Skip to main content

The immunomodulatory effects of Candida albicans isolated from the normal gastrointestinal microbiome of the elderly on colorectal cancer

Abstract

The association of gut microbiota with occurrence and development of colorectal cancer (CRC) has been reported in recent studies. Probiotics have been shown to mediate anti-cancer effects through immune system. The aim of this study was to evaluate the efficacy of Lactobacillus plantarum and Candida albicans in the suppression of azoxymethane-induced CRC in male Fischer 344 rats. 30 adult male Fischer 344 rats were divided into 6 distinct groups (n = 5 per group): non-treated animals, fat-food intake group, fat-food and carcinogen intake group, CRC cancer-induced rats treated with the chemotherapy drug, CRC-induced rats treated with Lactobacillus plantarum, and CRC-induced rats treated with Candida albicans. Identification of Candida albicans isolated from human feces was performed by microbiological, biochemical, and PCR methods. The serum levels of IFN-γ, IL-4, TGF-β, and TNF-α were measured by ELISA. Pathological studies were performed through hematoxylin and eosin (H&E) staining method. The data were analyzed using one-way ANOVA and Tukey's post-hoc analysis. Shrinking cancer cells with very dark nuclei were observed in CRC-induced rats treated with the chemotherapy drug, Lactobacillus plantarum, and Candida albicans indicating the occurrence of apoptosis. Serum levels of IFN-γ, IL-4, and TGF-β significantly decreased compared to the control group (p < 0.05). Lactobacillus plantarum and Candida albicans isolated from the gastrointestinal tract of the elderly and healthy individuals can efficiently improve CRC.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

References

  1. 1.

    Sivamaruthi BS, Kesika P, Chaiyasut C. The role of probiotics in colorectal cancer management. Evidence-Based Complement Altern Med Hindawi. 2020;2020:1–17.

    Google Scholar 

  2. 2.

    Mehralikhani A, Movahedi M, Larypoor M, Golab F. Evaluation of the Effect of Foeniculum vulgare on the Expression of E-Cadherin, Dysadherin and Ki-67 in BALB/C Mice with 4T1 Model of Breast Cancer. Nutr Cancer. 2020; 73, 318-328

  3. 3.

    Vipperla K, O’Keefe SJ. Diet, microbiota, and dysbiosis: a ‘recipe’ for colorectal cancer. Food Funct. 2016;7:1731–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Raskov H, Burcharth J, Pommergaard H-C. Linking gut microbiota to colorectal cancer. J Cancer. 2017;8:3378–95.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Meng C, Bai C, Brown TD, Hood LE, Tian Q. Human gut microbiota and gastrointestinal cancer. Genomics Proteomics Bioinformatics. 2018;16:33–49.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Sánchez B, Delgado S, Blanco-Míguez A, Lourenço A, Gueimonde M, Margolles A. Probiotics, gut microbiota, and their influence on host health and disease. Mol Nutr Food Res. 2017;61:1600240.

    Google Scholar 

  7. 7.

    Chakraborty C, Sharma AR, Sharma G, Lee S-S. The interplay among miRNAs, major cytokines, and cancer-related inflammation. Mol Ther - Nucleic Acids. 2020;20:606–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Mager LF, Wasmer M-H, Rau TT, Krebs P. Cytokine-induced modulation of colorectal cancer. Front Oncol. 2016;6:96.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Hallett MA, Venmar KT, Fingleton B. Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL-4 and IL-13. Cancer Res. 2012;72:6338–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Todaro M, Lombardo Y, Francipane MG, Alea MP, Cammareri P, Iovino F, et al. Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ. 2008;15:762–72.

    CAS  PubMed  Google Scholar 

  11. 11.

