Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Anticancer Effects of Gut Microbiota-Derived Short-Chain Fatty Acids in Cancers

  • Mi-Young Son (Korea Research Institute of Bioscience and Biotechnology) ;
  • Hyun-Soo Cho (Korea Research Institute of Bioscience and Biotechnology)
  • Received : 2023.01.20
  • Accepted : 2023.03.13
  • Published : 2023.07.28
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Abstract

Short-chain fatty acids (SCFAs), such as butyrate, propionate, and acetate produced by the gut microbiota have been implicated in physiological responses (defense mechanisms, immune responses, and cell metabolism) in the human body. In several types of cancers, SCFAs, especially butyrate, suppress tumor growth and cancer cell metastasis via the regulation of the cell cycle, autophagy, cancer-related signaling pathways, and cancer cell metabolism. In addition, combination treatment with SCFAs and anticancer drugs exhibits synergistic effects, increasing anticancer treatment efficiency and attenuating anticancer drug resistance. Therefore, in this review, we point out the importance of SCFAs and the mechanisms underlying their effects in cancer treatment and suggest using SCFA-producing microbes and SCFAs to increase therapeutic efficacy in several types of cancers.

Keywords

Acknowledgement

This work was supported by a grant from the Technology Innovation Program (No. 20008777) funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea), a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT, and Future Planning (NRF-2018M3A9H3023077/NRF-2021M3A9H3016046), and the KRIBB Research Initiative Program. The funders had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. All figures were made with biorender.com.

References

  1. Kamal N, Ilowefah MA, Hilles AR, Anua NA, Awin T, Alshwyeh HA, et al. 2022. Genesis and mechanism of some cancer types and an overview on the role of diet and nutrition in cancer prevention. Molecules 27: 1794. 
  2. Negrei C, Hudita A, Ginghina O, Galateanu B, Voicu SN, Stan M, et al. 2016. Colon cancer cells gene expression signature as response to 5- fluorouracil, oxaliplatin, and folinic acid treatment. Front. Pharmacol. 7: 172. 
  3. Ma Y, Yu S, Ni S, Zhang B, Kung ACF, Gao J, et al. 2021. Targeting strategies for enhancing paclitaxel specificity in chemotherapy. Front. Cell Dev. Biol. 9: 626910. 
  4. Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. 1995. Use of tamoxifen for breast cancer: twenty-eight years later. J. Clin. Oncol. 13: 513-529.  https://doi.org/10.1200/JCO.1995.13.2.513
  5. Prince HM, Hutchings M, Domingo-Domenech E, Eichenauer DA, Advani R. 2023. Anti-CD30 antibody-drug conjugate therapy in lymphoma: current knowledge, remaining controversies, and future perspectives. Ann. Hematol. 102: 13-29. 
  6. Morganti S, Tolaney SM. 2023. Role of immunotherapy in early- and late-stage triple-negative breast cancer. Hematol. Oncol. Clin. North Am. 37: 133-150.  https://doi.org/10.1016/j.hoc.2022.08.014
  7. Abelman RO, Keenan JC, Ryan PK, Spring LM, Bardia A. 2023. Current and emerging role of antibody-drug conjugates in HER2-negative breast cancer. Hematol. Oncol. Clin. North Am. 37: 151-167.  https://doi.org/10.1016/j.hoc.2022.08.015
  8. Martin C, Enrico D. 2022. Current and novel therapeutic strategies for optimizing immunotherapy outcomes in advanced non-small cell lung cancer. Front. Oncol. 12: 962947. 
  9. Fernandes MR, Aggarwal P, Costa RGF, Cole AM, Trinchieri G. 2022. Targeting the gut microbiota for cancer therapy. Nat. Rev. Cancer 22: 703-722.  https://doi.org/10.1038/s41568-022-00513-x
  10. Zhang W, An Y, Qin X, Wu X, Wang X, Hou H, et al. 2021. Gut microbiota-derived metabolites in colorectal cancer: the bad and the challenges. Front. Oncol. 11: 739648. 
