Host Microbiomes in Tumor Precision Medicine: How far are we?

Federica      D’Amico; Monica      Barone; Teresa      Tavella; Simone      Rampelli; Patrizia      Brigidi; Silvia      Turroni
doi:10.2174/0929867329666220105121754
Abstract

The human gut microbiome has received a crescendo of attention in recent years due to the countless influences on human pathophysiology, including cancer. Research on cancer and anticancer therapy is constantly looking for new hints to improve the response to therapy while reducing the risk of relapse. In this scenario, the gut microbiome and the plethora of microbial-derived metabolites are considered a new opening in the development of innovative anticancer treatments for a better prognosis. This narrative review summarizes the current knowledge on the role of the gut microbiome in the onset and progression of cancer, as well as in response to chemo-immunotherapy. Recent findings regarding the tumor microbiome and its implications for clinical practice are also commented on. Current microbiome-based intervention strategies (i.e., prebiotics, probiotics, live biotherapeutics and fecal microbiota transplantation) are then discussed, along with key shortcomings, including a lack of long-term safety information in patients who are already severely compromised by standard treatments. The implementation of bioinformatic tools applied to microbiomics and other omics data, such as machine learning, has an enormous potential to push research in the field, enabling the prediction of health risk and therapeutic outcomes, for a truly personalized precision medicine.
Keywords: Gut microbiome, microbial metabolites, tumor microbiome, anticancer therapy, probiotics, fecal microbiota transplantation, next-generation probiotics, machine learning.
« Previous Next »
[1] 
Gilbert, J.A.; Blaser, M.J.; Caporaso, J.G.; Jansson, J.K.; Lynch, S.V.; Knight, R. Current understanding of the human microbiome. Nat. Med.,  2018, 24(4), 392-400.
[http://dx.doi.org/10.1038/nm.4517] [PMID: 29634682] 
[2] 
Turnbaugh, P.J.; Ley, R.E.; Hamady, M.; Fraser-Liggett, C.M.; Knight, R.; Gordon, J.I. The human microbiome project. Nature,  2007, 449(7164), 804-810.
[http://dx.doi.org/10.1038/nature06244] [PMID: 17943116] 
[3] 
Lynch, S.V.; Pedersen, O. The human intestinal microbiome in health and disease. N. Engl. J. Med.,  2016, 375(24), 2369-2379.
[http://dx.doi.org/10.1056/NEJMra1600266] [PMID: 27974040] 
[4] 
Oh, C.M.; Lee, D.; Kong, H.J.; Lee, S.; Won, Y.J.; Jung, K.W.; Cho, H. Causes of death among cancer patients in the era of cancer survivorship in Korea: attention to the suicide and cardiovascular mortality. Cancer Med.,  2020, 9(5), 1741-1752.
[http://dx.doi.org/10.1002/cam4.2813] [PMID: 31960609] 
[5] 
Farré-Maduella, E.; Casals-Pascual, C. The origins of gut microbiome research in Europe: from escherich to nissle. Hum. Microbiome J.,  2019, 14, 100065.
[http://dx.doi.org/10.1016/j.humic.2019.100065] 
[6] 
Escherich, T. The intestinal bacteria of the infant and their relationship to the physiology of digestion; Enke Verlag: Stuttgart, 1886. 
[7] 
Rajilić-Stojanović, M.; de Vos, W.M. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol. Rev.,  2014, 38(5), 996-1047.
[http://dx.doi.org/10.1111/1574-6976.12075] [PMID: 24861948] 
[8] 
Savage, D.C. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol.,  1977, 31, 107-133.
[http://dx.doi.org/10.1146/annurev.mi.31.100177.000543] [PMID: 334036] 
[9] 
Sender, R.; Fuchs, S.; Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol.,  2016, 14(8), e1002533.
[http://dx.doi.org/10.1371/journal.pbio.1002533] [PMID: 27541692] 
[10] 
Neish, A.S. Microbes in gastrointestinal health and disease. Gastroenterology,  2009, 136(1), 65-80.
