Bugs as Drugs: Understanding the Linkage between Gut Microbiota and
Cancer Treatment

Dhwani      Rana; Sagar      Salave; Akhil      Perla; Akanksha      Nadkarni; Shital      Kolhe; Anil   B.   Jindal; Amit      Mandoli; Pradeep      Dwivedi; Derajram      Benival
Abstract

The commensal microbiota is known to regulate host physiology. Dysbiosis or compromised resilience in the microbial ecology is related to the impending risk of cancer. A potential link between cancer and microbiota is indicated by a lot of evidence.
The current review explores in detail the various links leading to and /or facilitating oncogenesis, providing sound reasoning or a basis for its utilization as potential therapeutic targets. The present review emphasizes the existing knowledge of the microbiome in cancer and further elaborates on the factors, like genetic modifications, effects of dietary components, and environmental agents, that are considered to assess the direct and indirect effect of microbes in the process of oncogenesis and on the host’s health. Strategies modulating the microbiome and novel biotherapeutics are also discussed. Pharmacomicrobiomics is one such niche accounting for the interplay between the microbiome, xenobiotic, and host responses, which is also looked upon.
The literature search strategy for this review was conducted by following the methodology of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). The method includes the collection of data from different search engines, like PubMed, ScienceDirect, SciFinder, etc., to get coverage of relevant literature for accumulating appropriate information regarding microbiome, cancer, and their linkages.
These considerations are made to expand the existing literature on the role of gut microbiota in the host's health, the interaction between host and microbiota, and the reciprocal relationship between the microbiome and modified neoplastic cells.
Potential therapeutic implications of cancer microbiomes that are yet unexplored and have rich therapeutic dividends improving human health are discussed in detail in this review.
Keywords: Gut microbiota, cancer, microbiome, targeted modulation, pharmacomicrobiomics, microbiome-based treatment.
Graphical Abstract

[1] 
Montané X, Bajek A, Roszkowski K, et al. Encapsulation for cancer therapy. Molecules  2020; 25(7): 1605.
[http://dx.doi.org/10.3390/molecules25071605] [PMID: 32244513] 
[2] 
Wiwanitkit V. Cancer nanotherapy: Concept for design of new drug. J Med Hypotheses Ideas  2013; 7(1): 3-4.
[http://dx.doi.org/10.1016/j.jmhi.2012.10.002] 
[3] 
International agency for research on cancer.. World cancer report 2014. Lyon, France: IARC 2014.
[4] 
Vivarelli S, Salemi R, Candido S, et al. Gut microbiota and cancer: From pathogenesis to therapy. Cancers  2019; 11(1): 38.
[http://dx.doi.org/10.3390/cancers11010038] [PMID: 30609850] 
[5] 
Sampathkumar K, Arulkumar S, Ramalingam M. Advances in stimuli responsive nanobiomaterials for cancer therapy. J Biomed Nanotechnol  2014; 10(3): 367-82.
[http://dx.doi.org/10.1166/jbn.2014.1778] [PMID: 24730233] 
[6] 
Afshar M, Madani S, Tarazoj AA, et al. Salehiniya. Physical activity and types of cancer. WCRJ  2018; 5(4): e1164.
[7] 
Anand P, Kunnumakkara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res  2008; 25(9): 2097-116.
[http://dx.doi.org/10.1007/s11095-008-9661-9] [PMID: 18626751] 
[8] 
Gunjur A. Cancer and the microbiome. Lancet Oncol  2020; 21(7): 888.
[http://dx.doi.org/10.1016/S1470-2045(20)30351-X] [PMID: 32563279] 
[9] 
Wong SH, Kwong TNY, Wu CY, Yu J. Clinical applications of gut microbiota in cancer biology. Semin Cancer Biol  2019; 55: 28-36.
[http://dx.doi.org/10.1016/j.semcancer.2018.05.003] [PMID: 29782923] 
[10] 
Gorbach SL. Microbiology of the Gastrointestinal Tract. In: Samuel B, Ed. Medical Microbiology.  4th ed. Galveston (TX): University of Texas Medical Branch at Galveston 1996; pp. 1-7.
[11] 
Zitvogel L, Galluzzi L, Viaud S, et al. Cancer and the gut microbiota: An unexpected link. Sci Transl Med  2015; 7(271): 271ps1.
[http://dx.doi.org/10.1126/scitranslmed.3010473] [PMID: 25609166] 
[12] 
Kho ZY, Lal SK. The human gut microbiome - A potential controller of wellness and disease. Front Microbiol  2018; 9: 1835.
[http://dx.doi.org/10.3389/fmicb.2018.01835] [PMID: 30154767] 
[13] 
Suraya R, Nagano T, Kobayashi K, Nishimura Y. Microbiome as a target for cancer therapy. Integr Cancer Ther  2020; 19: 1534735420920721.
[http://dx.doi.org/10.1177/1534735420920721] [PMID: 32564632] 
[14] 
Song W, Anselmo AC, Huang L. Nanotechnology intervention of the microbiome for cancer therapy. Nat Nanotechnol  2019; 14(12): 1093-103.
[http://dx.doi.org/10.1038/s41565-019-0589-5] [PMID: 31802032] 
[15] 
Poore GD, Kopylova E, Zhu Q, et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature  2020; 579(7800): 567-74.
[http://dx.doi.org/10.1038/s41586-020-2095-1] [PMID: 32214244] 
[16] 
Rao BC, Lou JM, Wang WJ, et al. Human microbiome is a diagnostic biomarker in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int  2020; 19(2): 109-15.
