DOI QR코드

DOI QR Code

Probiotics and the Role of Dietary Substrates in Maintaining the Gut Health: Use of Live Microbes and Their Products for Anticancer Effects against Colorectal Cancer

  • Yi Xu (Phase I Clinical Cancer Trial Center, The Affiliated Lianyungang Hospital of Xuzhou Medical University) ;
  • Xiahui Wu (Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University) ;
  • Yan Li (Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University) ;
  • Xuejie Liu (Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University) ;
  • Lijian Fang (Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University) ;
  • Ziyu Jiang (Phase I Clinical Cancer Trial Center, The Affiliated Lianyungang Hospital of Xuzhou Medical University)
  • Received : 2024.03.27
  • Accepted : 2024.07.28
  • Published : 2024.10.28

Abstract

The gut microbiome is an important and the largest endocrine organ linked to the microbes of the GI tract. The bacterial, viral and fungal communities are key regulators of the health and disease status in a host at hormonal, neurological, immunological, and metabolic levels. The useful microbes can compete with microbes exhibiting pathogenic behavior by maintaining resistance against their colonization, thereby maintaining eubiosis. As diagnostic tools, metagenomic, proteomic and genomic approaches can determine various microbial markers in clinic for early diagnosis of colorectal cancer (CRC). Probiotics are live non-pathogenic microorganisms such as lactic acid bacteria, Bifidobacteria, Firmicutes and Saccharomyces that can help maintain eubiosis when administered in appropriate amounts. In addition, the type of dietary intake contributes substantially to the composition of gut microbiome. The use of probiotics has been found to exert antitumor effects at preclinical levels and promote the antitumor effects of immunotherapeutic drugs at clinical levels. Also, modifying the composition of gut microbiota by Fecal Microbiota Transplantation (FMT), and using live lactic acid producing bacteria such as Lactobacillus, Bifidobacteria and their metabolites (termed postbiotics) can contribute to immunomodulation of the tumor microenvironment. This can lead to tumor-preventive effects at early stages and antitumor effects after diagnosis of CRC. To conclude, probiotics are presumably found to be safe to use in humans and are to be studied further to promote their appliance at clinical levels for management of CRC.

Keywords

Acknowledgement

This study was supported by the First People's Hospital of Lianyungang, Doctoral Startup Fund (BS1701) and the P roject of Jiangsu Province TCM Science and Technology Development Plan (ZT202112).

References

  1. Thursby E, Juge N. 2017. Introduction to the human gut microbiota. Biochem. J. 474: 1823-1836. 
  2. Afzaal M, Saeed F, Shah YA, Hussain M, Rabail R, Socol CT, et al. 2022. Human gut microbiota in health and disease: unveiling the relationship. Front. Microbiol. 13: 999001. 
  3. Guinane CM, Cotter PD. 2013. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therap. Adv. Gastroenterol. 6: 295-308. 
  4. Lee LH, Wong SH, Chin SF, Singh V, Ab Mutalib NS. 2021. Human microbiome: symbiosis to pathogenesis. Front. Microbiol. 12: 605783. 
  5. Pandey H, Tang DW, Wong SH, Lal D. 2023. Gut microbiota in colorectal cancer: biological role and therapeutic opportunities. Cancers 15: 866. 
  6. Wong CC, Yu J. 2023. Gut microbiota in colorectal cancer development and therapy. Nat. Rev. Clin. Oncol. 20: 429-452. 
  7. Kim J, Lee HK. 2022. Potential role of the gut microbiome in colorectal cancer progression. Front. Immunol. 12: 807648. 
  8. Li M, Wang B, Zhang M, Rantalainen M, Wang S, Zhou H, et al. 2008. Symbiotic gut microbes modulate human metabolic phenotypes. Proc. Natl. Acad. Sci. USA 105: 2117-2122. 
  9. Merenstein D, Pot B, Leyer G, Ouwehand AC, Preidis GA, Elkins CA, et al. 2023. Emerging issues in probiotic safety: 2023 perspectives. Gut Microbes 15: 2185034. 
  10. Latif A, Shehzad A, Niazi S, Zahid A, Ashraf W, Iqbal MW, et al. 2023. Probiotics: mechanism of action, health benefits and their application in food industries. Front. Microbiol. 14: 1216674. 