[http://dx.doi.org/10.1053/j.gastro.2008.10.080] [PMID: 19026645] 
[11] 
Gill, S.R.; Pop, M.; Deboy, R.T.; Eckburg, P.B.; Turnbaugh, P.J.; Samuel, B.S.; Gordon, J.I.; Relman, D.A.; Fraser-Liggett, C.M.; Nelson, K.E. Metagenomic analysis of the human distal gut microbiome. Science,  2006, 312(5778), 1355-1359.
[http://dx.doi.org/10.1126/science.1124234] [PMID: 16741115] 
[12] 
Candela, M.; Biagi, E.; Maccaferri, S.; Turroni, S.; Brigidi, P. Intestinal microbiota is a plastic factor responding to environmental changes. Trends Microbiol.,  2012, 20(8), 385-391.
[http://dx.doi.org/10.1016/j.tim.2012.05.003] [PMID: 22672911] 
[13] 
Robertson, R.C.; Manges, A.R.; Finlay, B.B.; Prendergast, A.J. The human microbiome and child growth - first 1000 days and beyond. Trends Microbiol.,  2019, 27(2), 131-147.
[http://dx.doi.org/10.1016/j.tim.2018.09.008] [PMID: 30529020] 
[14] 
Derrien, M.; Alvarez, A.S.; de Vos, W.M. The gut microbiota in the first decade of life. Trends Microbiol.,  2019, 27(12), 997-1010.
[http://dx.doi.org/10.1016/j.tim.2019.08.001] [PMID: 31474424] 
[15] 
Bäckhed, F.; Roswall, J.; Peng, Y.; Feng, Q.; Jia, H.; Kovatcheva-Datchary, P.; Li, Y.; Xia, Y.; Xie, H.; Zhong, H.; Khan, M.T.; Zhang, J.; Li, J.; Xiao, L.; Al-Aama, J.; Zhang, D.; Lee, Y.S.; Kotowska, D.; Colding, C.; Tremaroli, V.; Yin, Y.; Bergman, S.; Xu, X.; Madsen, L.; Kristiansen, K.; Dahlgren, J.; Wang, J. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe,  2015, 17(5), 690-703.
[http://dx.doi.org/10.1016/j.chom.2015.04.004] [PMID: 25974306] 
[16] 
Avershina, E.; Lundgård, K.; Sekelja, M.; Dotterud, C.; Storrø, O.; Øien, T.; Johnsen, R.; Rudi, K. Transition from infant- to adult-like gut microbiota. Environ. Microbiol.,  2016, 18(7), 2226-2236.
[http://dx.doi.org/10.1111/1462-2920.13248] [PMID: 26913851] 
[17] 
Pannaraj, P.S.; Li, F.; Cerini, C.; Bender, J.M.; Yang, S.; Rollie, A.; Adisetiyo, H.; Zabih, S.; Lincez, P.J.; Bittinger, K.; Bailey, A.; Bushman, F.D.; Sleasman, J.W.; Aldrovandi, G.M. Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr.,  2017, 171(7), 647-654.
[http://dx.doi.org/10.1001/jamapediatrics.2017.0378] [PMID: 28492938] 
[18] 
Vangay, P.; Ward, T.; Gerber, J.S.; Knights, D. Antibiotics, pediatric dysbiosis, and disease. Cell Host Microbe,  2015, 17(5), 553-564.
[http://dx.doi.org/10.1016/j.chom.2015.04.006] [PMID: 25974298] 
[19] 
Rooks, M.G.; Garrett, W.S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol.,  2016, 16(6), 341-352.
[http://dx.doi.org/10.1038/nri.2016.42] [PMID: 27231050] 
[20] 
Macpherson, A.J.; de Agüero, M.G.; Ganal-Vonarburg, S.C. How nutrition and the maternal microbiota shape the neonatal immune system. Nat. Rev. Immunol.,  2017, 17(8), 508-517.