[http://dx.doi.org/10.1016/j.hbpd.2020.01.003] [PMID: 32037278] 
[17] 
Wang J, Jia H. Metagenome-wide association studies: Fine-mining the microbiome. Nat Rev Microbiol  2016; 14(8): 508-22.
[http://dx.doi.org/10.1038/nrmicro.2016.83] [PMID: 27396567] 
[18] 
Zhuang H, Cheng L, Wang Y, et al. Dysbiosis of the gut microbiome in lung cancer. Front Cell Infect Microbiol  2019; 9: 112.
[http://dx.doi.org/10.3389/fcimb.2019.00112] [PMID: 31065547] 
[19] 
Wong SH, Kwong TNY, Chow TC, et al. Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting ad-vanced colorectal neoplasia. Gut  2017; 66(8): 1441-8.
[http://dx.doi.org/10.1136/gutjnl-2016-312766] [PMID: 27797940] 
[20] 
Hamada T, Zhang X, Mima K, et al. Fusobacterium nucleatum in colorectal cancer relates to immune response differentially by tumor microsatellite instability status. Cancer Immunol Res  2018; 6(11): 1327-36.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0174] [PMID: 30228205] 
[21] 
Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut  2016; 65(12): 1973-80.
[http://dx.doi.org/10.1136/gutjnl-2015-310101] [PMID: 26311717] 
[22] 
Wei Z, Cao S, Liu S, et al. Could gut microbiota serve as prognostic biomarker associated with colorectal cancer patients’ survival? A pilot study on relevant mechanism. Oncotarget  2016; 7(29): 46158-72.
[http://dx.doi.org/10.18632/oncotarget.10064] [PMID: 27323816] 
[23] 
Zheng Y, Fang Z, Xue Y, et al. Specific gut microbiome signature predicts the early-stage lung cancer. Gut Microbes  2020; 11(4): 1030-42.
[http://dx.doi.org/10.1080/19490976.2020.1737487] [PMID: 32240032] 
[24] 
Plottel CS, Blaser MJ. Microbiome and malignancy. Cell Host Microbe  2011; 10(4): 324-35.
[http://dx.doi.org/10.1016/j.chom.2011.10.003] [PMID: 22018233] 
[25] 
Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer  2013; 13(11): 800-12.
[http://dx.doi.org/10.1038/nrc3610] [PMID: 24132111] 
[26] 
Candela M, Guidotti M, Fabbri A, Brigidi P, Franceschi C, Fiorentini C. Human intestinal microbiota: Cross-talk with the host and its potential role in colorectal cancer. Crit Rev Microbiol  2011; 37(1): 1-14.
[http://dx.doi.org/10.3109/1040841X.2010.501760] [PMID: 20874522] 
[27] 
Cheng WY, Wu CY, Yu J. The role of gut microbiota in cancer treatment: Friend or foe? Gut  2020; 69(10): 1867-76.
[http://dx.doi.org/10.1136/gutjnl-2020-321153] [PMID: 32759302] 
[28] 
Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol  2017; 14(6): 356-65.
[http://dx.doi.org/10.1038/nrgastro.2017.20] [PMID: 28270698] 
[29] 
Sharma A, Das P, Buschmann M, Gilbert JA. The future of microbiome-based therapeutics in clinical applications. Clin Pharmacol Ther  2020; 107(1): 123-8.
[http://dx.doi.org/10.1002/cpt.1677] [PMID: 31617205] 
[30] 
Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science  2013; 342(6161): 971-6.
[http://dx.doi.org/10.1126/science.1240537] [PMID: 24264990] 
[31] 
Viaud S, Flament C, Zoubir M, et al. Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res  2011; 71(3): 661-5.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1259] [PMID: 21148486] 
[32] 
Ross AB, Bruce SJ, Blondel-Lubrano A, et al. A whole-grain cereal-rich diet increases plasma betaine, and tends to decrease total and LDL-cholesterol compared with a refined-grain diet in healthy subjects. Br J Nutr  2011; 105(10): 1492-502.
[http://dx.doi.org/10.1017/S0007114510005209] [PMID: 21272402] 
[33] 
Wallace BD, Wang H, Lane KT, et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science  2010; 330(6005): 831-5.
[http://dx.doi.org/10.1126/science.1191175] [PMID: 21051639] 
[34] 
Diasio RB. Sorivudine and 5-fluorouracil; A clinically significant drug-drug interaction due to inhibition of dihydropyrimidine dehydro-genase. Br J Clin Pharmacol  1998; 46(1): 1-4.
[http://dx.doi.org/10.1046/j.1365-2125.1998.00050.x] [PMID: 9690942] 
[35] 
Garrett WS. Cancer and the microbiota. Science  2015; 348(6230): 80-6.
[http://dx.doi.org/10.1126/science.aaa4972] [PMID: 25838377] 
[36] 
Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: A synthetic analysis. Lancet Glob Health  2016; 4(9): e609-16.
[http://dx.doi.org/10.1016/S2214-109X(16)30143-7] [PMID: 27470177] 
[37] 
Rea D, Coppola G, Palma G, et al. Microbiota effects on cancer: From risks to therapies. Oncotarget  2018; 9(25): 17915-27.
[http://dx.doi.org/10.18632/oncotarget.24681] [PMID: 29707157] 
[38] 
Eslami-SZ. Majidzadeh-AK, Halvaei S, Babapirali F, Esmaeili R. Microbiome and breast cancer: New role for an ancient population. Front Oncol  2020; 10: 120.