  11. Das TK, Pradhan S, Chakrabarti S, Mondal KC, Ghosh K. 2022. Current status of probiotic and related health benefits. Appl. Food Res. 2: 100185. 
  12. Stojanov S, Berlec A, Strukelj B. 2020. The influence of probiotics on the firmicutes/bacteroidetes ratio in the treatment of obesity and inflammatory bowel disease. Microorganisms 8: 1715. 
  13. Kareena A, Siripongvutikorn S, Usawakesmanee W, Wichienchot S. 2021. In vitro evaluation of probiotic bacteria and yeast growth, pH changes and metabolites produced in a pure culture system using protein base products with various added carbon sources. Food Sci. Technol. 42: e18321. 
  14. Soemarie YB, Milanda T, Barliana MI. 2021. Fermented foods as probiotics: a review. J. Adv. Pharm. Technol. Res. 12: 335-339. 
  15. Olson DW, Aryana KJ. 2022. Probiotic Incorporation into yogurt and various novel yogurt-based products. Appl. Sci. 12: 12607. 
  16. Sanders M, Merenstein D, Merrifield C, Hutkins R. 2018. Probiotics for human use. Nutr. Bull. 43: 212-225. 
  17. Fijan S. 2014. Microorganisms with claimed probiotic properties: an overview of recent literature. Int. J. Environ. Res. Public Health 11: 4745-4767. 
  18. Stiles ME, Holzapfel WH. 1997. Lactic acid bacteria of foods and their current taxonomy. Int. J. Food Microbiol. 36: 1-29. 
  19. Abid R, Waseem H. 2022. Probiotic yeast Saccharomyces: back to nature to improve human health. J. Fungi 8: 444. 
  20. Alhhazmi AA, Alhamawi RM, Almisned RM, Almutairi HA, Jan AA, Kurdi SM, et al. 2023. Gut Microbial and associated metabolite markers for colorectal cacncer diagnosis. Microorganisms 11: 2037. 
  21. Zwezerijnen-Jiwa FH, Sivov H, Paizs P, Zafeiropoulou K, Kinross J. 2023. A systematic review of microbiome-derived biomarkers for early colorectal cancer detection. Neoplasia 36: 100868. 
  22. Yu L, Zhao G, Wang L, Zhou X, Sun J, Li X, et al. 2022. A systematic review of microbial markers for risk prediction of colorectal neoplasia. Br. J. Cancer 126: 1318-1328. 
  23. Wu Y, Jiao N, Zhu R, Zhang Y, Wu D, Wang A-J, et al. 2021. Identification of microbial markers across populations in early detection of colorectal cancer. Nat. Commun. 12: 3063. 
  24. Jiang Z, Li L, Chen J, Wei G, Ji Y, Chen X, et al. 2021. Human gut-microbiome interplay: analysis of clinical studies for the emerging roles of diagnostic microbiology in inflammation, oncogenesis and cancer management. Infect. Genet. Evol. 93: 104946. 
  25. Sun Y, Guo Z, Liu X, Yang L, Jing Z, Cai M, et al. 2022. Noninvasive urinary protein signatures associated with colorectal cancer diagnosis and metastasis. Nat. Commun. 13: 2757. 
  26. Zhang Z, Liu X, Yang X, Jiang Y, Li A, Cong J, et al. 2023. Identification of faecal extracellular vesicles as novel biomarkers for the non-invasive diagnosis and prognosis of colorectal cancer. J. Extracell. Vesicles 12: 12300. 
  27. Ghazanfar S, Fatima I, Aslam M, Musharraf SG, Sherman NE, Moskaluk C, et al. 2017. Identification of actin beta-like 2 (ACTBL2) as novel, upregulated protein in colorectal cancer. J. Proteomics 152: 33-40. 
  28. Hao JJ, Zhi X, Wang Y, Zhang Z, Hao Z, Ye R, et al. 2017. Comprehensive proteomic characterization of the human colorectal carcinoma reveals signature proteins and perturbed pathways. Sci. Rep. 7: 42436. 
  29. Harlid S, Harbs J, Myte R, Brunius C, Gunter MJ, Palmqvist R, et al. 2021. A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk. Sci. Rep. 11: 5151. 