  11. van der Hee B, Wells JM. 2021. Microbial regulation of host physiology by short-chain fatty acids. Trends Microbiol. 29: 700-712.  https://doi.org/10.1016/j.tim.2021.02.001
  12. Correa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MA. 2016. Regulation of immune cell function by short-chain fatty acids. Clin. Transl. Immunol. 5: e73. 
  13. Machado MG, Sencio V, Trottein F. 2021. Short-chain fatty acids as a potential treatment for infections: a closer look at the lungs. Infect. Immun. 89: e0018821. 
  14. He J, Zhang P, Shen L, Niu L, Tan Y, Chen L, et al. 2020. Short-chain fatty acids and their association with signalling pathways in inflammation, glucose and lipid metabolism. Int. J. Mol. Sci. 21: 6356. 
  15. Davie JR. 2003. Inhibition of histone deacetylase activity by butyrate. J. Nutr. 133: 2485S-2493S.  https://doi.org/10.1093/jn/133.7.2485S
  16. An J, Ha EM. 2016. Combination therapy of Lactobacillus plantarum supernatant and 5-fluouracil increases chemosensitivity in colorectal cancer cells. J. Microbiol. Biotechnol. 26: 1490-1503.  https://doi.org/10.4014/jmb.1605.05024
  17. Shuwen H, Yangyanqiu W, Jian C, Boyang H, Gong C, Jing Z. 2023. Synergistic effect of sodium butyrate and oxaliplatin on colorectal cancer. Transl. Oncol. 27: 101598. 
  18. 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. 
  19. Ryu TY, Kim K, Han TS, Lee MO, Lee J, Choi J, et al. 2022. Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer. ISME J. 16: 1205-1221.  https://doi.org/10.1038/s41396-021-01119-1
  20. 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. 
  21. Chang SC, Shen MH, Liu CY, Pu CM, Hu JM, Huang CJ. 2020. A gut butyrate-producing bacterium Butyricicoccus pullicaecorum regulates short-chain fatty acid transporter and receptor to reduce the progression of 1,2-dimethylhydrazine-associated colorectal cancer. Oncol. Lett. 20: 327. 
  22. Chang CC, Kao WY, Liu CY, Su HH, Kan YA, Lin PY, et al. 2022. Butyrate supplementation regulates expression of chromosome segregation 1-like protein to reverse the genetic distortion caused by p53 mutations in colorectal cancer. Int. J. Oncol. 60: 64. 
  23. Chen D, Jin D, Huang S, Wu J, Xu M, Liu T, et al. 2020. Clostridium butyricum, a butyrate-producing probiotic, inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota. Cancer Lett. 469: 456-467.  https://doi.org/10.1016/j.canlet.2019.11.019
  24. Ali SR, Humphreys KJ, Simpson KJ, McKinnon RA, Meech R, Michael MZ. 2022. Functional high-throughput screen identifies microRNAs that promote butyrate-induced death in colorectal cancer cells. Mol. Ther. Nucleic Acids 30: 30-47.  https://doi.org/10.1016/j.omtn.2022.08.037
  25. Wang L, Shannar AAF, Wu R, Chou P, Sarwar MS, Kuo HC, et al. 2022. Butyrate drives metabolic rewiring and epigenetic reprogramming in human colon cancer cells. Mol. Nutr. Food Res. 66: e2200028. 
  26. Park M, Kwon J, Shin HJ, Moon SM, Kim SB, Shin US, et al. 2020. Butyrate enhances the efficacy of radiotherapy via FOXO3A in colorectal cancer patient-derived organoids. Int. J. Oncol. 57: 1307-1318.  https://doi.org/10.3892/ijo.2020.5132
  27. Geng HW, Yin FY, Zhang ZF, Gong X, Yang Y. 2021. Butyrate suppresses glucose metabolism of colorectal cancer cells via GPR109a-AKT signaling pathway and enhances chemotherapy. Front. Mol. Biosci. 8: 634874. 
  28. Zeng H, Safratowich BD, Wang TTY, Hamlin SK, Johnson LK. 2020. Butyrate inhibits deoxycholic-acid-resistant colonic cell proliferation via cell cycle arrest and apoptosis: A potential pathway linking dietary fiber to cancer prevention. Mol. Nutr. Food Res. 64: e1901014. 