[http://dx.doi.org/10.1038/nri.2017.58] [PMID: 28604736] 
[21] 
Olszak, T.; An, D.; Zeissig, S.; Vera, M.P.; Richter, J.; Franke, A.; Glickman, J.N.; Siebert, R.; Baron, R.M.; Kasper, D.L.; Blumberg, R.S. Microbial exposure during early life has persistent effects on natural killer T cell function. Science,  2012, 336(6080), 489-493.
[http://dx.doi.org/10.1126/science.1219328] [PMID: 22442383] 
[22] 
Cox, L.M.; Yamanishi, S.; Sohn, J.; Alekseyenko, A.V.; Leung, J.M.; Cho, I.; Kim, S.G.; Li, H.; Gao, Z.; Mahana, D.; Zárate Rodriguez, J.G.; Rogers, A.B.; Robine, N.; Loke, P.; Blaser, M.J. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell,  2014, 158(4), 705-721.
[http://dx.doi.org/10.1016/j.cell.2014.05.052] [PMID: 25126780] 
[23] 
Vatanen, T.; Franzosa, E.A.; Schwager, R.; Tripathi, S.; Arthur, T.D.; Vehik, K.; Lernmark, Å.; Hagopian, W.A.; Rewers, M.J.; She, J.X.; Toppari, J.; Ziegler, A.G.; Akolkar, B.; Krischer, J.P.; Stewart, C.J.; Ajami, N.J.; Petrosino, J.F.; Gevers, D.; Lähdesmäki, H.; Vlamakis, H.; Huttenhower, C.; Xavier, R.J. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature,  2018, 562(7728), 589-594.
[http://dx.doi.org/10.1038/s41586-018-0620-2] [PMID: 30356183] 
[24] 
Chua, H.H.; Chou, H.C.; Tung, Y.L.; Chiang, B.L.; Liao, C.C.; Liu, H.H.; Ni, Y.H. Intestinal dysbiosis featuring abundance of Ruminococcus gnavus associates with allergic diseases in infants. Gastroenterology,  2018, 154(1), 154-167.
[http://dx.doi.org/10.1053/j.gastro.2017.09.006] [PMID: 28912020] 
[25] 
Maruvada, P.; Leone, V.; Kaplan, L.M.; Chang, E.B. The human microbiome and obesity: moving beyond associations. Cell Host Microbe,  2017, 22(5), 589-599.
[http://dx.doi.org/10.1016/j.chom.2017.10.005] [PMID: 29120742] 
[26] 
Stewart, C.J.; Ajami, N.J.; O’Brien, J.L.; Hutchinson, D.S.; Smith, D.P.; Wong, M.C.; Ross, M.C.; Lloyd, R.E.; Doddapaneni, H.; Metcalf, G.A.; Muzny, D.; Gibbs, R.A.; Vatanen, T.; Huttenhower, C.; Xavier, R.J.; Rewers, M.; Hagopian, W.; Toppari, J.; Ziegler, A.G.; She, J.X.; Akolkar, B.; Lernmark, A.; Hyoty, H.; Vehik, K.; Krischer, J.P.; Petrosino, J.F. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature,  2018, 562(7728), 583-588.
[http://dx.doi.org/10.1038/s41586-018-0617-x] [PMID: 30356187] 
[27] 
He, Y.; Wu, W.; Zheng, H.M.; Li, P.; McDonald, D.; Sheng, H.F.; Chen, M.X.; Chen, Z.H.; Ji, G.Y.; Zheng, Z.D.; Mujagond, P.; Chen, X.J.; Rong, Z.H.; Chen, P.; Lyu, L.Y.; Wang, X.; Wu, C.B.; Yu, N.; Xu, Y.J.; Yin, J.; Raes, J.; Knight, R.; Ma, W.J.; Zhou, H.W. Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat. Med.,  2018, 24(10), 1532-1535.