  30. Rho J-h, Ladd JJ, Li CI, Potter JD, Zhang Y, Shelley D, et al. 2018. Protein and glycomic plasma markers for early detection of adenoma and colon cancer. Gut 67: 473-484. 
  31. Redondo M, Rodrigo I, Alcaide J, Tellez T, Roldan MJ, Funez R, et al. 2010. Clusterin expression is associated with decreased disease-free survival of patients with colorectal carcinomas. Histopathology 256: 932-936. 
  32. Yang Q, Bavi P, Wang JY, Roehrl MH. 2017. Immuno-proteomic discovery of tumor tissue autoantigens identifies olfactomedin 4, CD11b, and integrin alpha-2 as markers of colorectal cancer with liver metastases. J. Proteomics 168: 53-65. 
  33. Yang Q, Roehrl MH, Wang JY. 2018. Proteomic profiling of antibody-inducing immunogens in tumor tissue identifies PSMA1, LAP3, ANXA3, and maspin as colon cancer markers. Oncotarget. 9: 3996. 
  34. Yu J, Zhai X, Li X, Zhong C, Guo C, Yang F, et al. 2017. Identification of MST1 as a potential early detection biomarker for colorectal cancer through a proteomic approach. Sci. Rep. 7: 14265. 
  35. Fan NJ, Chen HM, Song W, Zhang ZY, Zhang MD, Feng LY, et al. 2016. Macrophage mannose receptor 1 and S100A9 were identified as serum diagnostic biomarkers for colorectal cancer through a label-free quantitative proteomic analysis. Cancer Biomarkers 16: 235-243. 
  36. Kirana C, Peng L, Miller R, Keating JP, Glenn C, Shi H, et al. 2019. Combination of laser microdissection, 2D-DIGE and MALDI-TOF MS to identify protein biomarkers to predict colorectal cancer spread. Clin. Proteomics 16: 3. 
  37. van Huizen NA, van den Braak RRC, Doukas M, Dekker LJ, IJzermans JN, Luider TM. 2019. Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue. J. Biol. Chem. 294: 281-289. 
  38. Lalmahomed ZS, Broker ME, van Huizen NA, van den Braak RRC, Dekker LJ, Rizopoulos D, et al. 2016. Hydroxylated collagen peptide in urine as biomarker for detecting colorectal liver metastases. Am. J. Cancer Res. 6: 321. 
  39. Clarke CN, Lee MS, Wei W, Manyam G, Jiang ZQ, Lu Y, et al. 2017. Proteomic features of colorectal cancer identify tumor subtypes independent of oncogenic mutations and independently predict relapse-free survival. Ann. Surg. Oncol. 24: 4051-4058. 
  40. Kudryavtseva AV, Lipatova AV, Zaretsky AR, Moskalev AA, Fedorova MS, Rasskazova AS, et al. 2016. Important molecular genetic markers of colorectal cancer. Oncotarget. 7: 53959. 
  41. Koncina E, Haan S, Rauh S, Letellier E. 2020. Prognostic and predictive molecular biomarkers for colorectal cancer: updates and challenges. Cancers 12: 319. 
  42. Ponomaryova AA, Rykova EY, Solovyova AI, Tarasova AS, Kostromitsky DN, Dobrodeev AY, et al. 2023. Genomic and transcriptomic research in the discovery and application of colorectal cancer circulating markers. Int. J. Mol. Sci. 24: 12407. 
  43. Capuano E. 2017. The behavior of dietary fiber in the gastrointestinal tract determines its physiological effect. Crit. Rev. Food Sci. Nutr. 57: 3543-3564. 
  44. Fu J, Zheng Y, Gao Y, Xu W. 2022. Dietary fiber intake and gut microbiota in human health. Microorganisms 10: 2507. 
  45. Goodman BE. 2010. Insights into digestion and absorption of major nutrients in humans. Adv. Physiol. Edu. 34: 44-53. 
  46. Southgate DA. 1998. How much and what classes of carbohydrate reach the colon. Eur. J. Cancer Prev. Supple 2: S81-2. 
  47. Afshin A, Sur PJ, Fay KA, Cornaby L, Ferrara G, Salama JS, et al. 2019. Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 393: 1958-1972. 
  48. Musso G, Gambino R, Cassader M. 2011. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Ann. Rev. Med. 62: 361-380. 