  29. Klepinina L, Klepinin A, Truu L, Chekulayev V, Vija H, Kuus K, et al. 2021. Colon cancer cell differentiation by sodium butyrate modulates metabolic plasticity of Caco-2 cells via alteration of phosphotransfer network. PLoS One 16: e0245348. 
  30. Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, et al. 2022. Interaction between microbiota and immunity and its implication in colorectal cancer. Front. Immunol. 13: 963819. 
  31. Coutzac C, Jouniaux JM, Paci A, Schmidt J, Mallardo D, Seck A, et al. 2020. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat. Commun. 11: 2168. 
  32. Hogh RI, Moller SH, Jepsen SD, Mellergaard M, Lund A, Pejtersen M, et al. 2020. Metabolism of short-chain fatty acid propionate induces surface expression of NKG2D ligands on cancer cells. FASEB J. 34: 15531-15546.  https://doi.org/10.1096/fj.202000162R
  33. Ma X, Zhou Z, Zhang X, Fan M, Hong Y, Feng Y, et al. 2020. Sodium butyrate modulates gut microbiota and immune response in colorectal cancer liver metastatic mice. Cell Biol. Toxicol. 36: 509-515.  https://doi.org/10.1007/s10565-020-09518-4
  34. Burd EM. 2003. Human papillomavirus and cervical cancer. Clin. Microbiol. Rev. 16: 1-17.  https://doi.org/10.1128/CMR.16.1.1-17.2003
  35. Zeber-Lubecka N, Kulecka M, Lindner B, Krynicki R, Paziewska A, Nowakowski A, et al. 2022. Increased diversity of a cervical microbiome associates with cervical cancer. Front. Oncol. 12: 1005537. 
  36. Chu H, Sun X, Wang J, Lei K, Shan Z, Zhao C, et al. 2022. Synergistic effects of sodium butyrate and cisplatin against cervical carcinoma in vitro and in vivo. Front. Oncol. 12: 999667. 
  37. Decrion-Barthod AZ, Bosset M, Plissonnier ML, Marchini A, Nicolier M, Launay S, et al. 2010. Sodium butyrate with UCN-01 has marked antitumour activity against cervical cancer cells. Anticancer Res. 30: 4049-4061. 
  38. Matsuya-Ogawa M, Shibata T, Itoh H, Murakami H, Yaguchi C, Sugihara K, et al. 2019. Oncoprotective effects of short-chain faftty acids on uterine cervical neoplasia. Nutr. Cancer 71: 312-319.  https://doi.org/10.1080/01635581.2019.1578388
  39. Pham CH, Lee JE, Yu J, Lee SH, Yu KR, Hong J, et al. 2021. Anticancer effects of propionic acid inducing cell death in cervical cancer cells. Molecules 26: 4951. 
  40. Yang J, Zhou X, Liu X, Ling Z, Ji F. 2021. Role of the gastric microbiome in gastric cancer: from carcinogenesis to treatment. Front. Microbiol. 12: 641322. 
  41. Gajewski A, Mnich E, Szymanski K, Hinc K, Obuchowski M, Moran AP, et al. 2016. Helicobacter pylori antigens, acetylsalicylic acid, LDL and 7-ketocholesterol - their potential role in destabilizing the gastric epithelial cell barrier. An in vitro model of Kato III cells. Acta Biochim. Pol. 63: 145-152.  https://doi.org/10.18388/abp.2015_1122
  42. Yonezawa H, Osaki T, Hanawa T, Kurata S, Zaman C, Woo TDH, et al. 2012. Destructive effects of butyrate on the cell envelope of Helicobacter pylori. J. Med. Microbiol. 61: 582-589.  https://doi.org/10.1099/jmm.0.039040-0
  43. Huang Y, Ding Y, Xu H, Shen C, Chen X, Li C. 2021. Effects of sodium butyrate supplementation on inflammation, gut microbiota, and short-chain fatty acids in Helicobacter pylori-infected mice. Helicobacter 26: e12785. 
  44. Li Y, He P, Liu Y, Qi M, Dong W. 2021. Combining sodium butyrate with cisplatin increases the apoptosis of gastric cancer in vivo and in vitro via the mitochondrial apoptosis pathway. Front. Pharmacol. 12: 708093. 