[http://dx.doi.org/10.3389/fonc.2020.00120] [PMID: 32117767] 
[39] 
Goodman B, Gardner H. The microbiome and cancer. J Pathol  2018; 244(5): 667-76.
[http://dx.doi.org/10.1002/path.5047] [PMID: 29377130] 
[40] 
Fulbright LE, Ellermann M, Arthur JC. The microbiome and the hallmarks of cancer. PLoS Pathog  2017; 13: e1006480.
[http://dx.doi.org/10.1371/journal.ppat.1006480] 
[41] 
Qu X, Tang Y, Hua S. Immunological approaches towards cancer and inflammation: A cross talk. Front Immunol  2018; 9: 563.
[http://dx.doi.org/10.3389/fimmu.2018.00563] [PMID: 29662489] 
[42] 
Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The tumor microenvironment: A milieu hindering and obstructing antitumor immune responses. Front Immunol  2020; 11: 940.
[http://dx.doi.org/10.3389/fimmu.2020.00940] [PMID: 32499786] 
[43] 
Dzutsev A, Goldszmid RS, Viaud S, Zitvogel L, Trinchieri G. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur J Immunol  2015; 45(1): 17-31.
[http://dx.doi.org/10.1002/eji.201444972] [PMID: 25328099] 
[44] 
Kuhn MA. Oxygen free radicals and antioxidants. Am J Nurs  2003; 103(4): 58-62.
[http://dx.doi.org/10.1097/00000446-200304000-00022] [PMID: 12677123] 
[45] 
Huycke MM, Moore D, Joyce W, et al. Extracellular superoxide production by Enterococcus faecalis requires demethylmenaquinone and is attenuated by functional terminal quinol oxidases. Mol Microbiol  2001; 42(3): 729-40.
[http://dx.doi.org/10.1046/j.1365-2958.2001.02638.x] [PMID: 11722738] 
[46] 
Elatrech I, Marzaioli V, Boukemara H, et al. Escherichia coli LF82 differentially regulates ROS production and mucin expression in intestinal epithelial T84 cells: Implication of NOX1. Inflamm Bowel Dis  2015; 21(5): 1018-26.
[http://dx.doi.org/10.1097/MIB.0000000000000365] [PMID: 25822013] 
[47] 
Shapiro O, Bratslavsky G. Genetic diseases Brenner’s Encycl Genet. Second  2013; 429: 246-7.
[48] 
Paul B, Barnes S, Demark-Wahnefried W, et al. Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin Epigenetics  2015; 7(1): 112.
[http://dx.doi.org/10.1186/s13148-015-0144-7] [PMID: 26478753] 
[49] 
Zhao Y, Wang C, Goel A. Role of gut microbiota in epigenetic regulation of colorectal cancer. Biochim Biophys Acta Rev Cancer  2021; 1875(1): 188490.
[http://dx.doi.org/10.1016/j.bbcan.2020.188490] [PMID: 33321173] 
[50] 
Zhou Z, Chen J, Yao H, Hu H. Fusobacterium and colorectal cancer. Front Oncol  2018; 8: 371.
[PMID:  30374420] 
[51] 
Nakata K, Sugi Y, Narabayashi H, et al. Commensal microbiota-induced microRNA modulates intestinal epithelial permeability through the small GTPase ARF4. J Biol Chem  2017; 292(37): 15426-33.
[http://dx.doi.org/10.1074/jbc.M117.788596] [PMID: 28760826] 
[52] 
Hullar MA, Fu BC. Diet, the gut microbiome, and epigenetics. Cancer J  2014; 20(3): 170-5.
[PMID:  24855003] 
[53] 
Bultman SJ. Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol Nutr Food Res  2017; 61(1): 1-12.
[http://dx.doi.org/10.1002/mnfr.201500902] [PMID: 27138454] 
[54] 
Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia  2015; 3: 83-92.
[http://dx.doi.org/10.2147/HP.S93413] [PMID: 27774485] 
[55] 
Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: Drivers of tumour metastasis. Nat Rev Cancer  2014; 14(6): 430-9.
[http://dx.doi.org/10.1038/nrc3726] [PMID: 24827502] 
[56] 
Gao J, Cao H, Zhang Q, Wang B. The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer. Sleep Breath  2021; 25(2): 1075-87.
[http://dx.doi.org/10.1007/s11325-020-02204-z] [PMID: 33029691] 
[57] 
Boleij A, Hechenbleikner EM, Goodwin AC, et al. The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal can-cer patients. Clin Infect Dis  2015; 60(2): 208-15.
[http://dx.doi.org/10.1093/cid/ciu787] [PMID: 25305284] 
[58] 
Bashiardes S, Tuganbaev T, Federici S, Elinav E. The microbiome in anti-cancer therapy. Semin Immunol  2017; 32: 74-81.
[http://dx.doi.org/10.1016/j.smim.2017.04.001] [PMID: 28431920] 
[59] 
Manzoor SS, Doedens A, Burns MB. The promise and challenge of cancer microbiome research. Genome Biol  2020; 21(1): 131.
[http://dx.doi.org/10.1186/s13059-020-02037-9] [PMID: 32487228] 
[60] 
Chakrabarty AM. Microorganisms and cancer: Quest for a therapy. J Bacteriol  2003; 185(9): 2683-6.
[http://dx.doi.org/10.1128/JB.185.9.2683-2686.2003] [PMID: 12700245] 
[61] 
Bernardes N, Seruca R, Chakrabarty AM, Fialho AM. Microbial-based therapy of cancer: Current progress and future prospects. Bioeng Bugs  2010; 1(3): 178-90.