  49. Leeming ER, Johnson AJ. 2019. Effect of diet on the gut microbiota: rethinking intervention duration. Nutrients 11: 2862. 
  50. Slizewska K, Markowiak-Kopec P, Slizewska W. 2020. The role of probiotics in cancer prevention. Cancers13: 20. 
  51. Wong SH, Yu J. 2019. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat. Rev. Gastroenterol. Hepatol. 16: 690-704. 
  52. McQuade JL, Daniel CR, Helmink BA, Wargo JA. 2019. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 20: e77-e91. 
  53. Conlon MA, Bird AR. 2014. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7: 17-44. 
  54. Syngai GG, Gopi R, Bharali R, Dey S, Lakshmanan GM, Ahmed G. 2016. Probiotics - the versatile functional food ingredients. J. Food Sci. Technol. 53: 921-933. 
  55. Fong W, Li Q, Yu J. 2020. Gut microbiota modulation: a novel strategy for prevention and treatment of colorectal cancer. Oncogene 39: 4925-4943. 
  56. Longhi G, Van Sinderen D, Ventura M, Turroni F. 2020. Microbiota and cancer: the emerging beneficial role of bifidobacteria in cancer immunotherapy. Front. Microbiol. 11: 575072. 
  57. Zhao J, Liao Y, Wei C, Ma Y, Wang F, Chen Y, et al. 2023. Potential ability of probiotics in the prevention and treatment of colorectal cancer. Clin. Med. Insights Oncol. 17: 11795549231188225. 
  58. Hardy H, Harris J, Lyon E, Beal J, Foey AD. 2013. Probiotics, prebiotics and immunomodulation of gut mucosal defences: homeostasis and immunopathology. Nutrients 5: 1869-1912. 
  59. Thoda C, Touraki M. 2023. Immunomodulatory properties of probiotics and their derived bioactive compounds. Appl. Sci. 13: 4726. 
  60. Galdeano CM, de Moreno de LeBlanc A, Vinderola G, Bonet ME, Perdigon G. 2007. Proposed model: mechanisms of immunomodulation induced by probiotic bacteria. Clin. Vaccine Immunol. 14: 485-492. 
  61. Cristofori F, Dargenio VN, Dargenio C, Miniello VL, Barone M, Francavilla R. 2021. Anti-inflammatory and immunomodulatory effects of probiotics in gut inflammation: a door to the body. Front. Immunol. 12: 578386. 
  62. Zaharuddin L, Mokhtar NM, Muhammad Nawawi KN, Raja Ali RA. 2019. A randomized double-blind placebo-controlled trial of probiotics in post-surgical colorectal cancer. BMC Gastroenterol. 19: 131. 
  63. Gopalakrishnan V SC, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, et al. 2018. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359: 97-103. 
  64. Matson V FJ, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, et al. 2018. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359: 104-108. 
  65. Jain R HA, Harkos C, Mishra A, Morad G, Johnson S, Ajami N, 2023. Dissecting the impact of the gut microbiome on cancer immunotherapy. Res. Sq. [Preprint] doi: 10.21203/rs.3.rs-3647386/v1. 
  66. Huang J, Zheng X, Kang W, Hao H, Mao Y, Zhang H, et al. 2022. Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer. Front. Immunol. 13: 874922. 
  67. Yu H, Li XX, Han X, Chen BX, Zhang XH, Gao S, et al. 2023. Fecal microbiota transplantation inhibits colorectal cancer progression: reversing intestinal microbial dysbiosis to enhance anti-cancer immune responses. Front. Microbiol. 14: 1126808. 
  68. Kazmierczak-Siedlecka K, Daca A, Fic M, van de Wetering T, Folwarski M, Makarewicz W. 2020. Therapeutic methods of gut microbiota modification in colorectal cancer management - fecal microbiota transplantation, prebiotics, probiotics, and synbiotics. Gut Microbes 11: 1518-1530. 
  69. Chang CW, Lee HC, Li LH, Chiang Chiau JS, Wang TE, Chuang WH, et al. 2020. Fecal microbiota transplantation prevents intestinal injury, upregulation of toll-like receptors, and 5-fluorouracil/oxaliplatin-induced toxicity in colorectal cancer. Int. J. Mol. Sci. 21: 386. 