    Kalvakolanu DV, Nallar SC, Kalakonda S. Cytokine-induced tumor suppressors: A GRIM story. Cytokine. 2010;52:128–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ganapathi SK, Beggs AD, Hodgson SV, Kumar D. Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance. Br J Cancer. 2014;111:1581–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Wang L, Wang Y, Song Z, Chu J, Qu X. Deficiency of interferon-gamma or its receptor promotes colorectal cancer development. J Interf Cytokine Res. 2015;35:273–80.

    CAS  Google Scholar 

  14. 14.

    Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS, Doetschman T. Transforming growth factor β1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res. 1999;59:3379–86.

    CAS  PubMed  Google Scholar 

  15. 15.

    Feagins LA. Role of transforming growth factor-β in inflammatory bowel disease and colitis-associated colon cancer. Inflamm Bowel Dis. 2010;16:1963–8.

    PubMed  Google Scholar 

  16. 16.

    Calon A, Espinet E, Palomo-Ponce S, Tauriello DVF, Iglesias M, Céspedes MV, et al. Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Shen Z, Zhou R, Liu C, Wang Y, Zhan W, Shao Z, et al. MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression. Cell Death Dis. 2017;8:3213.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kitahara CM, Trabert B, Katki HA, Chaturvedi AK, Kemp TJ, Pinto LA, et al. Body mass index, physical activity, and serum markers of inflammation, immunity, and insulin resistance. Cancer Epidemiol Biomarkers Prev. 2014;23:2840–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Zhong L. Emerging roles of lactic acid bacteria in protection against colorectal cancer. World J Gastroenterol. 2014;20:7878.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Zaharuddin L, Mokhtar NM, Muhammad Nawawi KN, Raja Ali RA. A randomized double-blind placebo-controlled trial of probiotics in post-surgical colorectal cancer. BMC Gastroenterol. 2019;19:131.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Soltani M, Larypoor M, Hamedani MP. Effect of allicin of garlic on production nitric oxide of macrophage to Candida albicans. J Med Plants. 2009;8:164–71.

    Google Scholar 

  22. 22.

    Ramirez-Garcia A, Rementeria A, Aguirre-Urizar JM, Moragues MD, Antoran A, Pellon A, et al. Candida albicans and cancer: Can this yeast induce cancer development or progression? Crit Rev Microbiol. 2014;42:1–13.

    Google Scholar 

  23. 23.

    Rodríguez-Cuesta J, Hernando FL, Mendoza L, Gallot N, de Cerio AAD, Martínez-de-Tejada G, et al. Candida albicans enhances experimental hepatic melanoma metastasis. Clin Exp Metastasis. 2010;27:35–42.

    PubMed  Google Scholar 

  24. 24.

    Peymaeei F, Sadeghi F, Safari E, Khorrami S, Falahati M, Roudbar Mohammadi S, et al. Candida albicans beta-glucan induce anti- cancer activity of mesenchymal stem cells against lung cancer cell line: an in-vitro experimental study. Asian Pacific J Cancer Prev. 2020;21:837–43.

    CAS  Google Scholar 

  25. 25.

    Raju J, Patlolla JMR, Swamy MV, Rao CV. Diosgenin, a Steroid Saponin of <em>Trigonella foenum graecum</em> (Fenugreek), inhibits azoxymethane-induced aberrant crypt foci formation in F344 rats and induces apoptosis in HT-29 human colon cancer cells. Cancer Epidemiol Biomarkers & Prev. 2004;13:1392–8.

    CAS  Google Scholar 

  26. 26.

    Jacouton E, Chain F, Sokol H, Langella P, Bermúdez-Humarán LG. Probiotic strain lactobacillus casei BL23 prevents colitis-associated colorectal cancer. Front Immunol. 2017;8:1553.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Lin J. Dietary fat and fatty acids and risk of colorectal cancer in women. Am J Epidemiol. 2004;160:1011–22.

    PubMed  Google Scholar 

  28. 28.