[http://dx.doi.org/10.4161/bbug.1.3.10903] [PMID: 21326924] 
[62] 
Roy S, Trinchieri G. Microbiota: A key orchestrator of cancer therapy. Nat Rev Cancer  2017; 17(5): 271-85.
[http://dx.doi.org/10.1038/nrc.2017.13] [PMID: 28303904] 
[63] 
Blaser M. Antibiotic overuse: Stop the killing of beneficial bacteria. Nature  2011; 476(7361): 393-4.
[http://dx.doi.org/10.1038/476393a] [PMID: 21866137] 
[64] 
Iizumi T, Battaglia T, Ruiz V, Perez Perez GI. Gut microbiome and antibiotics. Arch Med Res  2017; 48(8): 727-34.
[http://dx.doi.org/10.1016/j.arcmed.2017.11.004] [PMID: 29221800] 
[65] 
Hsu PI, Pan CY, Kao JY, et al. Taiwan Acid-related Disease (TARD) Study Group. Helicobacter pylori eradication with bismuth quadruple therapy leads to dysbiosis of gut microbiota with an increased relative abundance of Proteobacteria and decreased relative abundances of Bacteroidetes and Actinobacteria. Helicobacter  2018; 23(4): e12498.
[http://dx.doi.org/10.1111/hel.12498] [PMID: 29897654] 
[66] 
Tucak P. Plumb’s veterinary drug handbook. Wiley-Blackwell  8th. 2015; 93: 404.
[67] 
Vrieze A, Out C, Fuentes S, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol  2014; 60(4): 824-31.
[http://dx.doi.org/10.1016/j.jhep.2013.11.034] [PMID: 24316517] 
[68] 
Stewardson AJ, Gaïa N, François P, et al. SATURN WP1 and WP3 Study Groups. Collateral damage from oral ciprofloxacin versus nitro-furantoin in outpatients with urinary tract infections: A culture-free analysis of gut microbiota. Clin Microbiol Infect  2015; 21(4): 344.
[http://dx.doi.org/10.1016/j.cmi.2014.11.016] [PMID: 25658522] 
[69] 
Perrin-Guyomard A, Poul JM, Corpet DE, Sanders P, Fernández AH, Bartholomew M. Impact of residual and therapeutic doses of ciprofloxacin in the human-flora-associated mice model. Regul Toxicol Pharmacol  2005; 42(2): 151-60.
[http://dx.doi.org/10.1016/j.yrtph.2005.03.001] [PMID: 15963836] 
[70] 
Korpela K, Salonen A, Virta LJ, et al. Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nat Commun  2016; 7(1): 10410.
[http://dx.doi.org/10.1038/ncomms10410] [PMID: 26811868] 
[71] 
Nord CE, Lidbeck A, Orrhage K, Sjöstedt S. Oral supplementation with lactic acid-producing bacteria during intake of clindamycin. Clin Microbiol Infect  1997; 3(1): 124-32.
[http://dx.doi.org/10.1111/j.1469-0691.1997.tb00262.x] [PMID: 11864087] 
[72] 
Reikvam DH, Erofeev A, Sandvik A, et al. Depletion of murine intestinal microbiota: Effects on gut mucosa and epithelial gene expression. PLoS One  2011; 6(3): e17996.
[http://dx.doi.org/10.1371/journal.pone.0017996] [PMID: 21445311] 
[73] 
Panebianco C, Andriulli A, Pazienza V. Pharmacomicrobiomics: Exploiting the drug-microbiota interactions in anticancer therapies. Microbiome  2018; 6(1): 92.
[http://dx.doi.org/10.1186/s40168-018-0483-7] [PMID: 29789015] 
[74] 
Shurin MR, Naiditch H, Gutkin DW, Umansky V, Shurin GV. ChemoImmunoModulation: Immune regulation by the antineoplastic chemotherapeutic agents. Curr Med Chem  2012; 19(12): 1792-803.
[http://dx.doi.org/10.2174/092986712800099785] [PMID: 22414087] 
[75] 
Patel RM, Denning PW. Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: What is the current evidence? Clin Perinatol  2013; 40(1): 11-25.
[http://dx.doi.org/10.1016/j.clp.2012.12.002] [PMID: 23415261] 
[76] 
Gibson GR, Hutkins R, Sanders ME, et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol  2017; 14(8): 491-502.
[http://dx.doi.org/10.1038/nrgastro.2017.75] [PMID: 28611480] 
[77] 
Guarner F, Khan AG, Garisch J, et al. World Gastroenterology Organization. World gastroenterology organisation global guidelines: Pro-biotics and prebiotics October 2011. J Clin Gastroenterol  2012; 46(6): 468-81.
[http://dx.doi.org/10.1097/MCG.0b013e3182549092] [PMID: 22688142] 
[78] 
Pineiro M, Stanton C. Probiotic bacteria: Legislative framework-requirements to evidence basis. J Nutr  2007; 137(3)(Suppl. 2): 850S-3S.
[http://dx.doi.org/10.1093/jn/137.3.850S] [PMID: 17311986] 
[79] 
O’Hara AM, Shanahan F. Mechanisms of action of probiotics in intestinal diseases. Scientific World J  2007; 7: 31-46.
[http://dx.doi.org/10.1100/tsw.2007.26] [PMID: 17221140] 
[80] 
Dobson A, Cotter PD, Ross RP, Hill C. Bacteriocin production: A probiotic trait? Appl Environ Microbiol  2012; 78(1): 1-6.
