Microbiota in cancer diagnosis, therapy and prevention

Background. An in-depth study of the participation of the microbiota in the pathogenesis of tumors has opened up new opportunities for the development of alternative approaches to the diagnosis, therapy and prevention of malignant neoplasms.

Aim. To summarize the data on the practical use of microbiota profile features as a marker of carcinogenesis and diagnosis, as well as to consider its participation in the combined treatment and prevention of cancer.

Materials and methods. A literature search was carried out in the databases NCBI MedLine (PubMed), Scopus, web of Science using keywords that determine the purpose of the study. Results from original studies, meta-analyses, randomized controlled clinical trials, and traditional, systematic, and umbrella reviews published in recent years were analysed.

Results. Qualitative and quantitative changes in the composition of the microbiota associated with the pathogenesis of oncological diseases make it possible to use them as markers for determining the risk of developing malignant neoplasms and predicting a wide range of tumors. The mechanisms that determine the use of the microbiota in anticancer therapy are diverse. The effect on the immune system is the most significant. Of great interest are artificially created hybrid nanoparticles covered with a membrane of bacterial vesicles and tumor cells to activate specific antitumor immunity. In terms of cancer prevention, the use of probiotics, prebiotics and synbiotics discovered by I.I. Mechnikov was fundamentally substantiated.

Conclusion. The complex of scientific genomic and epigenetic data obtained in mechanistic and epidemiological studies on the role of the microbiota in the pathogenesis of tumors is currently evaluated as the most significant result justifying its practical application as a component of cancer diagnosis, therapy and prevention.

1. Busch W. Aus der Sitzung der medicinischen Section vom 13 November 1867. Berlin Klin Wochenschr. 1868;5:137. (Ger).

2. Fehleisen F. Ueber die Züchtung der Erysipelkokken auf künstlichem Nährboden und ihre Übertragbarkeit auf den Menschen. Dtsch Med Wochenschr 1882;8:553–4. (In Germ.).

3. Coley W.B. The treatment of malignant inoperable tumors with the mixed toxins of erysipelas and Bacillus prodigiosus. Brussels: M Weissenbruch, 1914. URL: https://archive.org/details/McGillLibrary-osl_treatment-tumors_C69588t1914-17842/ page/n3/mode/2up

4. Yen S., Johnson J.S. Metagenomics: a path to understanding the gut microbiome. Mamm Genome 2021;32(4):282–96. DOI: 10.1007/s00335-021-09889-x

5. Wensel C.R., Pluznick J.L., Salzberg S.L., Sears C.L. Nextgeneration sequencing: insights to advance clinical investigations of the microbiome. J Clin Invest 2022;132(7):e154944. DOI: 10.1172/JCI154944

6. Shirazi M.S.R, Al-Alo K.Z.K., Al-Yasiri M.H. et al. Microbiome dysbiosis and predominant bacterial species as human cancer biomarkers. J Gastrointest Cancer 2020;51(3):725–8. DOI: 10.1007/s12029-019-00311-z

7. Dan W., Peng L., Yan B. et al. Human microbiota in esophageal adenocarcinoma: pathogenesis, diagnosis, prognosis and therapeutic implications. Front Microbiol 2022;12:791274. DOI: 10.3389/fmicb.2021.791274

8. Zhang X., Hoffman K.L., Wei P. et al. Baseline oral microbiome and all-cancer incidence in a cohort of nonsmoking Mexican American women. Cancer Prev Res (Phila) 2021;14(3):383–92. DOI: 10.1158/1940-6207.CAPR-20-0405

9. Su S.C., Chang L.C., Huang H.D. et al. Oral microbial dysbiosis and its performance in predicting oral cancer. Carcinogenesis 2021;42(1):127–35. DOI: 10.1093/carcin/bgaa062

10. Rai A.K., Panda M., Das A.K. et al. Dysbiosis of salivary microbiome and cytokines influence oral squamous cell carcinoma through inflammation. Arch Microbiol 2021;203(1):137–52. DOI: 10.1007/s00203-020-02011-w

11. Park S.Y., Hwang B.O., Lim M. et al. Oral-gut microbiome axis in gastrointestinal disease and cancer. Cancers (Basel) 2021;13(9):2124. DOI: 10.3390/cancers13092124

12. Sun J., Tang Q., Yu S. et al. Role of the oral microbiota in cancer evolution and progression. Cancer Med 2020;9(17):6306–21. DOI: 10.1002/cam4.3206

13. Stasiewicz M., Kwaśniewski M., Karpiński T.M. Microbial associations with pancreatic cancer: a new frontier in biomarkers. Cancers (Basel) 2021;13(15):3784. DOI: 10.3390/cancers13153784