    Struck MB, Andrutis KA, Ramirez HE, Battles AH. Effect of a short-term fast on ketamine–xylazine anesthesia in rats. J Am Assoc Lab Anim Sci. 2011;50:344–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Maroof H, Hassan ZM, Mobarez AM, Mohamadabadi MA. Lactobacillus acidophilus could modulate the immune response against breast cancer in murine model. J Clin Immunol. 2012;32:1353–9.

    CAS  PubMed  Google Scholar 

  30. 30.

    Jang S-O, Kim H-J, Kim Y-J, Kang M-J, Kwon J-W, Seo J-H, et al. Asthma prevention by lactobacillus rhamnosus in a mouse model is associated with CD4 + CD25 + Foxp3 + T Cells. Allergy Asthma Immunol Res. 2012;4:150.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Marinho SA, Teixeira AB, Santos OS, Cazanova RF, Ferreira CAS, Cherubini K, et al. Identification. 2010;41:286–94.

    Google Scholar 

  32. 32.

    Sengupta S, Shaila MS, Rao GR. Purification and characterization of assimilatory nitrite reductase from Candida utilis. Biochem J. 1996;317:147–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Dhamgaye S, Devaux F, Manoharlal R, Vandeputte P, Shah AH, Singh A, et al. In Vitro Effect of Malachite Green on Candida albicans Involves Multiple Pathways and Transcriptional Regulators UPC2 and STP2. Antimicrob Agents Chemother content/56/1/495

  34. 34.

    Bitar I, Khalaf RA, Harastani H, Tokajian S. Identification, typing, antifungal resistance profile, and biofilm formation of candida albicans isolates from Lebanese hospital patients. Biomed Res Int. 2014;2014:1–10.

    Google Scholar 

  35. 35.

    Tay ST, Tan HW, Na SL, Lim SL. Phenotypic and genotypic characterization of two closely related subgroups of Candida rugosa in clinical specimens. J Med Microbiol. 2011;60:1591–7.

    CAS  PubMed  Google Scholar 

  36. 36.

    Cassone A, Bistoni F, Cenci E, Pesce CD, Tissi L, Marconi P. Immunopotentiation of anticancer chemotherapy by Candida albicans, other yeasts and insoluble glucan in an experimental lymphoma model. Med Mycol. 1982;20:115–25.

    CAS  Google Scholar 

  37. 37.

    Ozel L, Ozel MS, Toros AB, Kara M, Ozkan KS, Tellioglu G, et al. Effect of early preoperative 5-fluorouracil on the integrity of colonic anastomoses in rats. World J Gastroenterol. 2009;15:4156.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Beeton C, Garcia A, Chandy KG. Drawing blood from rats through the saphenous vein and by cardiac puncture. J Vis Exp. 2007;e266.

  39. 39.

    Stringer AM, Gibson RJ, Logan RM, Bowen JM, Yeoh ASJ, Hamilton J, et al. Gastrointestinal microflora and mucins may play a critical role in the development of 5-fluorouracil-induced gastrointestinal mucositis. Exp Biol Med. 2009;234:430–41.

    CAS  Google Scholar 

  40. 40.

    Sanders ME, Merenstein D, Merrifield CA, Hutkins R. Probiotics for human use Nutr Bull. 2018;43:212–25.

    Google Scholar 

  41. 41.

    Larypoor M, Bayat M, Zuhair MH, Akhavan Sepahy A, Amanlou M. Evaluation of the number of CD4(+) CD25(+) FoxP3(+) treg cells in normal mice exposed to AFB1 and treated with aged garlic extract. Cell J Royan Institute. 2013;15:37–44.

    Google Scholar 

  42. 42.

    Flórez AB, Sierra M, Ruas-Madiedo P, Mayo B. Susceptibility of lactic acid bacteria, bifidobacteria and other bacteria of intestinal origin to chemotherapeutic agents. Int J Antimicrob Agents. 2016;48:547–50.

    PubMed  Google Scholar 

  43. 43.