[http://dx.doi.org/10.1038/s41591-018-0164-x] [PMID: 30150716] 
[28] 
Rothschild, D.; Weissbrod, O.; Barkan, E.; Kurilshikov, A.; Korem, T.; Zeevi, D.; Costea, P.I.; Godneva, A.; Kalka, I.N.; Bar, N.; Shilo, S.; Lador, D.; Vila, A.V.; Zmora, N.; Pevsner-Fischer, M.; Israeli, D.; Kosower, N.; Malka, G.; Wolf, B.C.; Avnit-Sagi, T.; Lotan-Pompan, M.; Weinberger, A.; Halpern, Z.; Carmi, S.; Fu, J.; Wijmenga, C.; Zhernakova, A.; Elinav, E.; Segal, E. Environment dominates over host genetics in shaping human gut microbiota. Nature,  2018, 555(7695), 210-215.
[http://dx.doi.org/10.1038/nature25973] [PMID: 29489753] 
[29] 
Wild, C.P. Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol. Biomarkers Prev.,  2005, 14(8), 1847-1850.
[http://dx.doi.org/10.1158/1055-9965.EPI-05-0456] [PMID: 16103423] 
[30] 
Fassarella, M.; Blaak, E.E.; Penders, J.; Nauta, A.; Smidt, H.; Zoetendal, E.G. Gut microbiome stability and resilience: elucidating the response to perturbations in order to modulate gut health. Gut,  2021, 70(3), 595-605.
[http://dx.doi.org/10.1136/gutjnl-2020-321747] [PMID: 33051190] 
[31] 
Iacob, S.; Iacob, D.G.; Luminos, L.M. Intestinal microbiota as a host defense mechanism to infectious threats. Front. Microbiol.,  2019, 9, 3328.
[http://dx.doi.org/10.3389/fmicb.2018.03328] [PMID: 30761120] 
[32] 
Thaiss, C.A.; Zmora, N.; Levy, M.; Elinav, E. The microbiome and innate immunity. Nature,  2016, 535(7610), 65-74.
[http://dx.doi.org/10.1038/nature18847] [PMID: 27383981] 
[33] 
Turroni, S.; Brigidi, P.; Cavalli, A.; Candela, M. Microbiota-host transgenomic metabolism, bioactive molecules from the Inside. J. Med. Chem.,  2018, 61(1), 47-61.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00244] [PMID: 28745893] 
[34] 
Sonnenburg, E.D.; Sonnenburg, J.L. Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab.,  2014, 20(5), 779-786.
[http://dx.doi.org/10.1016/j.cmet.2014.07.003] [PMID: 25156449] 
[35] 
Koh, A.; De Vadder, F.; Kovatcheva-Datchary, P.; Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell,  2016, 165(6), 1332-1345.
[http://dx.doi.org/10.1016/j.cell.2016.05.041] [PMID: 27259147] 
[36] 
Desai, M.S.; Seekatz, A.M.; Koropatkin, N.M.; Kamada, N.; Hickey, C.A.; Wolter, M.; Pudlo, N.A.; Kitamoto, S.; Terrapon, N.; Muller, A.; Young, V.B.; Henrissat, B.; Wilmes, P.; Stappenbeck, T.S.; Núñez, G.; Martens, E.C. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell,  2016, 167(5), 1339-1353.
[http://dx.doi.org/10.1016/j.cell.2016.10.043] [PMID: 27863247] 
[37] 
Oh, J.H.; Alexander, L.M.; Pan, M.; Schueler, K.L.; Keller, M.P.; Attie, A.D.; Walter, J.; van Pijkeren, J.P. Dietary fructose and microbiota-derived short-chain fatty acids promote bacteriophage production in the gut symbiont Lactobacillus reuteri. Cell Host Microbe,  2019, 25(2), 273-284.
[http://dx.doi.org/10.1016/j.chom.2018.11.016] [PMID: 30658906] 
[38] 
Davie, J.R. Inhibition of histone deacetylase activity by butyrate. J. Nutr.,  2003, 133(7)(Suppl.), 2485S-2493S.
[http://dx.doi.org/10.1093/jn/133.7.2485S] [PMID: 12840228] 
[39] 
Fukuda, S.; Toh, H.; Hase, K.; Oshima, K.; Nakanishi, Y.; Yoshimura, K.; Tobe, T.; Clarke, J.M.; Topping, D.L.; Suzuki, T.; Taylor, T.D.; Itoh, K.; Kikuchi, J.; Morita, H.; Hattori, M.; Ohno, H. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature,  2011, 469(7331), 543-547.
