10.3748/wjg.v23.i25.4491 28740337; PubMed Central PMCID: PMC5504364.

16. Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010;138(2):746–74, 74 e1-4; quiz e12-3. Epub 2010/02/10. doi: 10.1053/j.gastro.2009.12.035 20141809.

17. Woolrich AJ, DaSilva MD, Korelitz BI. Surveillance in the routine management of ulcerative colitis: the predictive value of low-grade dysplasia. Gastroenterology. 1992;103(2):431–8. Epub 1992/08/01. doi: 10.1016/0016-5085(92)90831-i 1634062.

18. Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut. 1990;31(7):800–6. Epub 1990/07/01. doi: 10.1136/gut.31.7.800 2370015; PubMed Central PMCID: PMC1378540.

19. Ullman TA, Loftus EV Jr., Kakar S, Burgart LJ, Sandborn WJ, Tremaine WJ. The fate of low grade dysplasia in ulcerative colitis. Am J Gastroenterol. 2002;97(4):922–7. Epub 2002/05/15. doi: 10.1111/j.1572-0241.2002.05610.x 12008669.

20. Jess T, Loftus EV Jr., Velayos FS, Harmsen WS, Zinsmeister AR, Smyrk TC, et al. Incidence and prognosis of colorectal dysplasia in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Inflamm Bowel Dis. 2006;12(8):669–76. Epub 2006/08/19. doi: 10.1097/00054725-200608000-00001 16917220.

21. Eaton JE, Smyrk TC, Imam M, Pardi DS, Loftus EV Jr., Owens VL, et al. The fate of indefinite and low-grade dysplasia in ulcerative colitis and primary sclerosing cholangitis colitis before and after liver transplantation. Aliment Pharmacol Ther. 2013;38(8):977–87. Epub 2013/09/17. doi: 10.1111/apt.12469 24033551.

22. Baxter NT, Zackular JP, Chen GY, Schloss PD. Structure of the gut microbiome following colonization with human feces determines colonic tumor burden. Microbiome. 2014;2:20. Epub 2014/06/27. doi: 10.1186/2049-2618-2-20 24967088; PubMed Central PMCID: PMC4070349.

23. Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe. 2010;8(3):292–300. Epub 2010/09/14. doi: 10.1016/j.chom.2010.08.004 20833380; PubMed Central PMCID: PMC2952357.

24. Sinha R, Ahn J, Sampson JN, Shi J, Yu G, Xiong X, et al. Fecal Microbiota, Fecal Metabolome, and Colorectal Cancer Interrelations. PLoS One. 2016;11(3):e0152126. Epub 2016/03/26. doi: 10.1371/journal.pone.0152126 27015276; PubMed Central PMCID: PMC4807824.

25. Kim M, Friesen L, Park J, Kim HM, Kim CH. Microbial metabolites, short-chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice. Eur J Immunol. 2018;48(7):1235–47. Epub 2018/04/13. doi: 10.1002/eji.201747122 29644622.

26. Sekirov I, Tam NM, Jogova M, Robertson ML, Li Y, Lupp C, et al. Antibiotic-induced perturbations of the intestinal microbiota alter host susceptibility to enteric infection. Infect Immun. 2008;76(10):4726–36. Epub 2008/08/06. doi: 10.1128/IAI.00319-08 18678663; PubMed Central PMCID: PMC2546810.

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden