Postbiotics are health-promoting microbial metabolites delivered as a functional food or a food supplement. They either directly influence signaling pathways of the body or indirectly manipulate metabolism and the composition of intestinal microflora. Cancer is the second leading cause of death worldwide and even though the prognosis of patients is improving, it is still poor in the substantial part of the cases. The preventable nature of cancer and the importance of a complex multi-level approach in anticancer therapy motivate the search for novel avenues of establishing the anticancer environment in the human body. This review summarizes the principal findings demonstrating the usefulness of both natural and synthetic sources of postbotics in the prevention and therapy of cancer. Specifically, the effects of crude cell-free supernatants, the short-chain fatty acid butyrate, lactic acid, hydrogen sulfide, and β-glucans are described. Contradictory roles of postbiotics in healthy and tumor tissues are highlighted. In conclusion, the application of postbiotics is an efficient complementary strategy to combat cancer.

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague 16628 Prague Czech Republic

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Qin J., Li R., Raes J., Arumugam M., Burgdorf K.S., Manichanh C., Nielsen T., Pons N., Levenez F., Yamada T., et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65. doi: 10.1038/nature08821. PubMed DOI PMC

Bäckhed F., Ley R.E., Sonnenburg J.L., Peterson D.A., Gordon J.I. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915–1920. doi: 10.1126/science.1104816. PubMed DOI

Karasov W.H., Martínez del Rio C., Caviedes-Vidal E. Ecological physiology of diet and digestive systems. Annu. Rev. Physiol. 2011;73:69–93. doi: 10.1146/annurev-physiol-012110-142152. PubMed DOI

Claus S.P., Guillou H., Ellero-Simatos S. The gut microbiota: A major player in the toxicity of environmental pollutants? NPJ Biofilms Microbiomes. 2016;2:16003. doi: 10.1038/npjbiofilms.2016.3. PubMed DOI PMC

LeBlanc J.G., Milani C., de Giori G.S., Sesma F., van Sinderen D., Ventura M. Bacteria as vitamin suppliers to their host: A gut microbiota perspective. Curr. Opin. Biotechnol. 2013;24:160–168. doi: 10.1016/j.copbio.2012.08.005. PubMed DOI

Hooper L.V., Littman D.R., Macpherson A.J. Interactions between the microbiota and the immune system. Science. 2012;336:1268–1273. doi: 10.1126/science.1223490. PubMed DOI PMC

Żółkiewicz J., Marzec A., Ruszczyński M., Feleszko W. Postbiotics-A Step Beyond Pre- and Probiotics. Nutrients. 2020;12:2189. doi: 10.3390/nu12082189. PubMed DOI PMC

Wikoff W.R., Anfora A.T., Liu J., Schultz P.G., Lesley S.A., Peters E.C., Siuzdak G. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl. Acad. Sci. USA. 2009;106:3698–3703. doi: 10.1073/pnas.0812874106. PubMed DOI PMC

Sartor R.B. Gut microbiota: Diet promotes dysbiosis and colitis in susceptible hosts. Nat. Rev. Gastroenterol. Hepatol. 2012;9:561–562. doi: 10.1038/nrgastro.2012.157. PubMed DOI

Tlaskalová-Hogenová H., Stěpánková R., Kozáková H., Hudcovic T., Vannucci L., Tučková L., Rossmann P., Hrnčíř T., Kverka M., Zákostelská Z., et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: Contribution of germ-free and gnotobiotic animal models of human diseases. Cell. Mol. Immunol. 2011;8:110–120. doi: 10.1038/cmi.2010.67. PubMed DOI PMC

Tsilingiri K., Barbosa T., Penna G., Caprioli F., Sonzogni A., Viale G., Rescigno M. Probiotic and postbiotic activity in health and disease: Comparison on a novel polarised ex-vivo organ culture model. Gut. 2012;61:1007–1015. doi: 10.1136/gutjnl-2011-300971. PubMed DOI

Escamilla J., Lane M., Maitin V. Cell-Free Supernatants from Probiotic Lactobacillus casei and Lactobacillus rhamnosus GG Decrease Colon Cancer Cell Invasion In Vitro. Nutr. Cancer. 2012;64:871–878. doi: 10.1080/01635581.2012.700758. PubMed DOI

Sauer J., Richter K.K., Pool-Zobel B.L. Physiological concentrations of butyrate favorably modulate genes of oxidative and metabolic stress in primary human colon cells. J. Nutr. Biochem. 2007;18:736–745. doi: 10.1016/j.jnutbio.2006.12.012. PubMed DOI

Abrahamse S.L., Pool-Zobel B.L., Rechkemmer G. Potential of short chain fatty acids to modulate the induction of DNA damage and changes in the intracellular calcium concentration by oxidative stress in isolated rat distal colon cells. Carcinogenesis. 1999;20:629–634. doi: 10.1093/carcin/20.4.629. PubMed DOI

Hague A., Paraskeva C. The short-chain fatty acid butyrate induces apoptosis in colorectal tumour cell lines. Eur. J. Cancer Prev. 1995;4:359–364. doi: 10.1097/00008469-199510000-00005. PubMed DOI

Hague A., Elder D.J., Hicks D.J., Paraskeva C. Apoptosis in colorectal tumour cells: Induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate. Int. J. Cancer. 1995;60:400–406. doi: 10.1002/ijc.2910600322. PubMed DOI

Śliżewska K., Markowiak-Kopeć P., Śliżewska W. The Role of Probiotics in Cancer Prevention. Cancers. 2020;13:13. doi: 10.3390/cancers13010020. PubMed DOI PMC

Dos Reis S.A., da Conceição L.L., Siqueira N.P., Rosa D.D., da Silva L.L., Peluzio M.D. Review of the mechanisms of probiotic actions in the prevention of colorectal cancer. Nutr. Res. 2017;37:1–19. doi: 10.1016/j.nutres.2016.11.009. PubMed DOI

Perillo F., Amoroso C., Strati F., Giuffrè M.R., Díaz-Basabe A., Lattanzi G., Facciotti F. Gut Microbiota Manipulation as a Tool for Colorectal Cancer Management: Recent Advances in Its Use for Therapeutic Purposes. Int. J. Mol. Sci. 2020;21:5389. doi: 10.3390/ijms21155389. PubMed DOI PMC

Cheng Y., Ling Z., Li L. The Intestinal Microbiota and Colorectal Cancer. Front. Immunol. 2020;11:615056. doi: 10.3389/fimmu.2020.615056. PubMed DOI PMC

Ding S., Hu C., Fang J., Liu G. The Protective Role of Probiotics against Colorectal Cancer. Oxid. Med. Cell. Longev. 2020;2020:8884583. doi: 10.1155/2020/8884583. PubMed DOI PMC

Fong W., Li Q., Yu J. Gut microbiota modulation: A novel strategy for prevention and treatment of colorectal cancer. Oncogene. 2020;39:4925–4943. doi: 10.1038/s41388-020-1341-1. PubMed DOI PMC

Zelenka J., Koncošová M., Ruml T. Targeting of stress response pathways in the prevention and treatment of cancer. Biotechnol. Adv. 2018;36:583–602. doi: 10.1016/j.biotechadv.2018.01.007. PubMed DOI

Wang W., Fang D., Zhang H., Wangchuk D., Du J., Jiang L. Sodium butyrate selectively kills cancer cells and inhibits migration in colorectal cancer by targeting thioredoxin-1. Oncotargets Ther. 2020;13:4691–4704. doi: 10.2147/OTT.S235575. PubMed DOI PMC

Cao X., Xie Z., Yang Y., Whiteman M., Moore P.K., Bian J. A review of hydrogen sulfide synthesis, metabolism, and measurment: Is modulation of hydrogen sulfide a novel therapeutic for cancer? Antioxid. Redox Signal. 2019;31:1–38. doi: 10.1089/ars.2017.7058. PubMed DOI PMC

Fay J.R., Steele V., Crowell J.A. Energy homeostasis and cancer prevention: The AMP-activated protein kinase. Cancer Prev. Res. 2009;2:301–309. doi: 10.1158/1940-6207.CAPR-08-0166. PubMed DOI

Wang N., Liu H., Liu G., Li M., He X., Yin C., Tu Q., Shen X., Bai W., Wang Q., et al. Yeast β-glucan exerts antitumour activity in liver cancer through impairing autophagy and lysosomal function, promoting reactive oxygen species production and apoptosis. Redox Biol. 2020;32:101495. doi: 10.1016/j.redox.2020.101495. PubMed DOI PMC

Zhang W., Feng Y., Guo Q., Xu H., Li X., Guan Y., Geng N., Wang P., Cao L., O’Rouke B.P., et al. SIRT1 modulates cell cycle progression by regulating CHK2 acetylation—phosphorylation. Cell Death Differ. 2020;27:482–496. doi: 10.1038/s41418-019-0369-7. PubMed DOI PMC

Sun B., Jia Y., Yang S., Zhao N., Hu Y., Hong J., Gao S., Zhao R. Sodium butyrate protects against high-fat diet-induced oxidative stress in rat liver by promoting expression of nuclear factor E2-related factor 2. Br. J. Nutr. 2019;122:400–410. doi: 10.1017/S0007114519001399. PubMed DOI

Bahmani S., Azarpira N., Moazamian E. Anti-colon cancer activity of Bifidobacterium metabolites on colon cancer cell line SW742. Turk. J. Gastroenterol. 2019;30:835–842. doi: 10.5152/tjg.2019.18451. PubMed DOI PMC

Kim Y., Lee D., Kim D., Cho J., Yang J., Chung M., Kim K., Ha N. Inhibition of proliferation in colon cancer cell lines and harmful enzyme activity of colon bacteria by Bifidobacterium adolescentis SPM0212. Arch. Pharm. Res. 2008;31:468–473. doi: 10.1007/s12272-001-1180-y. PubMed DOI

Leeman M.F., Curran S., Murray G.I. New insights into the roles of matrix metalloproteinases in colorectal cancer development and progression. J. Pathol. 2003;201:528–534. doi: 10.1002/path.1466. PubMed DOI

Yu Q.H., Yang Q. Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biol. Int. 2009;33:78–82. doi: 10.1016/j.cellbi.2008.09.007. PubMed DOI

Yue Y., Ye K., Lu J., Wang X., Zhang S., Liu L., Yang B., Nassar K., Xu X., Pang X., et al. Probiotic strain Lactobacillus plantarum YYC-3 prevents colon cancer in mice by regulating the tumour microenvironment. Biomed. Pharmacother. 2020;127:110159. doi: 10.1016/j.biopha.2020.110159. PubMed DOI

An J., Ha E.M. Combination Therapy of Lactobacillus plantarum Supernatant and 5-Fluouracil Increases Chemosensitivity in Colorectal Cancer Cells. J. Microbiol. Biotechnol. 2016;26:1490–1503. doi: 10.4014/jmb.1605.05024. PubMed DOI

Topping D.L., Clifton P.M. Short-chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 2001;81:1031–1064. doi: 10.1152/physrev.2001.81.3.1031. PubMed DOI

Bergman E.N. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol. Rev. 1990;70:567–590. doi: 10.1152/physrev.1990.70.2.567. PubMed DOI

Bultman S.J. Molecular pathways: Gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention. Clin. Cancer Res. 2014;20:799–803. doi: 10.1158/1078-0432.CCR-13-2483. PubMed DOI PMC