14. Yamamura K., Baba Y., Nakagawa S. et al. Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res 2016;22(22):5574–81. DOI: 10.1158/1078-0432.CCR-16-1786

15. Zhang S., Kong C., Yang Y. et al. Human oral microbiome dysbiosis as a novel non-invasive biomarker in detection of colorectal cancer. Theranostics 2020;10(25):11595–606. DOI: 10.7150/thno.49515

16. Kim M., Vogtmann E., Ahlquist D.A. et al. Fecal metabolomic signatures in colorectal adenoma patients are associated with gut microbiota and early events of colorectal cancer pathogenesis. mBio 2020;11(1):e03186–19. DOI: 10.1128/mBio.03186-19

17. Gao R., Wang Z., Li H. et al. Gut microbiota dysbiosis signature is associated with the colorectal carcinogenesis sequence and improves the diagnosis of colorectal lesions. J Gastroenterol Hepatol 2020;35(12):2109–21. DOI: 10.1111/jgh.15077

18. Li N., Bai C., Zhao L. et al. Characterization of the fecal microbiota in gastrointestinal cancer patients and healthy people. Clin Transl Oncol 2022;24(6):1134–47. DOI: 10.1007/s12094-021-02754-y

19. Ren Z., Li A., Jiang J. et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 2019;68(6):1014–23. DOI: 10.1136/gutjnl-2017-315084

20. Wheatley R.C., Kilgour E., Jacobs T. et al. Potential influence of the microbiome environment in patients with biliary tract cancer and implications for therapy. Br J Cancer 2022;126(5):693–705. DOI: 10.1038/s41416-021-01583-8

21. Kirishima M., Yokoyama S., Matsuo K. et al. Gallbladder microbiota composition is associated with pancreaticobiliary and gallbladder cancer prognosis. BMC Microbiol 2022;22(1):147. DOI: 10.1186/s12866-022-02557-3

22. Zhuang H., Cheng L., Wang Y. et al. Dysbiosis of the gut microbiome in lung cancer. Front Cell Infect Microbiol 2019;9:112. DOI: 10.3389/fcimb.2019.00112

23. Zheng Y., Fang Z., Xue Y. et al. Specific gut microbiome signature predicts the early-stage lung cancer. Gut Microbes 2020;11(4):1030–42. DOI: 10.1080/19490976.2020.1737487

24. Zhao F., An R., Wang L. et al. Specific gut microbiome and serum metabolome changes in lung cancer patients. Front Cell Infect Microbiol 2021;11:725284. DOI: 10.3389/fcimb.2021.725284

25. Laliani G., Ghasemian Sorboni S., Lari R. et al. Bacteria and cancer: different sides of the same coin. Life Sci 2020;246:117398. DOI: 10.1016/j.lfs.2020.117398

26. Nomura M. Association of the gut microbiome with cancer immunotherapy. Int J Clin Oncol 2023;28(3):347–53. DOI: 10.1007/s10147-022-02180-2

27. Matson V., Fessler J., Bao R. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–8. DOI: 10.1126/science.aao3290

28. Davar D., Dzutsev A.K., McCulloch J.A. et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021;371(6529):595–602. DOI: 10.1126/science.abf3363

29. Tomita Y., Ikeda T., Sakata S. et al. Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. Cancer Immunol Res 2020;8(10):1236–42. DOI: 10.1158/2326-6066.CIR-20-0051

30. Gupta K.H., Nowicki C., Giurini E.F. et al. Bacterial-based cancer therapy (BBCT): recent advances, current challenges, and future prospects for cancer immunotherapy. Vaccines (Basel) 2021;9(12):1497. DOI: 10.3390/vaccines9121497

31. Routy B., Le Chatelier E., Derosa L. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–7. DOI: 10.1126/science.aan3706

32. Lapteva O.G. Development of submerged cultivation method for vaccine Mycoplasma mycoides subsp. mycoides strain. Veterinariya segodnya = Veterinary Science Today 2023;12(2):158–63. (In Russ.). DOI: 10.29326/2304-196X-2023-12-2-158-163

33. Huang X., Li M., Hou S., Tian B. Role of the microbiome in systemic therapy for pancreatic ductal adenocarcinoma (Review). Int J Oncol 2021;59(6):101. DOI: 10.3892/ijo.2021.5281

34. Vitiello G.A., Cohen D.J., Miller G. Harnessing the microbiome for pancreatic cancer immunotherapy. Trends Cancer 2019;5(11):670–6. DOI: 10.1016/j.trecan.2019.10.005

35. Leinwand J., Miller G. Regulation and modulation of antitumor immunity in pancreatic cancer. Nat Immunol 2020;21(10): 1152–9. DOI: 10.1038/s41590-020-0761-y