  70. Zhao W, Lei J, Ke S, Chen Y, Xiao J, Tang Z, et al. 2023. Fecal microbiota transplantation plus tislelizumab and fruquintinib in refractory microsatellite stable metastatic colorectal cancer: an open-label, single-arm, phase II trial (RENMIN-215). EClinicalMedicine 66: 102315. 
  71. Gholipour F, Amini M, Baradaran B, Mokhtarzadeh A, Eskandani M. 2023. Anticancer properties of curcumin-treated Lactobacillus plantarum against the HT-29 colorectal adenocarcinoma cells. Sci. Rep. 13: 2860. 
  72. Tukenmez U, Aktas B, Aslim B, Yavuz S. 2019. The relationship between the structural characteristics of lactobacilli-EPS and its ability to induce apoptosis in colon cancer cells in vitro. Sci. Rep. 9: 8268. 
  73. Yue Y, Wang S, Shi J, Xie Q, Li N, Guan J, et al. 2022. Effects of Lactobacillus acidophilus KLDS1. 0901 on proliferation and apoptosis of colon cancer cells. Front. Microbiol. 12: 788040. 
  74. Baldwin C, Millette M, Oth D, Ruiz MT, Luquet FM, Lacroix M. 2010. Probiotic Lactobacillus acidophilus and L. casei mix sensitize colorectal tumoral cells to 5-fluorouracil-induced apoptosis. Nutr. Cancer 62: 371-378. 
  75. Ghoneum M, Felo N. 2015. Selective induction of apoptosis in human gastric cancer cells by Lactobacillus kefiri (PFT), a novel kefir product. Oncol. Rep. 34: 1659-1666. 
  76. Lee JE, Lee J, Kim JH, Cho N, Lee SH, Park SB, et al. 2019. Characterization of the anti-cancer activity of the probiotic bacterium Lactobacillus fermentum using 2D vs. 3D culture in colorectal cancer cells. Biomolecules 9: 557. 
  77. Konishi H, Fujiya M, Tanaka H, Ueno N, Moriichi K, Sasajima J, et al. 2016. Probiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis. Nat. Commun. 7: 12365. 
  78. Isazadeh A, Hajazimian S, Shadman B, Safaei S, Bedoustani AB, Chavoshi R, et al. 2020. Anti-cancer effects of probiotic Lactobacillus acidophilus for colorectal cancer cell line caco-2 through apoptosis induction. Pharm. Sci. 27: 262-267. 
  79. Salemi R, Vivarelli S, Ricci D, Scillato M, Santagati M, Gattuso G, et al. 2023. Lactobacillus rhamnosus GG cell-free supernatant as a novel anti-cancer adjuvant. J. Transl. Med. 21: 195. 
  80. Wang S, Han X, Zhang L, Zhang Y, Li H, Jiao Y. 2018. Whole peptidoglycan extracts from the Lactobacillus paracasei subsp. paracasei M5 strain exert anticancer activity in vitro. BioMed Res. Int. 2018: 11. 
  81. Dehghani N, Tafvizi F, Jafari P. 2021. Cell cycle arrest and anti-cancer potential of probiotic Lactobacillus rhamnosus against HT-29 cancer cells. Bioimpacts 11: 245-252. 
  82. Guo Y, Zhang T, Gao J, Jiang X, Tao M, Zeng X, et al. 2020. Lactobacillus acidophilus CICC 6074 inhibits growth and induces apoptosis in colorectal cancer cells in vitro and in HT-29 cells induced-mouse model. J. Funct. Foods 75: 104290. 
  83. Kuugbee ED, Shang X, Gamallat Y, Bamba D, Awadasseid A, Suliman MA, et al. 2016. Structural change in microbiota by a probiotic cocktail enhances the gut barrier and reduces cancer via TLR2 signaling in a rat model of colon cancer. Dig. Dis. Sci. 61: 2908-2920. 
  84. Tiptiri-Kourpeti A, Spyridopoulou K, Santarmaki V, Aindelis G, Tompoulidou E, Lamprianidou EE, et al. 2016. Lactobacillus casei exerts anti-proliferative effects accompanied by apoptotic cell death and up-regulation of TRAIL in colon carcinoma cells. PLoS One 11: e0147960. 