Ahmad M.S., Krishnan S., Ramakrishna B.S., Mathan M., Pulimood A.B., Murthy S.N. Butyrate and glucose metabolism by colonocytes in experimental colitis in mice. Gut. 2000;46:493–499. doi: 10.1136/gut.46.4.493. PubMed DOI PMC

Chen H.M., Yu Y.N., Wang J.L., Lin Y.W., Kong X., Yang C.Q., Yang L., Liu Z.J., Yuan Y.Z., Liu F., et al. Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma. Am. J. Clin. Nutr. 2013;97:1044–1052. doi: 10.3945/ajcn.112.046607. PubMed DOI

Charney A.N., Micic L., Egnor R.W. Nonionic diffusion of short-chain fatty acids across rat colon. Am. J. Physiol. 1998;274:G518–G524. doi: 10.1152/ajpgi.1998.274.3.G518. PubMed DOI

Hadjiagapiou C., Schmidt L., Dudeja P.K., Layden T.J., Ramaswamy K. Mechanism(s) of butyrate transport in Caco-2 cells: Role of monocarboxylate transporter 1. Am. J. Physiol. Gastrointest. Liver Physiol. 2000;279:G775–G780. doi: 10.1152/ajpgi.2000.279.4.G775. PubMed DOI

Ganapathy V., Thangaraju M., Prasad P.D., Martin P.M., Singh N. Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Curr. Opin. Pharmacol. 2013;13:869–874. doi: 10.1016/j.coph.2013.08.006. PubMed DOI

Cuff M., Dyer J., Jones M., Shirazi-Beechey S. The human colonic monocarboxylate transporter Isoform 1: Its potential importance to colonic tissue homeostasis. Gastroenterology. 2005;128:676–686. doi: 10.1053/j.gastro.2004.12.003. PubMed DOI

Thibault R., De Coppet P., Daly K., Bourreille A., Cuff M., Bonnet C., Mosnier J.F., Galmiche J.P., Shirazi-Beechey S., Segain J.P. Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology. 2007;133:1916–1927. doi: 10.1053/j.gastro.2007.08.041. PubMed DOI

Lambert D.W., Wood I.S., Ellis A., Shirazi-Beechey S.P. Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy. Br. J. Cancer. 2002;86:1262–1269. doi: 10.1038/sj.bjc.6600264. PubMed DOI PMC

Koukourakis M.I., Giatromanolaki A., Harris A.L., Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: A metabolic survival role for tumor-associated stroma. Cancer Res. 2006;66:632–637. doi: 10.1158/0008-5472.CAN-05-3260. PubMed DOI

Heidor R., Ortega J.F., de Conti A., Ong T.P., Moreno F.S. Anticarcinogenic actions of tributyrin, a butyric acid prodrug. Curr. Drug Targets. 2012;13:1720–1729. doi: 10.2174/138945012804545443. PubMed DOI

Gupta N., Martin P.M., Prasad P.D., Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci. 2006;78:2419–2425. doi: 10.1016/j.lfs.2005.10.028. PubMed DOI

Borthakur A., Anbazhagan A.N., Kumar A., Raheja G., Singh V., Ramaswamy K., Dudeja P.K. The probiotic Lactobacillus plantarum counteracts TNF-{alpha}-induced downregulation of SMCT1 expression and function. Am. J. Physiol. Gastrointest. Liver Physiol. 2010;299:G928–G934. doi: 10.1152/ajpgi.00279.2010. PubMed DOI PMC

Ganapathy V., Thangaraju M., Gopal E., Martin P., Itagaki S., Miyauchi S., Prasad P. Sodium-coupled Monocarboxylate Transporters in Normal Tissues and in Cancer. AAPS J. 2008;10:193–199. doi: 10.1208/s12248-008-9022-y. PubMed DOI PMC

Doshi M., Takiue Y., Saito H., Hosoyamada M. The Increased Protein Level of URAT1 was Observed in Obesity/Metabolic Syndrome Model Mice. Nucleosides Nucleotides Nucleic Acids. 2011;30:1290–1294. doi: 10.1080/15257770.2011.603711. PubMed DOI

Whitman S.P., Hackanson B., Liyanarachchi S., Liu S., Rush L.J., Maharry K., Margeson D., Davuluri R., Wen J., Witte T., et al. DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication. Blood. 2008;112:2013–2016. doi: 10.1182/blood-2008-01-128595. PubMed DOI PMC

Dohgen M., Hayahshi H., Yajima T., Suzuki Y. Stimulation of Bicarbonate Secretion by Luminal Short-Chain Fatty Acid in the Rat and Human Colon In Vitro. Jpn. J. Physiol. 1994;44:519–531. doi: 10.2170/jjphysiol.44.519. PubMed DOI

Dietrich C.G., Vehr A.-K., Martin I.V., Gaßler N., Rath T., Roeb E., Schmitt J., Trautwein C., Geier A. Downregulation of breast cancer resistance protein in colon adenomas reduces cellular xenobiotic resistance and leads to accumulation of a food-derived carcinogen. Int. J. Cancer. 2011;129:546–552. doi: 10.1002/ijc.25958. PubMed DOI

Gupta N., Martin P.M., Miyauchi S., Ananth S., Herdman A.V., Martindale R.G., Podolsky R., Ganapathy V. Down-regulation of BCRP/ABCG2 in colorectal and cervical cancer. Biochem. Biophys. Res. Commun. 2006;343:571–577. doi: 10.1016/j.bbrc.2006.02.172. PubMed DOI

Liu H.G., Pan Y.F., You J., Wang O.C., Huang K.T., Zhang X.H. Expression of ABCG2 and its significance in colorectal cancer. Asian Pac. J. Cancer Prev. 2010;11:845–848. PubMed

Nakanishi T., Ross D.D. Breast cancer resistance protein (BCRP/ABCG2): Its role in multidrug resistance and regulation of its gene expression. Chin. J. Cancer. 2012;31:73–99. doi: 10.5732/cjc.011.10320. PubMed DOI PMC

Nakamura S., Haga S., Kimura K., Matsuyama S. Propionate and butyrate induce gene expression of monocarboxylate transporter 4 and cluster of differentiation 147 in cultured rumen epithelial cells derived from preweaning dairy calves. J. Anim. Sci. 2018;96:4902–4911. doi: 10.1093/jas/sky334. PubMed DOI PMC

Gonçalves P., Martel F. Butyrate and colorectal cancer: The role of butyrate transport. Curr. Drug. Metab. 2013;14:994–1008. doi: 10.2174/1389200211314090006. PubMed DOI

Hamer H.M., Jonkers D., Venema K., Vanhoutvin S., Troost F.J., Brummer R.J. Review article: The role of butyrate on colonic function. Aliment. Pharmacol. Ther. 2008;27:104–119. doi: 10.1111/j.1365-2036.2007.03562.x. PubMed DOI

Donohoe D.R., Garge N., Zhang X., Sun W., O’Connell T.M., Bunger M.K., Bultman S.J. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13:517–526. doi: 10.1016/j.cmet.2011.02.018. PubMed DOI PMC

Donohoe D.R., Collins L.B., Wali A., Bigler R., Sun W., Bultman S.J. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell. 2012;48:612–626. doi: 10.1016/j.molcel.2012.08.033. PubMed DOI PMC

Burgess D.J. Warburg behind the butyrate paradox? Nat. Rev. Cancer. 2012;12:798–799. doi: 10.1038/nrc3401. PubMed DOI

Davie J.R. Inhibition of histone deacetylase activity by butyrate. J. Nutr. 2003;133:2485s–2493s. doi: 10.1093/jn/133.7.2485S. PubMed DOI

Sengupta S., Muir J.G., Gibson P.R. Does butyrate protect from colorectal cancer? J. Gastroenterol. Hepatol. 2006;21:209–218. doi: 10.1111/j.1440-1746.2006.04213.x. PubMed DOI

Rosignoli P., Fabiani R., De Bartolomeo A., Spinozzi F., Agea E., Pelli M.A., Morozzi G. Protective activity of butyrate on hydrogen peroxide-induced DNA damage in isolated human colonocytes and HT29 tumour cells. Carcinogenesis. 2001;22:1675–1680. doi: 10.1093/carcin/22.10.1675. PubMed DOI

Pool-Zobel B.L., Selvaraju V., Sauer J., Kautenburger T., Kiefer J., Richter K.K., Soom M., Wölfl S. Butyrate may enhance toxicological defence in primary, adenoma and tumor human colon cells by favourably modulating expression of glutathione S-transferases genes, an approach in nutrigenomics. Carcinogenesis. 2005;26:1064–1076. doi: 10.1093/carcin/bgi059. PubMed DOI

Stein J., Schröder O., Bonk M., Oremek G., Lorenz M., Caspary W.F. Induction of glutathione-S-transferase-pi by short-chain fatty acids in the intestinal cell line Caco-2. Eur. J. Clin. Investig. 1996;26:84–87. doi: 10.1046/j.1365-2362.1996.113252.x. PubMed DOI

Ebert M.N., Klinder A., Peters W.H., Schäferhenrich A., Sendt W., Scheele J., Pool-Zobel B.L. Expression of glutathione S-transferases (GSTs) in human colon cells and inducibility of GSTM2 by butyrate. Carcinogenesis. 2003;24:1637–1644. doi: 10.1093/carcin/bgg122. PubMed DOI

Liu E.Y., Ryan K.M. Autophagy and cancer--issues we need to digest. J. Cell Sci. 2012;125:2349–2358. doi: 10.1242/jcs.093708. PubMed DOI

Luo S., Li Z., Mao L., Chen S., Sun S. Sodium butyrate induces autophagy in colorectal cancer cells through LKB1/AMPK signaling. J. Physiol. Biochem. 2019;75:53–63. doi: 10.1007/s13105-018-0651-z. PubMed DOI

Zhang J., Yi M., Zha L., Chen S., Li Z., Li C., Gong M., Deng H., Chu X., Chen J., et al. Sodium Butyrate Induces Endoplasmic Reticulum Stress and Autophagy in Colorectal Cells: Implications for Apoptosis. PLoS ONE. 2016;11:e0147218. doi: 10.1371/journal.pone.0147218. PubMed DOI PMC

Sawada N. Tight junction-related human diseases. Pathol. Int. 2013;63:1–12. doi: 10.1111/pin.12021. PubMed DOI PMC

Lester B.R., McCarthy J.B. Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Metastasis Rev. 1992;11:31–44. doi: 10.1007/BF00047601. PubMed DOI

Rudzki Z., Jothy S. CD44 and the adhesion of neoplastic cells. Mol. Pathol. 1997;50:57–71. doi: 10.1136/mp.50.2.57. PubMed DOI PMC

Zeng H., Briske-Anderson M. Prolonged butyrate treatment inhibits the migration and invasion potential of HT1080 tumor cells. J. Nutr. 2005;135:291–295. doi: 10.1093/jn/135.2.291. PubMed DOI

Barshishat M., Levi I., Benharroch D., Schwartz B. Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line. Br. J. Cancer. 2002;87:1314–1320. doi: 10.1038/sj.bjc.6600574. PubMed DOI PMC

Cousin F.J., Jouan-Lanhouet S., Dimanche-Boitrel M.-T., Corcos L., Jan G. Milk fermented by Propionibacterium freudenreichii induces apoptosis of HGT-1 human gastric cancer cells. PLoS ONE. 2012;7:e31892. doi: 10.1371/journal.pone.0031892. PubMed DOI PMC

Hague A., Manning A.M., Hanlon K.A., Huschtscha L.I., Hart D., Paraskeva C. Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53-independent pathway: Implications for the possible role of dietary fibre in the prevention of large-bowel cancer. Int. J. Cancer. 1993;55:498–505. doi: 10.1002/ijc.2910550329. PubMed DOI

Chirakkal H., Leech S.H., Brookes K.E., Prais A.L., Waby J.S., Corfe B.M. Upregulation of BAK by butyrate in the colon is associated with increased Sp3 binding. Oncogene. 2006;25:7192–7200. doi: 10.1038/sj.onc.1209702. PubMed DOI

Watkins S.M., Carter L.C., Mak J., Tsau J., Yamamoto S., German J.B. Butyric acid and tributyrin induce apoptosis in human hepatic tumour cells. J. Dairy Res. 1999;66:559–567. doi: 10.1017/S0022029999003830. PubMed DOI

Maier S., Reich E., Martin R., Bachem M., Altug V., Hautmann R.E., Gschwend J.E. Tributyrin induces differentiation, growth arrest and apoptosis in androgen-sensitive and androgen-resistant human prostate cancer cell lines. Int. J. Cancer. 2000;88:245–251. doi: 10.1002/1097-0215(20001015)88:2<245::AID-IJC16>3.0.CO;2-X. PubMed DOI

Yan J., Xu Y.-H. Tributyrin inhibits human gastric cancer SGC-7901 cell growth by inducing apoptosis and DNA synthesis arrest. World J. Gastroenterol. 2003;9:660–664. doi: 10.3748/wjg.v9.i4.660. PubMed DOI PMC

Giermasz A., Nowis D., Jalili A., Basak G., Marczak M., Makowski M., Czajka A., Młynarczuk I., Hoser G., Stok osa T., et al. Antitumor activity of tributyrin in murine melanoma model. Cancer Lett. 2001;164:143–148. doi: 10.1016/S0304-3835(01)00375-5. PubMed DOI

Kuefer R., Hofer M.D., Altug V., Zorn C., Genze F., Kunzi-Rapp K., Hautmann R.E., Gschwend J.E. Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer. Br. J. Cancer. 2004;90:535–541. doi: 10.1038/sj.bjc.6601510. PubMed DOI PMC

Edelman M.J., Bauer K., Khanwani S., Tait N., Trepel J., Karp J., Nemieboka N., Chung E.-J., Van Echo D. Clinical and pharmacologic study of tributyrin: An oral butyrate prodrug. Cancer Chemother. Pharmacol. 2003;51:439–444. doi: 10.1007/s00280-003-0580-5. PubMed DOI

Kuroiwa-Trzmielina J., de Conti A., Scolastici C., Pereira D., Horst M.A., Purgatto E., Ong T.P., Moreno F.S. Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug. Int. J. Cancer. 2009;124:2520–2527. doi: 10.1002/ijc.24212. PubMed DOI

Glueck B., Han Y., Cresci G.A.M. Tributyrin Supplementation Protects Immune Responses and Vasculature and Reduces Oxidative Stress in the Proximal Colon of Mice Exposed to Chronic-Binge Ethanol Feeding. J. Immunol. Res. 2018;2018:9671919. doi: 10.1155/2018/9671919. PubMed DOI PMC

Cresci G., Nagy L.E., Ganapathy V. Lactobacillus GG and tributyrin supplementation reduce antibiotic-induced intestinal injury. JPEN J. Parenter. Enter. Nutr. 2013;37:763–774. doi: 10.1177/0148607113486809. PubMed DOI PMC

Halestrap A.P., Price N.T. The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation. Biochem. J. 1999;343 Pt 2:281–299. doi: 10.1042/bj3430281. PubMed DOI PMC

Halestrap A.P. The SLC16 gene family—structure, role and regulation in health and disease. Mol. Asp. Med. 2013;34:337–349. doi: 10.1016/j.mam.2012.05.003. PubMed DOI

Halestrap A.P. The monocarboxylate transporter family--Structure and functional characterization. IUBMB Life. 2012;64:1–9. doi: 10.1002/iub.573. PubMed DOI

Ganapathy V., Gopal E., Miyauchi S., Prasad P.D. Biological functions of SLC5A8, a candidate tumour suppressor. Biochem. Soc. Trans. 2005;33:237–240. doi: 10.1042/BST0330237. PubMed DOI

Srinivas S.R., Gopal E., Zhuang L., Itagaki S., Martin P.M., Fei Y.J., Ganapathy V., Prasad P.D. Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2) Biochem. J. 2005;392:655–664. doi: 10.1042/BJ20050927. PubMed DOI PMC

Brooks G.A. Lactate as a fulcrum of metabolism. Redox Biol. 2020;35:101454. doi: 10.1016/j.redox.2020.101454. PubMed DOI PMC

Roland C.L., Arumugam T., Deng D., Liu S.H., Philip B., Gomez S., Burns W.R., Ramachandran V., Wang H., Cruz-Monserrate Z., et al. Cell Surface Lactate Receptor GPR81 Is Crucial for Cancer Cell Survival. Cancer Res. 2014;74:5301–5310. doi: 10.1158/0008-5472.CAN-14-0319. PubMed DOI PMC

de Bari L., Atlante A. Including the mitochondrial metabolism of L-lactate in cancer metabolic reprogramming. Cell. Mol. Life Sci. 2018;75:2763–2776. doi: 10.1007/s00018-018-2831-y. PubMed DOI PMC