[http://dx.doi.org/10.1128/AEM.05576-11] [PMID: 22038602] 
[81] 
Corr SC, Hill C, Gahan CG. Understanding the mechanisms by which probiotics inhibit gastrointestinal pathogens. Adv Food Nutr Res  2009; 56: 1-15.
[http://dx.doi.org/10.1016/S1043-4526(08)00601-3] [PMID: 19389605] 
[82] 
Chenoll E, Casinos B, Bataller E, et al. Novel probiotic Bifidobacterium bifidum CECT 7366 strain active against the pathogenic bacte-rium Helicobacter pylori. Appl Environ Microbiol  2011; 77(4): 1335-43.
[http://dx.doi.org/10.1128/AEM.01820-10] [PMID: 21169430] 
[83] 
Atassi F, Servin AL. Individual and co-operative roles of lactic acid and hydrogen peroxide in the killing activity of enteric strain Lacto-bacillus johnsonii NCC933 and vaginal strain Lactobacillus gasseri KS120.1 against enteric, uropathogenic and vaginosis-associated pathogens. FEMS Microbiol Lett  2010; 304(1): 29-38.
[http://dx.doi.org/10.1111/j.1574-6968.2009.01887.x] [PMID: 20082639] 
[84] 
Lim CC, Ferguson LR, Tannock GW. Dietary fibres as “prebiotics”: Implications for colorectal cancer. Mol Nutr Food Res  2005; 49(6): 609-19.
[http://dx.doi.org/10.1002/mnfr.200500015] [PMID: 15864790] 
[85] 
Saarela M, Mogensen G, Fondén R, Mättö J, Mattila-Sandholm T. Probiotic bacteria: Safety, functional and technological properties. J Biotechnol  2000; 84(3): 197-215.
[http://dx.doi.org/10.1016/S0168-1656(00)00375-8] [PMID: 11164262] 
[86] 
Hirayama K, Rafter J. The role of lactic acid bacteria in colon cancer prevention: Mechanistic considerations. Antonie van Leeuwenhoek  1999; 76(1-4): 391-4.
[PMID:  10532395] 
[87] 
Timmerman HM, Koning CJ, Mulder L, Rombouts FM, Beynen AC. Monostrain, multistrain and multispecies probiotics--A comparison of functionality and efficacy. Int J Food Microbiol  2004; 96(3): 219-33.
[http://dx.doi.org/10.1016/j.ijfoodmicro.2004.05.012] [PMID: 15454313] 
[88] 
Gupta V, Garg R. Probiotics. Indian J Med Microbiol  2009; 27(3): 202-9.
[http://dx.doi.org/10.4103/0255-0857.53201] [PMID: 19584499] 
[89] 
Hosono A, Kashina T, Kada T. Antimutagenic properties of lactic acid-cultured milk on chemical and fecal mutagens. J Dairy Sci  1986; 69(9): 2237-42.
[http://dx.doi.org/10.3168/jds.S0022-0302(86)80662-2] [PMID: 3097092] 
[90] 
Fernandes CF, Shahani KM. Anticarcinogenic and immunological properties of dietary Lactobacilli. J Food Prot  1990; 53(8): 704-10.
[http://dx.doi.org/10.4315/0362-028X-53.8.704] [PMID: 31018334] 
[91] 
Zhang XB, Ohta Y, Hosono A. Antimutagenicity and binding of lactic acid bacteria from a Chinese cheese to mutagenic pyrolyzates. J Dairy Sci  1990; 73(10): 2702-10.
[http://dx.doi.org/10.3168/jds.S0022-0302(90)78955-2] [PMID: 1980923] 
[92] 
Thyagaraja N, Hosono A. Antimutagenicity of lactic acid bacteria from ″idly″ against food-related mutagens. J Food Prot  1993; 56(12): 1061-6.
[http://dx.doi.org/10.4315/0362-028X-56.12.1061] [PMID: 31113116] 
[93] 
El-Nezami H, Kankaanpaa P, Salminen S, Ahokas J. Ability of dairy strains of lactic acid bacteria to bind a common food carcinogen, aflatoxin B1. Food Chem Toxicol  1998; 36(4): 321-6.
[http://dx.doi.org/10.1016/S0278-6915(97)00160-9] [PMID: 9651049] 
[94] 
Bowen JM, Stringer AM, Gibson RJ, Yeoh ASJ, Hannam S, Keefe DMK. VSL#3 probiotic treatment reduces chemotherapy-induced diarrhea and weight loss. Cancer Biol Ther  2007; 6(9): 1449-54.
[http://dx.doi.org/10.4161/cbt.6.9.4622] [PMID: 17881902] 
[95] 
Bindels LB, Delzenne NM, Cani PD, Walter J. Towards a more comprehensive concept for prebiotics. Nat Rev Gastroenterol Hepatol  2015; 12(5): 303-10.
[http://dx.doi.org/10.1038/nrgastro.2015.47] [PMID: 25824997] 
[96] 
Larrosa M, González-Sarrías A, García-Conesa MT, Tomás-Barberán FA, Espín JC. Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities. J Agric Food Chem  2006; 54(5): 1611-20.
[http://dx.doi.org/10.1021/jf0527403] [PMID: 16506809] 
[97] 
Scharlau D, Borowicki A, Habermann N, et al. Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutat Res  2009; 682(1): 39-53.
[http://dx.doi.org/10.1016/j.mrrev.2009.04.001] [PMID: 19383551] 
[98] 
Roberfroid M, Gibson GR, Hoyles L, et al. Prebiotic effects: Metabolic and health benefits. Br J Nutr  2010; 104(Suppl. 2): S1-S63.
[PMID:  20920376] 
[99] 
Smith SC, Choy R, Johnson SK, Hall RS, Wildeboer-Veloo AC, Welling GW. Lupin kernel fiber consumption modifies fecal microbiota in healthy men as determined by rRNA gene fluorescent in situ hybridization. Eur J Nutr  2006; 45(6): 335-41.
[http://dx.doi.org/10.1007/s00394-006-0603-1] [PMID: 16763747] 
[100] 
Clarke SF, Murphy EF, Nilaweera K, et al. The gut microbiota and its relationship to diet and obesity: New insights. Gut Microbes  2012; 3(3): 186-202.
[http://dx.doi.org/10.4161/gmic.20168] [PMID: 22572830] 
[101] 
Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell  2018; 33(4): 570-80.
[http://dx.doi.org/10.1016/j.ccell.2018.03.015] [PMID: 29634945] 
[102] 
Gerhauser C. Cancer chemoprevention and nutriepigenetics: State of the art and future challenges. Top Curr Chem  2013; 329: 73-132.
[http://dx.doi.org/10.1007/128_2012_360] [PMID: 22955508] 
[103] 
Gerhäuser C. Cancer cell metabolism, epigenetics and the potential influence of dietary components-A perspective Cancer cell metabolism.  Cancer Metab Biomed Res 2012; p. 23.
[104] 
Huang J, Plass C, Gerhauser C. Cancer chemoprevention by targeting the epigenome. Curr Drug Targets  2011; 12(13): 1925-56.
[http://dx.doi.org/10.2174/138945011798184155] [PMID: 21158707] 
[105] 
van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med  2013; 368(5): 407-15.
[http://dx.doi.org/10.1056/NEJMoa1205037] [PMID: 23323867] 
[106] 
Bakken JS, Borody T, Brandt LJ, et al. Treating clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol  2011; 9(12): 1044-9.
[http://dx.doi.org/10.1016/j.cgh.2011.08.014] [PMID: 21871249] 
[107] 
Chen D, Wu J, Jin D, Wang B, Cao H. Fecal microbiota transplantation in cancer management: Current status and perspectives. Int J Cancer  2019; 145(8): 2021-31.
[http://dx.doi.org/10.1002/ijc.32003] [PMID: 30458058] 
[108] 
Kaiser J. Gut microbes shape response to cancer immunotherapy. Science  2017; 358(6363): 573-3.
[http://dx.doi.org/10.1126/science.358.6363.573] [PMID: 29097525] 
[109] 
Chang CW, Lee HC, Li LH, et al. Fecal microbiota transplantation prevents intestinal injury, upregulation of toll-like receptors, and 5-fluorouracil/oxaliplatin-induced toxicity in colorectal cancer. Int J Mol Sci  2020; 21(2): 386.
[http://dx.doi.org/10.3390/ijms21020386] [PMID: 31936237] 
[110] 
Pagano L, Tacconelli E, Tumbarello M, et al. Bacteremia in patients with hematological malignancies. Analysis of risk factors, etiological agents and prognostic indicators. Haematologica  1997; 82(4): 415-9.
[PMID:  9299853] 
[111] 
Danai PA, Moss M, Mannino DM, Martin GS. The epidemiology of sepsis in patients with malignancy. Chest  2006; 129(6): 1432-40.
[http://dx.doi.org/10.1378/chest.129.6.1432] [PMID: 16778259] 
[112] 
Papanicolas LE, Gordon DL, Wesselingh SL, Rogers GB. Not just antibiotics: Is cancer chemotherapy driving antimicrobial resistance? Trends Microbiol  2018; 26(5): 393-400.
[http://dx.doi.org/10.1016/j.tim.2017.10.009] [PMID: 29146383] 
[113] 
McKinney CA, Oliveira BC, Bedenice D, et al. The fecal microbiota of healthy donor horses and geriatric recipients undergoing fecal microbial transplantation for the treatment of diarrhea. PLoS One  2020; 15(3): e0230148.
[http://dx.doi.org/10.1371/journal.pone.0230148] [PMID: 32155205] 
[114] 
Xu MQ, Cao HL, Wang WQ, et al. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol  2015; 21(1): 102-11.
[http://dx.doi.org/10.3748/wjg.v21.i1.102] [PMID: 25574083] 
[115] 
Li X, Li X, Shang Q, et al. Fecal Microbiota Transplantation (FMT) could reverse the severity of experimental necrotizing enterocolitis (NEC) via oxidative stress modulation. Free Radic Biol Med  2017; 108: 32-43.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.03.011] [PMID: 28323128] 
[116] 
Mohty M, Malard F, Vekhoff A, et al. The odyssee study: Prevention of dysbiosis complications with autologous Fecal Microbiota Transfer (FMT) in Acute Myeloid Leukemia (AML) patients undergoing intensive treatment: Results of a prospective multicenter trial. Blood  2018; 132(Suppl. 1): 1444.
[http://dx.doi.org/10.1182/blood-2018-99-112825] 
[117] 
McQuade JL, Daniel CR, Helmink BA, Wargo JA. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol  2019; 20(2): e77-91.
[http://dx.doi.org/10.1016/S1470-2045(18)30952-5] [PMID: 30712808] 
[118] 
An J, Ha EM. Combination therapy of lactobacillus plantarum supernatant and 5-fluouracil increases chemosensitivity in colorectal can-cer cells. J Microbiol Biotechnol  2016; 26(8): 1490-503.
[http://dx.doi.org/10.4014/jmb.1605.05024] [PMID: 27221111] 
[119] 
Yeung CY, Chan WT, Jiang CB, et al. Amelioration of chemotherapy-induced intestinal mucositis by orally administered probiotics in a mouse model. PLoS One  2015; 10(9): e0138746.
[http://dx.doi.org/10.1371/journal.pone.0138746] [PMID: 26406888] 
[120] 
Sharma A, Rath GK, Chaudhary SP, Thakar A, Mohanti BK, Bahadur S. Lactobacillus brevis CD2 lozenges reduce radiation- and chemo-therapy-induced mucositis in patients with head and neck cancer: A randomized double-blind placebo-controlled study. Eur J Cancer  2012; 48(6): 875-81.
[http://dx.doi.org/10.1016/j.ejca.2011.06.010] [PMID: 21741230] 
[121] 
Choi SK, Myc A, Silpe JE, et al. Dendrimer-based multivalent vancomycin nanoplatform for targeting the drug-resistant bacterial surface. ACS Nano  2013; 7(1): 214-28.
[http://dx.doi.org/10.1021/nn3038995] [PMID: 23259666] 
[122] 
Karavolos M, Holban A. Nanosized drug delivery systems in gastrointestinal targeting: Interactions with microbiota. Pharmaceuticals  2016; 9(4): 9.
[http://dx.doi.org/10.3390/ph9040062] [PMID: 27690060] 
[123] 
Ting SY, Martínez-García E, Huang S, et al. Targeted depletion of bacteria from mixed populations by programmable adhesion with antagonistic competitor cells. Cell Host Microbe  2020; 28(2): 313-321.e6.
[http://dx.doi.org/10.1016/j.chom.2020.05.006] [PMID: 32470328] 
[124] 
Silverman JM, Brunet YR, Cascales E, Mougous JD. Structure and regulation of the type VI secretion system. Annu Rev Microbiol  2012; 66(1): 453-72.
[http://dx.doi.org/10.1146/annurev-micro-121809-151619] [PMID: 22746332] 
[125] 
Kiga K, Tan XE, Ibarra-Chávez R, et al. Development of CRISPR-Cas13a-based antimicrobials capable of sequence-specific killing of target bacteria. Nat Commun  2020; 11(1): 2934.
[http://dx.doi.org/10.1038/s41467-020-16731-6] [PMID: 32523110] 
[126] 
Ambalam P, Raman M, Purama RK, Doble M. Probiotics, prebiotics and colorectal cancer prevention. Best Pract Res Clin Gastroenterol  2016; 30(1): 119-31.
[http://dx.doi.org/10.1016/j.bpg.2016.02.009] [PMID: 27048903] 
[127] 
Xie X, He Y, Li H, et al. Effects of prebiotics on immunologic indicators and intestinal microbiota structure in perioperative colorectal cancer patients. Nutrition  2019; 61: 132-42.
[http://dx.doi.org/10.1016/j.nut.2018.10.038] [PMID: 30711862] 
[128] 
Paulos CM, Wrzesinski C, Kaiser A, et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest  2007; 117(8): 2197-204.
[http://dx.doi.org/10.1172/JCI32205] [PMID: 17657310] 
[129] 
Barzegari A, Saei AA. Designing probiotics with respect to the native microbiome. Future Microbiol  2012; 7(5): 571-5.
[http://dx.doi.org/10.2217/fmb.12.37] [PMID: 22568713] 
[130] 
Sleator RD, Hill C. New frontiers in probiotic research. Lett Appl Microbiol  2008; 46(2): 143-7.
[http://dx.doi.org/10.1111/j.1472-765X.2007.02293.x] [PMID: 18028323] 
[131] 
Sasaki T, Fujimori M, Hamaji Y, et al. Genetically engineered Bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats. Cancer Sci  2006; 97(7): 649-57.
[http://dx.doi.org/10.1111/j.1349-7006.2006.00221.x] [PMID: 16827806] 
[132] 
Chung Y, Ryu Y, An BC, et al. A synthetic probiotic engineered for colorectal cancer therapy modulates gut microbiota. Microbiome  2021; 9(1): 122.
[http://dx.doi.org/10.1186/s40168-021-01071-4] [PMID: 34039418] 
[133] 
Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage  2011; 1(2): 66-85.
[http://dx.doi.org/10.4161/bact.1.2.15845] [PMID: 22334863] 
[134] 
Zhang S, Chen DC. Facing a new challenge: The adverse effects of antibiotics on gut microbiota and host immunity. Chin Med J  2019; 132(10): 1135-8.
[http://dx.doi.org/10.1097/CM9.0000000000000245] [PMID: 30973451] 
[135] 
Kelly CJ, Zheng L, Campbell EL, et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe  2015; 17(5): 662-71.
[http://dx.doi.org/10.1016/j.chom.2015.03.005] [PMID: 25865369] 
[136] 
Zheng DW, Dong X, Pan P, et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat Biomed Eng  2019; 3(9): 717-28.
[http://dx.doi.org/10.1038/s41551-019-0423-2] [PMID: 31332342] 
[137] 
Dong X, Pan P, Zheng DW, Bao P, Zeng X, Zhang XZ. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to re-model tumor-immune microenvironment against colorectal cancer. Sci Adv  2020; 6(20): eaba1590.
[http://dx.doi.org/10.1126/sciadv.aba1590] [PMID: 32440552] 
[138] 
Guthrie L, Kelly L. Bringing microbiome-drug interaction research into the clinic. EBioMedicine  2019; 44: 708-15.