  45. Zhou Y, Ji X, Chen J, Fu Y, Huang J, Guo R, et al. 2021. Short-chain fatty acid butyrate: a novel shield against chronic gastric ulcer. Exp. Ther. Med. 21: 329. 
  46. Kim YL, Lee W, Chung SH, Yu BM, Lee YC, Hong J. 2022. Metabolic alterations of short-chain fatty acids and TCA cycle intermediates in human plasma from patients with gastric cancer. Life Sci. 309: 121010. 
  47. Sun G, Duan H, Meng J, Zhang D. 2022. Profiling and Characterization of microRNAs responding to sodium butyrate treatment in gastric cancer cells. Comb. Chem. High Throughput. Screen 25: 1875-1888.  https://doi.org/10.2174/1386207325666211027154207
  48. Carrasquilla M, Paudel N, Collins BT, Anderson E, Krochmal R, Margolis M, et al. 2023. High-risk non-small cell lung cancer treated with active scanning proton beam radiation therapy and Immunotherapy. Adv. Radiat. Oncol. 8: 101125. 
  49. Gui Q, Li H, Wang A, Zhao X, Tan Z, Chen L, et al. 2020. The association between gut butyrate-producing bacteria and non-small-cell lung cancer. J. Clin. Lab. Anal. 34: e23318. 
  50. Xiao X, Cao Y, Chen H. 2018. Profiling and characterization of microRNAs responding to sodium butyrate treatment in A549 cells. J. Cell Biochem. 119: 3563-3573.  https://doi.org/10.1002/jcb.26547
  51. Jin X, Wu N, Dai J, Li Q, Xiao X. 2017. TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4-phenylbutyrate treatment. Cancer Med. 6: 424-438.  https://doi.org/10.1002/cam4.977
  52. Zhang XZ, Chen MJ, Fan PM, Su TS, Liang SX, Jiang W. 2022. Prediction of the mechanism of sodium butyrate against radiation-induced lung injury in non-small cell lung cancer based on network pharmacology and molecular dynamic simulations and molecular dynamic simulations. Front. Oncol. 12: 809772. 
  53. Chen L, Zhou X, Wang Y, Wang D, Ke Y, Zeng X. 2021. Propionate and butyrate produced by gut microbiota after probiotic supplementation attenuate lung metastasis of melanoma cells in mice. Mol. Nutr. Food Res. 65: e2100096. 
  54. Kim K, Kwon O, Ryu TY, Jung CR, Kim J, Min JK, et al. 2019. Propionate of a microbiota metabolite induces cell apoptosis and cell cycle arrest in lung cancer. Mol. Med. Rep. 20: 1569-1574.  https://doi.org/10.3892/mmr.2019.10431
  55. Cristiano C, Cuozzo M, Coretti L, Liguori FM, Cimmino F, Turco L, et al. 2022. Oral sodium butyrate supplementation ameliorates paclitaxel-induced behavioral and intestinal dysfunction. Biomed. Pharmacother. 153: 113528. 
  56. Chen M, Jiang W, Xiao C, Yang W, Qin Q, Mao A, et al. 2020. Sodium butyrate combined with docetaxel for the treatment of lung adenocarcinoma A549 cells by targeting gli1. Onco. Targets Ther. 13: 8861-8875.  https://doi.org/10.2147/OTT.S252323
  57. Shi B, Xu FF, Xiang CP, Jia R, Yan CH, Ma SQ, et al. 2020. Effect of sodium butyrate on ABC transporters in lung cancer A549 and colorectal cancer HCT116 cells. Oncol. Lett. 20: 148. 
  58. Kim K, Son MY, Jung CR, Kim DS, Cho HS. 2018. EHMT2 is a metastasis regulator in breast cancer. Biochem. Biophys. Res. Commun. 496: 758-762.  https://doi.org/10.1016/j.bbrc.2018.01.074
  59. Kim SK, Kim K, Ryu JW, Ryu TY, Lim JH, Oh JH, et al. 2019. The novel prognostic marker, EHMT2, is involved in cell proliferation via HSPD1 regulation in breast cancer. Int. J. Oncol. 54: 65-76.  https://doi.org/10.3892/ijo.2018.4608
  60. Ryu TY, Kim K, Kim SK, Oh JH, Min JK, Jung CR, et al. 2019. SETDB1 regulates SMAD7 expression for breast cancer metastasis. BMB Rep. 52: 139-144.  https://doi.org/10.5483/BMBRep.2019.52.2.235
  61. Schoeller A, Karki K, Jayaraman A, Chapkin RS, Safe S. 2022. Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer. Am. J. Cancer Res. 12: 3422-3436. 