Yang X., Lu Y., Hang J., Zhang J., Zhang T., Huo Y., Liu J., Lai S., Luo D., Wang L., et al. Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer. Cancer Immunol. Res. 2020;8:1440–1451. doi: 10.1158/2326-6066.CIR-20-0111. PubMed DOI

Raychaudhuri D., Bhattacharya R., Sinha B.P., Liu C.S.C., Ghosh A.R., Rahaman O., Bandopadhyay P., Sarif J., D’Rozario R., Paul S., et al. Lactate Induces Pro-tumor Reprogramming in Intratumoral Plasmacytoid Dendritic Cells. Front. Immunol. 2019;10:1878. doi: 10.3389/fimmu.2019.01878. PubMed DOI PMC

Brown T.P., Bhattacharjee P., Ramachandran S., Sivaprakasam S., Ristic B., Sikder M.O.F., Ganapathy V. The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. Oncogene. 2020;39:3292–3304. doi: 10.1038/s41388-020-1216-5. PubMed DOI

Hashimoto T., Hussien R., Oommen S., Gohil K., Brooks G.A. Lactate sensitive transcription factor network in L6 cells: Activation of MCT1 and mitochondrial biogenesis. FASEB J. 2007;21:2602–2612. doi: 10.1096/fj.07-8174com. PubMed DOI

Zelenka J., Dvořák A., Alán L. L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis. Oxid. Med. Cell. Longev. 2015;2015:351698. doi: 10.1155/2015/351698. PubMed DOI PMC

Tauffenberger A., Fiumelli H., Almustafa S., Magistretti P.J. Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling. Cell Death Dis. 2019;10:653. doi: 10.1038/s41419-019-1877-6. PubMed DOI PMC

Walenta S., Mueller-Klieser W.F. Lactate: Mirror and motor of tumor malignancy. Semin. Radiat. Oncol. 2004;14:267–274. doi: 10.1016/j.semradonc.2004.04.004. PubMed DOI

Pérez-Tomás R., Pérez-Guillén I. Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment. Cancers. 2020;12:3244. doi: 10.3390/cancers12113244. PubMed DOI PMC

Hoque R., Farooq A., Ghani A., Gorelick F., Mehal W.Z. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology. 2014;146:1763–1774. doi: 10.1053/j.gastro.2014.03.014. PubMed DOI PMC

Ranganathan P., Shanmugam A., Swafford D., Suryawanshi A., Bhattacharjee P., Hussein M.S., Koni P.A., Prasad P.D., Kurago Z.B., Thangaraju M., et al. GPR81, a Cell-Surface Receptor for Lactate, Regulates Intestinal Homeostasis and Protects Mice from Experimental Colitis. J. Immunol. 2018;200:1781–1789. doi: 10.4049/jimmunol.1700604. PubMed DOI PMC

Yang K., Xu J., Fan M., Tu F., Wang X., Ha T., Williams D.L., Li C. Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling. Front. Immunol. 2020;11:587913. doi: 10.3389/fimmu.2020.587913. PubMed DOI PMC

Huang Y., Zhang J., Dong R., Ji X., Jiang Y., Cen J., Bai Z., Hong K., Li H., Chen J., et al. Lactate as a metabolite from probiotic Lactobacilli mitigates ethanol-induced gastric mucosal injury: An in vivo study. BMC Complement. Med. Ther. 2021;21:26. doi: 10.1186/s12906-020-03198-7. PubMed DOI PMC

Lee Y.S., Kim T.Y., Kim Y., Lee S.H., Kim S., Kang S.W., Yang J.Y., Baek I.J., Sung Y.H., Park Y.Y., et al. Microbiota-Derived Lactate Accelerates Intestinal Stem-Cell-Mediated Epithelial Development. Cell Host Microbe. 2018;24:833–846.e6. doi: 10.1016/j.chom.2018.11.002. PubMed DOI

Larsson S.C., Andersson S.O., Johansson J.E., Wolk A. Cultured milk, yogurt, and dairy intake in relation to bladder cancer risk in a prospective study of Swedish women and men. Am. J. Clin. Nutr. 2008;88:1083–1087. doi: 10.1093/ajcn/88.4.1083. PubMed DOI

Bermejo L.M., López-Plaza B., Santurino C., Cavero-Redondo I., Gómez-Candela C. Milk and Dairy Product Consumption and Bladder Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies. Adv. Nutr. 2019;10:S224–S238. doi: 10.1093/advances/nmy119. PubMed DOI PMC

Pala V., Sieri S., Berrino F., Vineis P., Sacerdote C., Palli D., Masala G., Panico S., Mattiello A., Tumino R., et al. Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort. Int. J. Cancer. 2011;129:2712–2719. doi: 10.1002/ijc.26193. PubMed DOI

Michels K.B., Willett W.C., Vaidya R., Zhang X., Giovannucci E. Yogurt consumption and colorectal cancer incidence and mortality in the Nurses’ Health Study and the Health Professionals Follow-Up Study. Am. J. Clin. Nutr. 2020;112:1566–1575. doi: 10.1093/ajcn/nqaa244. PubMed DOI PMC

Kampman E., Goldbohm R.A., van den Brandt P.A., van ‘t Veer P. Fermented dairy products, calcium, and colorectal cancer in The Netherlands Cohort Study. Cancer Res. 1994;54:3186–3190. PubMed

Nimptsch K., Lee D.H., Zhang X., Song M., Farvid M.S., Rezende L.F.M., Cao Y., Chan A.T., Fuchs C., Meyerhardt J., et al. Dairy intake during adolescence and risk of colorectal adenoma later in life. Br. J. Cancer. 2021 doi: 10.1038/s41416-020-01203-x. PubMed DOI PMC