36. Gopalakrishnan V., Spencer C.N., Nezi L. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103. DOI: 10.1126/science.aan4236

37. Limeta A., Ji B., Levin M. et al. Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma. JCI Insight 2020;5(23):e140940. DOI: 10.1172/jci.insight.140940

38. Szczyrek M., Bitkowska P., Chunowski P. et al. Diet, microbiome, and cancer immunotherapy – a comprehensive review. Nutrients 2021;13(7):2217. DOI: 10.3390/nu13072217

39. Peters B.A., Wilson M., Moran U. et al. Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients. Genome Med 2019;11(1):61. DOI: 10.1186/s13073-019-0672-4

40. Sharma P.C., Sharma D., Sharma A. et al. Recent advances in microbial toxin-related strategies to combat cancer. Semin Cancer Biol 2022;86(Pt 3):753–68. DOI: 10.1016/j.semcancer.2021.07.007

41. Khoshnood S., Fathizadeh H., Neamati F. et al. Bacteria-derived chimeric toxins as potential anticancer agents. Front Oncol 2022;12:953678. DOI: 10.3389/fonc.2022.953678

42. Erwert R.D, Eiting K.T., Tupper J.C. et al. Shiga toxin induces decreased expression of the anti-apoptotic protein Mcl-1 concomitant with the onset of endothelial apoptosis. Microb Pathog 2003;35(2):87–93. DOI: 10.1016/s0882-4010(03)00100-1

43. Robert A., Wiels J. Shiga toxins as antitumor tools. Toxins (Basel) 2021;13(10):690. DOI: 10.3390/toxins13100690

44. Trivanović D., Pavelić K., Peršurić Ž. Fighting cancer with bacteria and their toxins. Int J Mol Sci 2021;22(23):12980. DOI: 10.3390/ijms222312980

45. LaCourse K.D., Zepeda-Rivera M., Kempchinsky A.G. et al. The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota. Cell Rep 2022;41(7):111625. DOI: 10.1016/j.celrep.2022.111625

46. Kim O.Y., Dinh N.T., Park H.T. et al. Bacterial protoplastderived nanovesicles for tumor targeted delivery of chemotherapeutics. Biomaterials 2017;113:68-79. DOI: 10.1016/j.biomaterials.2016.10.037

47. Sartorio M.G., Pardue E.J., Feldman M.F., Haurat M.F. Bacterial outer membrane vesicles: from discovery to applications. Annu Rev Microbiol 2021;75:609–30. DOI: 10.1146/annurev-micro-052821-031444

48. Tropini C., Earle K.A., Huang K.C., Sonnenburg J.L. The gut microbiome: connecting spatial organization to function. Cell Host Microbe 2017;21(4):433–42. DOI: 10.1016/j.chom.2017.03.010

49. Turner L., Bitto N.J., Steer D.L. et al. Helicobacter pylori outer membrane vesicle size determines their mechanisms of host cell entry and protein content. Front Immunol 2018;9:1466. DOI: 10.3389/fimmu.2018.01466

50. Patten D.A., Hussein E., Davies S.P. et al. Commensal-derived OMVs elicit a mild proinflammatory response in intestinal epithelial cells. Microbiology (Reading) 2017;163(5):702–11. DOI: 10.1099/mic.0.000468

51. Wang X., Ni J., You Y. et al. SNX10-mediated LPS sensing causes intestinal barrier dysfunction via a caspase-5-dependent signaling cascade. EMBO J 2021;40(24):e108080. DOI: 10.15252/embj.2021108080

52. Francescone R., Hou V., Grivennikov S.I. Cytokines, IBD, and colitis-associated cancer. Inflamm Bowel Dis 2015;21(2):409–18. DOI: 10.1097/MIB.0000000000000236

53. Wong S.H., Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol 2019;16(11):690–704. DOI: 10.1038/s41575-019-0209-8

54. Bian X., Yang L., Wu W. et al. Pediococcus pentosaceus LI05 alleviates DSS-induced colitis by modulating immunological profiles, the gut microbiota and short-chain fatty acid levels in a mouse model. Microb Biotechnol 2020;13(4):1228–44. DOI: 10.1111/1751-7915.13583

55. Shi Y., Meng L., Zhang C. et al. Extracellular vesicles of Lacticaseibacillus paracasei PC-H1 induce colorectal cancer cells apoptosis via PDK1/AKT/Bcl-2 signaling pathway. Microbiol Res 2021;255:126921. DOI: 10.1016/j.micres.2021.126921

56. Fernández-Borbolla A., García-Hevia L., Fanarraga M.L. Cell membrane-coated nanoparticles for precision medicine: a comprehensive review of coating techniques for tissue-specific therapeutics. Int J Mol Sci 2024;25(4):2071. DOI: 10.3390/ijms25042071

57. Liang X., Dai N., Sheng K. et al. Gut bacterial extracellular vesicles: important players in regulating intestinal microenvironment. Gut Microbes 2022;14(1):2134689. DOI: 10.1080/19490976.2022.2134689

58. Wang D., Liu C., You S. et al. Bacterial vesicle-cancer cell hybrid membrane-coated nanoparticles for tumor specific immune activation and photothermal therapy. ACS Appl Mater Interfaces 2020;12(37):41138–47. DOI: 10.1021/acsami.0c13169

59. Meng Y., Chen S., Wang C., Ni X. Advances in composite biofilm biomimetic nanodrug delivery systems for cancer treatment. Technol Cancer Res Treat 2024;23:15330338241250244. DOI: 10.1177/15330338241250244

60. Chen Q., Huang G., Wu W. et al. A hybrid eukaryotic-prokaryotic nanoplatform with photothermal modality for enhanced antitumor vaccination. Adv Mater 2020;32(16):e1908185. DOI: 10.1002/adma.201908185

61. Rommasi F. Bacterial-based methods for cancer treatment: what we know and where we are. Oncol Ther 2022;10(1):23–54. DOI: 10.1007/s40487-021-00177-x

62. Behrouzi A., Nafari A.H., Siadat S.D. The significance of microbiome in personalized medicine. Clin Transl Med 2019;8(1):16. DOI: 10.1186/s40169-019-0232-y

63. Partula V., Mondot S., Torres M.J. et al. Associations between usual diet and gut microbiota composition: results from the Milieu Intérieur cross-sectional study. Am J Clin Nutr 2019;109(5):1472–83. DOI: 10.1093/ajcn/nqz029

64. Koponen K.K., Salosensaari A., Ruuskanen M.O. et al. Associations of healthy food choices with gut microbiota profiles. Am J Clin Nutr 2021;114(2):605–16. DOI: 10.1093/ajcn/nqab077

65. da Silva T.F., Casarotti S.N., de Oliveira G.L.V., Penna A.L.B. The impact of probiotics, prebiotics, and synbiotics on the biochemical, clinical, and immunological markers, as well as on the gut microbiota of obese hosts. Crit Rev Food Sci Nutr 2021;61(2):337–55. DOI: 10.1080/10408398.2020.1733483

66. Serban D.E. Gastrointestinal cancers: influence of gut microbiota, probiotics and prebiotics. Cancer Lett 2014;345(2):258–70. DOI: 10.1016/j.canlet.2013.08.013

67. Vivarelli S., Falzone L., Basile M.S. et al. Benefits of using probiotics as adjuvants in anticancer therapy (Review). World Acad Sci J 2019;1(3):125–35. DOI: 10.3892/wasj.2019.13

68. Chen S., Chen Y., Ma S. et al. Dietary fibre intake and risk of breast cancer: A systematic review and meta-analysis of epidemiological studies. Oncotarget 2016;7(49):80980–9. DOI: 10.18632/oncotarget.13140

69. Cong J., Zhou P., Zhang R. Intestinal microbiota-derived short chain fatty acids in host health and disease. Nutrients 2022;14(9):1977. DOI: 10.3390/nu14091977

70. Davani-Davari D., Negahdaripour M., Karimzadeh I. et al. Prebiotics: definition, types, sources, mechanisms, and clinical applications. Foods 2019;8(3):92. DOI: 10.3390/foods8030092

71. Hamada T., Nowak J.A., Milner D.A. Jr. et al. Integration of microbiology, molecular pathology, and epidemiology: a new paradigm to explore the pathogenesis of microbiome-driven neoplasms. J Pathol 2019;247(5):615–28. DOI: 10.1002/path.5236

72. Yano Y., Abnet C.C., Poustchi H. et al. Oral health and risk of upper gastrointestinal cancers in a large prospective study from a high-risk region: golestan cohort study. Cancer Prev Res (Phila) 2021;14(7):709–18. DOI: 10.1158/1940-6207.CAPR-20-0577

73. Newman K.L., Kamada N. Pathogenic associations between oral and gastrointestinal diseases. Trends Mol Med 2022;28(12): 1030–9. DOI: 10.1016/j.molmed.2022.05.006

74. Teratani T., Mikami Y., Nakamoto N. et al. The liver-brain-gut neural arc maintains the Treg cell niche in the gut. Nature 2020;585(7826):591–6. DOI: 10.1038/s41586-020-2425-3

75. Mikami Y., Tsunoda J., Kiyohara H. et al. Vagus nerve-mediated intestinal immune regulation: therapeutic implications of inflammatory bowel diseases. Int Immunol 2022;34(2):97–106. DOI: 10.1093/intimm/dxab039