  62. Semaan J, El-Hakim S, Ibrahim JN, Safi R, Elnar AA, El Boustany C. 2020. Comparative effect of sodium butyrate and sodium propionate on proliferation, cell cycle and apoptosis in human breast cancer cells MCF-7. Breast Cancer 27: 696-705.  https://doi.org/10.1007/s12282-020-01063-6
  63. Yuksel B, Deveci Ozkan A, Aydin D, Betts Z. 2022. Evaluation of the antioxidative and genotoxic effects of sodium butyrate on breast cancer cells. Saudi J. Biol. Sci. 29: 1394-1401.  https://doi.org/10.1016/j.sjbs.2021.12.061
  64. Li X, Yang J, Peng L, Sahin AA, Huo L, Ward KC, et al. 2017. Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer. Breast Cancer Res. Treat. 161: 279-287.  https://doi.org/10.1007/s10549-016-4059-6
  65. Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. 2016. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat. Rev. Clin. Oncol. 13: 674-690.  https://doi.org/10.1038/nrclinonc.2016.66
  66. Sharma M, Tollefsbol TO. 2022. Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition. Exp. Cell. Res. 416: 113160. 
  67. Karimi Z, Taymouri S, Minaiyan M, Mirian M. 2022. Evaluation of thermosensitive chitosan hydrogel containing gefitinib loaded cellulose acetate butyrate nanoparticles in a subcutaneous breast cancer model. Int. J. Pharm. 624: 122036. 
  68. Richters A, Aben KKH, Kiemeney L. 2020. The global burden of urinary bladder cancer: an update. World J. Urol. 38: 1895-1904.  https://doi.org/10.1007/s00345-019-02984-4
  69. Tran L, Xiao JF, Agarwal N, Duex JE, Theodorescu D. 2021. Advances in bladder cancer biology and therapy. Nat. Rev. Cancer 21: 104-121.  https://doi.org/10.1038/s41568-020-00313-1
  70. Martin A, Woolbright BL, Umar S, Ingersoll MA, Taylor JA, 3rd. 2022. Bladder cancer, inflammageing and microbiomes. Nat. Rev. Urol. 19: 495-509.  https://doi.org/10.1038/s41585-022-00611-3
  71. Wang YC, Ku WC, Liu CY, Cheng YC, Chien CC, Chang KW, et al. 2021. Supplementation of probiotic Butyricicoccus pullicaecorum mediates anticancer effect on bladder urothelial cells by regulating butyrate-responsive molecular signatures. Diagnostics (Basel) 11: 2270. 
  72. Wang F, Wu H, Fan M, Yu R, Zhang Y, Liu J, et al. 2020. Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells. FASEB J. 34: 4266-4282.  https://doi.org/10.1096/fj.201902626R
  73. Maruyama T, Yamamoto S, Qiu J, Ueda Y, Suzuki T, Nojima M, et al. 2012. Apoptosis of bladder cancer by sodium butyrate and cisplatin. J. Infect. Chemother. 18: 288-295.  https://doi.org/10.1007/s10156-011-0322-2
  74. Yu Q, Dai W, Ji J, Wu L, Feng J, Li J, et al. 2022. Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c-myc/hexokinase 2 pathway. J. Cell. Mol. Med. 26: 3031-3045.  https://doi.org/10.1111/jcmm.17322
  75. Panebianco C, Villani A, Pisati F, Orsenigo F, Ulaszewska M, Latiano TP, et al. 2022. Butyrate, a postbiotic of intestinal bacteria, affects pancreatic cancer and gemcitabine response in in vitro and in vivo models. Biomed. Pharmacother. 151: 113163. 
  76. Wang R, Yang X, Liu J, Zhong F, Zhang C, Chen Y, et al. 2022. Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate. Nat. Commun. 13: 2522.