Rifkin S.B., Giardiello F.M., Zhu X., Hylind L.M., Ness R.M., Drewes J.L., Murff H.J., Spence E.H., Smalley W.E., Gills J.J., et al. Yogurt consumption and colorectal polyps. Br. J. Nutr. 2020;124:80–91. doi: 10.1017/S0007114520000550. PubMed DOI PMC

Liu M., Wu L., Montaut S., Yang G. Hydrogen Sulfide Signaling Axis as a Target for Prostate Cancer Therapeutics. Prostate Cancer. 2016;2016:8108549. doi: 10.1155/2016/8108549. PubMed DOI PMC

Ono K., Akaike T., Rahaman M., Kumagai Y., Wink D., Tantillo D., Hobbs A., Nagy P., Xian M., Lin J., et al. The Redox Chemistry and Chemical Biology of H2S, Hydropersulfides and Derived Species: Implications to Their Possible Biological Activity and Utility. Free Radic. Biol. Med. 2014;77:82–94. doi: 10.1016/j.freeradbiomed.2014.09.007. PubMed DOI PMC

Medani M., Collins D., Docherty N.G., Baird A.W., O’Connell P.R., Winter D.C. Emerging role of hydrogen sulfide in colonic physiology and pathophysiology. Inflamm. Bowel Dis. 2011;17:1620–1625. doi: 10.1002/ibd.21528. PubMed DOI

Tomasova L., Konopelski P., Ufnal M. Gut Bacteria and Hydrogen Sulfide: The New Old Players in Circulatory System Homeostasis. Molecules. 2016;21:1558. doi: 10.3390/molecules21111558. PubMed DOI PMC

Szabó C. Hydrogen sulphide and its therapeutic potential. Nat. Rev. Drug Discov. 2007;6:917–935. doi: 10.1038/nrd2425. PubMed DOI

Zhao Y., Biggs T.D., Xian M. Hydrogen sulfide (H2S) releasing agents: Chemistry and biological applications. Chem. Commun. 2014;50:11788–11805. doi: 10.1039/C4CC00968A. PubMed DOI PMC

Mustafa A.K., Sikka G., Gazi S.K., Steppan J., Jung S.M., Bhunia A.K., Barodka V.M., Gazi F.K., Barrow R.K., Wang R., et al. Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ. Res. 2011;109:1259–1268. doi: 10.1161/CIRCRESAHA.111.240242. PubMed DOI PMC

Cai W.J., Wang M.J., Moore P.K., Jin H.M., Yao T., Zhu Y.C. The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc. Res. 2007;76:29–40. doi: 10.1016/j.cardiores.2007.05.026. PubMed DOI

Coletta C., Papapetropoulos A., Erdelyi K., Olah G., Módis K., Panopoulos P., Asimakopoulou A., Gerö D., Sharina I., Martin E., et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc. Natl. Acad. Sci. USA. 2012;109:9161–9166. doi: 10.1073/pnas.1202916109. PubMed DOI PMC

Florin T., Neale G., Gibson G.R., Christl S.U., Cummings J.H. Metabolism of dietary sulphate: Absorption and excretion in humans. Gut. 1991;32:766–773. doi: 10.1136/gut.32.7.766. PubMed DOI PMC

Wu Y.C., Wang X.J., Yu L., Chan F.K.L., Cheng A.S.L., Yu J., Sung J.J.Y., Wu W.K.K., Cho C.H. Hydrogen sulfide lowers proliferation and induces protective autophagy in colon epithelial cells. PLoS ONE. 2012;7:e37572. doi: 10.1371/journal.pone.0037572. PubMed DOI PMC

Szabo C., Coletta C., Chao C., Módis K., Szczesny B., Papapetropoulos A., Hellmich M.R. Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc. Natl. Acad. Sci. USA. 2013;110:12474–12479. doi: 10.1073/pnas.1306241110. PubMed DOI PMC

Szabo C., Hellmich M.R. Endogenously produced hydrogen sulfide supports tumor cell growth and proliferation. Cell Cycle. 2013;12:2915–2916. doi: 10.4161/cc.26064. PubMed DOI PMC

Ianaro A., Cirino G., Wallace J.L. Hydrogen sulfide-releasing anti-inflammatory drugs for chemoprevention and treatment of cancer. Pharmacol. Res. 2016;111:652–658. doi: 10.1016/j.phrs.2016.07.041. PubMed DOI

Wang R. Two’s company, three’s a crowd: Can H2S be the third endogenous gaseous transmitter? FASEB J. 2002;16:1792–1798. doi: 10.1096/fj.02-0211hyp. PubMed DOI

Cakmak Y.O. Provotella-derived hydrogen sulfide, constipation, and neuroprotection in Parkinson’s disease. Mov. Disord. 2015;30:1151. doi: 10.1002/mds.26258. PubMed DOI

Chwatko G., Forma E., Wilkosz J., Głowacki R., Jóźwiak P., Różański W., Bryś M., Krześlak A. Thiosulfate in urine as a facilitator in the diagnosis of prostate cancer for patients with prostate-specific antigen less or equal 10 ng/mL. Clin. Chem. Lab. Med. 2013;51:1825–1831. doi: 10.1515/cclm-2013-0069. PubMed DOI

Pei Y., Wu B., Cao Q., Wu L., Yang G. Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells. Toxicol. Appl. Pharmacol. 2011;257:420–428. doi: 10.1016/j.taap.2011.09.026. PubMed DOI

Duan F., Li Y., Chen L., Zhou X., Chen J., Chen H., Li R. Sulfur inhibits the growth of androgen-independent prostate cancer in vivo. Oncol. Lett. 2015;9:437–441. doi: 10.3892/ol.2014.2700. PubMed DOI PMC