    Ito S, Shirota H, Kasahara Y, Saijo K, Ishioka C. IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model. Cancer Immunol Immunother. 2017;66:1485–96.

    CAS  PubMed  Google Scholar 

  44. 44.

    Jia Y, Xie X, Shi X, Li S. Associations of common IL-4 gene polymorphisms with cancer risk: A meta-analysis. Mol Med Rep. 2017;16:1927–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Camp BJ, Dyhrman ST, Memoli VA, Mott LA, Barth RJ. In situ cytokine production by breast cancer tumor-infiltrating lymphocytes. Ann Surg Oncol. 1996;3:176–84.

    CAS  PubMed  Google Scholar 

  46. 46.

    Dumont N, Arteaga CL. Transforming growth factor-beta and breast cancer: Tumor promoting effects of transforming growth factor-β. Breast Cancer Res. 2000;2:125.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Markowitz S. Tumor suppressor activity of the TGF-β pathway in human cancers. Cytokine Growth Factor Rev. 1996;7:93–102.

    CAS  PubMed  Google Scholar 

  48. 48.

    Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, et al. TGFβ1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell. 1996;86:531–42.

    CAS  PubMed  Google Scholar 

  49. 49.

    Murphy EA, Davis JM, Barrilleaux TL, McClellan JL, Steiner JL, Carmichael MD, et al. Benefits of exercise training on breast cancer progression and inflammation in C3(1)SV40Tag mice. Cytokine. 2011;55:274–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Mocellin S. TNF and cancer: the two sides of the coin. Front Biosci. 2008;13:2774.

    CAS  PubMed  Google Scholar 

  51. 51.

    Kawai N, Tsuji S, Tsujii M, Ito T, Yasumaru M, Kakiuchi Y, et al. Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells. Gastroenterology. 2002;122:331–9.

    CAS  PubMed  Google Scholar 

  52. 52.

    Cruceriu D, Baldasici O, Balacescu O, Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: molecular insights and therapeutic approaches. Cell Oncol. 2020;43:1–18.

    CAS  Google Scholar 

  53. 53.

    Vázquez-Frias R, Gutiérrez-Reyes G, Urbán-Reyes M, Velázquez-Guadarrama N, Fortoul-van der Goes TI, Reyes-López A, et al. Proinflammatory and anti-inflammatory cytokine profile in pediatric patients with irritable bowel syndrome. Rev Gastroenterol México. 2015;80:6–12.

  54. 54.

    Bennet SMP, Polster A, Törnblom H, Isaksson S, Capronnier S, Tessier A, et al. Global cytokine profiles and association with clinical characteristics in patients with irritable bowel syndrome. Am J Gastroenterol. 2016;111:1165–76.

    CAS  PubMed  Google Scholar 

  55. 55.

    Schmulson M, Pulido-London D, Rodríguez Ó, Morales-Rochlin N, Martínez-García R, Gutiérrez-Ruiz MC, et al. IL-10 and TNF-α polymorphisms in subjects with irritable bowel syndrome in Mexico. Rev Española Enfermedades Dig. 2013;105:392–9.

    CAS  Google Scholar 

  56. 56.

    Kursunel MA, Esendagli G. The untold story of IFN-γ in cancer biology. Cytokine Growth Factor Rev. 2016;31:73–81.

    PubMed  Google Scholar 

Download references

Funding

No funding was received for conducting this study.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mohaddeseh Larypoor.

Ethics declarations

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Additional information

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

Verify currency and authenticity via CrossMark

Cite this article

Shams, K., Larypoor, M. & Salimian, J. The immunomodulatory effects of Candida albicans isolated from the normal gastrointestinal microbiome of the elderly on colorectal cancer. Med Oncol 38, 140 (2021). https://doi.org/10.1007/s12032-021-01591-x

Download citation

Keywords

  • Colorectal cancer
  • Candida albicans
  • IFN-γ
  • IL-4
  • TGF-β
  • TNF-α