  85. Gamallat Y, Meyiah A, Kuugbee ED, Hago AM, Chiwala G, Awadasseid A, et al. 2016. Lactobacillus rhamnosus induced epithelial cell apoptosis, ameliorates inflammation and prevents colon cancer development in an animal model. Biomed. Pharmacother. 83: 536-541. 
  86. Del Carmen S, de LeBlanc AdM, Levit R, Azevedo V, Langella P, Bermudez-Humaran LG, et al. 2017. Anti-cancer effect of lactic acid bacteria expressing antioxidant enzymes or IL-10 in a colorectal cancer mouse model. Int. Immunopharmacol. 42: 122-129. 
  87. Chen CC, Lin WC, Kong MS, Shi HN, Walker WA, Lin CY, et al. 2012. Oral inoculation of probiotics Lactobacillus acidophilus NCFM suppresses tumour growth both in segmental orthotopic colon cancer and extra-intestinal tissue. Br. J. Nutr. 107: 1623-1634. 
  88. Asadollahi P, Ghanavati R, Rohani M, Razavi S, Esghaei M, Talebi M. 2020. Anti-cancer effects of Bifidobacterium species in colon cancer cells and a mouse model of carcinogenesis. PLoS One 15: e0232930. 
  89. Ren Z, Chen S, Lv H, Peng L, Yang W, Chen J, et al. 2022. Effect of Bifidobacterium animalis subsp. lactis SF on enhancing the tumor suppression of irinotecan by regulating the intestinal flora. Pharm. Res. 184: 106406. 
  90. Faghfoori Z, Faghfoori MH, Saber A, Izadi A, Yari Khosroushahi A. 2021. Anticancer effects of bifidobacteria on colon cancer cell lines. Cancer Cell Int. 21: 258. 
  91. Bahmani S, Azarpira N, Moazamian E. 2019. Anti-colon cancer activity of Bifidobacterium metabolites on colon cancer cell line SW742. Turkish J. Gastroenterol. 30: 835. 
  92. Mager LF, Burkhard R, Pett N, Cooke NC, Brown K, Ramay H, et al. 2020. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 369: 1481-1489. 
  93. Kim Y, Lee D, Kim D, Cho J, Yang J, Chung M, et al. 2008. Inhibition of proliferation in colon cancer cell lines and harmful enzyme activity of colon bacteria by Bifidobacterium adolescentis SPM0212. Arch. Pharm. Res. 31: 468-473. 
  94. Wei H, Chen L, Lian G, Yang J, Li F, Zou Y, et al. 2018. Antitumor mechanisms of bifidobacteria. Oncol. Lett. 16: 3-8. 
  95. Whelan J, Fritsche K. 2023. Linoleic acid. Adv. Nutr. 4: 311-312. 
  96. Yuce M, Gumuskaptan C, Con AH, Yazici F. 2023. Conjugated linoleic acid strengthens the apoptotic effect of cisplatin in A549 cells. Prostaglandins Other Lipid Mediat. 166: 106731. 
  97. Cho HJ, Kim WK, Kim EJ, Jung KC, Park S, Lee HS, et al. 2003. Conjugated linoleic acid inhibits cell proliferation and ErbB3 signaling in HT-29 human colon cell line. Am. J. Physiol. Gastrointest. Liver Physiol. 284: G996-G1005. 
  98. Kim EJ, Holthuizen PE, Park HS, Ha YL, Jung KC, Park JH. 2002. Trans-10, cis-12-conjugated linoleic acid inhibits Caco-2 colon cancer cell growth. Am. J. Physiol. Gastrointest. Liver Physiol. 283: G357-G67. 
  99. Lampen A, Leifheit M, Voss J, Nau H. 2005. Molecular and cellular effects of cis-9, trans-11-conjugated linoleic acid in enterocytes: effects on proliferation, differentiation, and gene expression. Biochim. Biophys. Acta 1735: 30-40. 
  100. Cheng FS, Pan D, Chang B, Jiang M, Sang LX. 2020. Probiotic mixture VSL#3: an overview of basic and clinical studies in chronic diseases. World J. Clin. Cases 8: 1361-1384. 
  101. Ewaschuk JB, Walker JW, Diaz H, Madsen KL. 2006. Bioproduction of conjugated linoleic acid by probiotic bacteria occurs in vitro and in vivo in mice. J. Nutr. 136: 1483-1487. 