Arunkumar A., Vijayababu M.R., Gunadharini N., Krishnamoorthy G., Arunakaran J. Induction of apoptosis and histone hyperacetylation by diallyl disulfide in prostate cancer cell line PC-3. Cancer Lett. 2007;251:59–67. doi: 10.1016/j.canlet.2006.11.001. PubMed DOI

Sielicka-Dudzin A., Borkowska A., Herman-Antosiewicz A., Wozniak M., Jozwik A., Fedeli D., Antosiewicz J. Impact of JNK1, JNK2, and ligase Itch on reactive oxygen species formation and survival of prostate cancer cells treated with diallyl trisulfide. Eur. J. Nutr. 2012;51:573–581. doi: 10.1007/s00394-011-0241-0. PubMed DOI

Chiao J.W., Chung F.L., Kancherla R., Ahmed T., Mittelman A., Conaway C.C. Sulforaphane and its metabolite mediate growth arrest and apoptosis in human prostate cancer cells. Int. J. Oncol. 2002;20:631–636. doi: 10.3892/ijo.20.3.631. PubMed DOI

Borkowska A., Knap N., Antosiewicz J. Diallyl trisulfide is more cytotoxic to prostate cancer cells PC-3 than to noncancerous epithelial cell line PNT1A: A possible role of p66Shc signaling axis. Nutr. Cancer. 2013;65:711–717. doi: 10.1080/01635581.2013.789115. PubMed DOI

Arunkumar A., Vijayababu M.R., Venkataraman P., Senthilkumar K., Arunakaran J. Chemoprevention of rat prostate carcinogenesis by diallyl disulfide, an organosulfur compound of garlic. Biol. Pharm. Bull. 2006;29:375–379. doi: 10.1248/bpb.29.375. PubMed DOI

Cheung N.K., Modak S., Vickers A., Knuckles B. Orally administered beta-glucans enhance anti-tumor effects of monoclonal antibodies. Cancer Immunol. Immunother. 2002;51:557–564. doi: 10.1007/s00262-002-0321-3. PubMed DOI PMC

Wasser S.P., Weis A.L. Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: A modern perspective. Crit. Rev. Immunol. 1999;19:65–96. PubMed

BeMiller J.A.B.J.N. (1→3)-β-d-Glucans as biological response modifiers: A review of structure-functional activity relationships. Carbohydr. Polym. 1995;28:3–14.

Yan J., Vetvicka V., Xia Y., Coxon A., Carroll M.C., Mayadas T.N., Ross G.D. Beta-glucan, a “specific” biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18) J. Immunol. 1999;163:3045–3052. PubMed

Hong F., Yan J., Baran J.T., Allendorf D.J., Hansen R.D., Ostroff G.R., Xing P.X., Cheung N.K., Ross G.D. Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models. J. Immunol. 2004;173:797–806. doi: 10.4049/jimmunol.173.2.797. PubMed DOI

Li B., Cramer D., Wagner S., Hansen R., King C., Kakar S., Ding C., Yan J. Yeast glucan particles activate murine resident macrophages to secrete proinflammatory cytokines via MyD88- and Syk kinase-dependent pathways. Clin. Immunol. 2007;124:170–181. doi: 10.1016/j.clim.2007.05.002. PubMed DOI PMC

Gawronski M., Park J.T., Magee A.S., Conrad H. Microfibrillar structure of PGG-glucan in aqueous solution as triple-helix aggregates by small angle x-ray scattering. Biopolymers. 1999;50:569–578. doi: 10.1002/(SICI)1097-0282(199911)50:6<569::AID-BIP1>3.0.CO;2-B. PubMed DOI

Li B., Allendorf D.J., Hansen R., Marroquin J., Ding C., Cramer D.E., Yan J. Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway. J. Immunol. 2006;177:1661–1669. doi: 10.4049/jimmunol.177.3.1661. PubMed DOI

Hong F., Hansen R.D., Yan J., Allendorf D.J., Baran J.T., Ostroff G.R., Ross G.D. β-Glucan Functions as an Adjuvant for Monoclonal Antibody Immunotherapy by Recruiting Tumoricidal Granulocytes as Killer Cells. Cancer Res. 2003;63:9023–9031. PubMed

Liu J., Gunn L., Hansen R., Yan J. Combined yeast-derived beta-glucan with anti-tumor monoclonal antibody for cancer immunotherapy. Exp. Mol. Pathol. 2009;86:208–214. doi: 10.1016/j.yexmp.2009.01.006. PubMed DOI PMC

Vetvicka V., Thornton B.P., Ross G.D. Soluble beta-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J. Clin. Investig. 1996;98:50–61. doi: 10.1172/JCI118777. PubMed DOI PMC

Yan J., Větvička V., Xia Y., Hanikýřová M., Mayadas T.N., Ross G.D. Critical role of Kupffer cell CR3 (CD11b/CD18) in the clearance of IgM-opsonized erythrocytes or soluble β-glucan. Immunopharmacology. 2000;46:39–54. doi: 10.1016/S0162-3109(99)00157-5. PubMed DOI

Wilczak J., Błaszczyk K., Kamola D., Gajewska M., Harasym J.P., Jałosińska M., Gudej S., Suchecka D., Oczkowski M., Gromadzka-Ostrowska J. The effect of low or high molecular weight oat beta-glucans on the inflammatory and oxidative stress status in the colon of rats with LPS-induced enteritis. Food Funct. 2015;6:590–603. doi: 10.1039/C4FO00638K. PubMed DOI

Liu B., Lin Q., Yang T., Zeng L., Shi L., Chen Y., Luo F. Oat β-glucan ameliorates dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. Food Funct. 2015;6:3454–3463. doi: 10.1039/C5FO00563A. PubMed DOI