[http://dx.doi.org/10.1016/j.ebiom.2019.05.009] [PMID: 31151933] 
[139] 
Pierrard J, Seront E. Impact of the gut microbiome on immune checkpoint inhibitor efficacy-A systematic review. Curr Oncol  2019; 26(6): 395-403.
[http://dx.doi.org/10.3747/co.26.5177] [PMID: 31896938] 
[140] 
Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: Microenvironment-targeting combinations. Cell Res  2020; 30(6): 507-19.
[http://dx.doi.org/10.1038/s41422-020-0337-2] [PMID: 32467593] 
[141] 
Haslam A, Prasad V. Estimation of the percentage of us patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open  2019; 2(5): e192535.
[http://dx.doi.org/10.1001/jamanetworkopen.2019.2535] [PMID: 31050774] 
[142] 
Jin Y, Dong H, Xia L, et al. The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC. J Thorac Oncol  2019; 14(8): 1378-89.
[http://dx.doi.org/10.1016/j.jtho.2019.04.007] [PMID: 31026576] 
[143] 
Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science  2018; 359(6371): 91-7.
[http://dx.doi.org/10.1126/science.aan3706] [PMID: 29097494] 
[144] 
Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science  2018; 359(6371): 97-103.
[http://dx.doi.org/10.1126/science.aan4236] [PMID: 29097493] 
[145] 
Zheng Y, Wang T, Tu X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer  2019; 7(1): 193.
[http://dx.doi.org/10.1186/s40425-019-0650-9] [PMID: 31337439] 
[146] 
ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK. Pharmacomicrobiomics: The impact of human microbiome variations on systems pharmacology and personalized therapeutics. Integr Biol  2014; 18(7): 402-14.
[PMID:  24785449] 
[147] 
Saad R, Rizkallah MR, Aziz RK. Gut pharmacomicrobiomics: The tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog  2012; 4(1): 16.
[http://dx.doi.org/10.1186/1757-4749-4-16] [PMID: 23194438] 
[148] 
Doestzada M, Vila AV, Zhernakova A, et al. Pharmacomicrobiomics: A novel route towards personalized medicine? Protein Cell  2018; 9(5): 432-45.
[http://dx.doi.org/10.1007/s13238-018-0547-2] [PMID: 29705929] 
[149] 
Rizkallah M, Saad R, Aziz R. The human microbiome project, personalized medicine and the birth of pharmacomicrobiomics. Curr Pharmacogenomics Person Med  2012; 8(3): 182-93.
[http://dx.doi.org/10.2174/187569210792246326] 
[150] 
Sharma A, Buschmann MM, Gilbert JA. Pharmacomicrobiomics: The holy grail to variability in drug response? Clin Pharmacol Ther  2019; 106(2): 317-28.
[http://dx.doi.org/10.1002/cpt.1437] [PMID: 30937887] 
[151] 
Koppel N, Maini Rekdal V, Balskus EP. Chemical transformation of xenobiotics by the human gut microbiota. Science  2017; 356(6344): 1246-57.
[PMID:  28642381] 
[152] 
Wu H, Esteve E, Tremaroli V, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med  2017; 23(7): 850-8.
[http://dx.doi.org/10.1038/nm.4345] [PMID: 28530702] 
[153] 
Lindenbaum J, Rund DG, Butler VP Jr, Tse-Eng D, Saha JR. Inactivation of digoxin by the gut flora: Reversal by antibiotic therapy. N Engl J Med  1981; 305(14): 789-94.
[http://dx.doi.org/10.1056/NEJM198110013051403] [PMID: 7266632] 
[154] 
Holoch PA, Griffith TS. TNF-Related Apoptosis-Inducing Ligand (TRAIL): A new path to anti-cancer therapies. Eur J Pharmacol  2009; 625(1-3): 63-72.
[http://dx.doi.org/10.1016/j.ejphar.2009.06.066] [PMID: 19836385] 
[155] 
Heilbronner S, Krismer B, Brötz-Oesterhelt H, Peschel A. The microbiome-shaping roles of bacteriocins. Nat Rev Microbiol  2021; 19(11): 726-39.
[http://dx.doi.org/10.1038/s41579-021-00569-w] [PMID: 34075213] 
[156] 
Sharma P, Tiwari SK. Bacteriocins of probiotics as potent anticancer agents.  Probiotic Res Ther 2021; pp. 231-50.
[http://dx.doi.org/10.1007/978-981-15-8214-1_11] 
[157] 
Nguyen C, Nguyen VD. Discovery of azurin-like anticancer bacteriocins from human gut microbiome through homology modeling and molecular docking against the tumor suppressor p53. BioMed Res Int  2016; 2016: 8490482.
[http://dx.doi.org/10.1155/2016/8490482] [PMID: 27239476] 
[158] 
Bitschar K, Sauer B, Focken J, et al. Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors. Nat Commun  2019; 10(1): 2730.
[http://dx.doi.org/10.1038/s41467-019-10646-7] [PMID: 31227691] 
[159] 
Cousin FJ, Jouan-Lanhouet S, Théret N, et al. The probiotic Propionibacterium freudenreichii as a new adjuvant for TRAIL-based thera-py in colorectal cancer. Oncotarget  2016; 7(6): 7161-78.
[http://dx.doi.org/10.18632/oncotarget.6881] [PMID: 26771233] 
[160] 
Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B. Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Natl Acad Sci  2001; 98(26): 15155-60.
[http://dx.doi.org/10.1073/pnas.251543698] [PMID: 11724950] 
Cite As
Current Drug Targets

Bugs as Drugs: Understanding the Linkage between Gut Microbiota and Cancer Treatment

Abstract

Graphical Abstract