  102. Dubey V, Mishra AK, Ghosh AR. 2023. Appraisal of the possible role of PPARγ upregulation by CLA of probiotic Pediococcus pentosaceus GS4 in colon cancer mitigation. PPAR Res. 2023: 15. 
  103. Dubey V, Ghosh AR, Bishayee K, Khuda-Bukhsh AR. 2016. Appraisal of the anti-cancer potential of probiotic Pediococcus pentosaceus GS4 against colon cancer: in vitro and in vivo approaches. J. Funct. Foods 23: 66-79. 
  104. Mohammadzadeh M, Faramarzi E, Mahdavi R, Nasirimotlagh B, Asghari Jafarabadi M. 2013. Effect of conjugated linoleic acid supplementation on inflammatory factors and matrix metalloproteinase enzymes in rectal cancer patients undergoing chemoradiotherapy. Integr. Cancer Ther. 12: 496-502. 
  105. Dachev M, Bryndova J, Jakubek M, Moucka Z, Urban M. 2021. The effects of conjugated linoleic acids on cancer: a systematic review. Adv. Biomed. Res. 9: 454. 
  106. Mirzaei R, Afaghi A, Babakhani S, Sohrabi MR, Hosseini-Fard SR, Babolhavaeji K, et al. 2021. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomed. Pharmacother. 139: 111619. 
  107. Botta C, Spyridopoulou K, Bertolino M, Rantsiou K, Chlichlia K, Cocolin L. 2022. Lactiplantibacillus plantarum inhibits colon cancer cell proliferation as function of its butyrogenic capability. Biomed. Pharmacother. 149: 112755. 
  108. He Y, Fu L, Li Y, Wang W, Gong M, Zhang J, et al. 2021. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+  T cell immunity. Cell Metab. 33: 988-1000. 
  109. Al-Qadami GH, Secombe KR, Subramaniam CB, Wardill HR, Bowen JM. 2022. Gut microbiota-derived short-chain fatty acids: impact on cancer treatment response and toxicities. Microorganisms 10: 2048. 
  110. Chen J, Zhao KN, Vitetta L. 2019. Effects of intestinal microbial-elaborated butyrate on oncogenic signaling pathways. Nutrients 11: 1026. 
  111. Mowat C, Dhatt J, Bhatti I, Hamie A, Baker K. 2023. Short chain fatty acids prime colorectal cancer cells to activate antitumor immunity. Front. Immunol. 14: 1190810. 
  112. Clarke JM, Topping DL, Bird AR, Young GP, Cobiac L. 2008. Effects of high-amylose maize starch and butyrylated high-amylose maize starch on azoxymethane-induced intestinal cancer in rats. Carcinogenesis 29: 2190-2194. 
  113. Li N, Liu Y, Niu L, Wang Y, Su X, Xu C, et al. 2023. Taking SCFAs produced by Lactobacillus reuteri orally reshapes gut microbiota and elicits antitumor responses. Preprint from Research Square, 2023. 
  114. Kang J, Sun M, Chang Y, Chen H, Zhang J, Liang X, et al. 2023. Butyrate ameliorates colorectal cancer through regulating intestinal microecological disorders. Anticancer Drugs 34: 227-237. 
  115. Tian Y, Xu Q, Sun L, Ye Y, Ji G. 2018. Short-chain fatty acids administration is protective in colitis-associated colorectal cancer development. J. Nutr. Biochem. 57: 103-109. 
  116. Gomes S, Baltazar F, Silva E, Preto A. 2022. Microbiota-derived short-chain fatty acids: new road in colorectal cancer therapy. Pharmaceutics 14: 2359. 
  117. Nakkarach A, Foo HL, Song AA-L, Mutalib NEA, Nitisinprasert S, Withayagiat U. 2021. Anti-cancer and anti-inflammatory effects elicited by short chain fatty acids produced by Escherichia coli isolated from healthy human gut microbiota. Microb. Cell Fact. 20: 36. 
  118. Huang C, Deng W, Xu H-z, Zhou C, Zhang F, Chen J, et al. 2023.Short-chain fatty acids reprogram metabolic profiles with the induction of reactive oxygen species production in human colorectal adenocarcinoma cells. Comput. Struct. Biotechnol. J. 21: 1606-1620.