[http://dx.doi.org/10.1038/nature09646] [PMID: 21270894] 
[40] 
Brown, A.J.; Goldsworthy, S.M.; Barnes, A.A.; Eilert, M.M.; Tcheang, L.; Daniels, D.; Muir, A.I.; Wigglesworth, M.J.; Kinghorn, I.; Fraser, N.J.; Pike, N.B.; Strum, J.C.; Steplewski, K.M.; Murdock, P.R.; Holder, J.C.; Marshall, F.H.; Szekeres, P.G.; Wilson, S.; Ignar, D.M.; Foord, S.M.; Wise, A.; Dowell, S.J. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem.,  2003, 278(13), 11312-11319.
[http://dx.doi.org/10.1074/jbc.M211609200] [PMID: 12496283] 
[41] 
Kelly, C.J.; Zheng, L.; Campbell, E.L.; Saeedi, B.; Scholz, C.C.; Bayless, A.J.; Wilson, K.E.; Glover, L.E.; Kominsky, D.J.; Magnuson, A.; Weir, T.L.; Ehrentraut, S.F.; Pickel, C.; Kuhn, K.A.; Lanis, J.M.; Nguyen, V.; Taylor, C.T.; Colgan, S.P. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe,  2015, 17(5), 662-671.
[http://dx.doi.org/10.1016/j.chom.2015.03.005] [PMID: 25865369] 
[42] 
Di Martino, M.L.; Campilongo, R.; Casalino, M.; Micheli, G.; Colonna, B.; Prosseda, G. Polyamines: emerging players in bacteria-host interactions. Int. J. Med. Microbiol.,  2013, 303(8), 484-491.
[http://dx.doi.org/10.1016/j.ijmm.2013.06.008] [PMID: 23871215] 
[43] 
Chen, J.; Rao, J.N.; Zou, T.; Liu, L.; Marasa, B.S.; Xiao, L.; Zeng, X.; Turner, D.J.; Wang, J.Y. Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity. Am. J. Physiol. Gastrointest. Liver Physiol.,  2007, 293(3), G568-G576.
[http://dx.doi.org/10.1152/ajpgi.00201.2007] [PMID: 17600044] 
[44] 
Liu, L.; Rao, J.N.; Zou, T.; Xiao, L.; Wang, P.Y.; Turner, D.J.; Gorospe, M.; Wang, J.Y. Polyamines regulate c-Myc translation through Chk2-dependent HuR phosphorylation. Mol. Biol. Cell,  2009, 20(23), 4885-4898.
[http://dx.doi.org/10.1091/mbc.e09-07-0550] [PMID: 19812253] 
[45] 
Pérez-Cano, F.J.; González-Castro, A.; Castellote, C.; Franch, A.; Castell, M. Influence of breast milk polyamines on suckling rat immune system maturation. Dev. Comp. Immunol.,  2010, 34(2), 210-218.
[http://dx.doi.org/10.1016/j.dci.2009.10.001] [PMID: 19825390] 
[46] 
Ma, L.; Ni, Y.; Wang, Z.; Tu, W.; Ni, L.; Zhuge, F.; Zheng, A.; Hu, L.; Zhao, Y.; Zheng, L.; Fu, Z. Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes,  2020, 12(1), 1-19.
[http://dx.doi.org/10.1080/19490976.2020.1832857] [PMID: 33151120] 
[47] 
Miller-Fleming, L.; Olin-Sandoval, V.; Campbell, K.; Ralser, M. Remaining mysteries of molecular biology: the role of polyamines in the cell. J. Mol. Biol.,  2015, 427(21), 3389-3406.
[http://dx.doi.org/10.1016/j.jmb.2015.06.020] [PMID: 26156863] 
[48] 
Gerner, E.W.; Meyskens, F.L.Jr.  Polyamines and cancer: old molecules, new understanding. Nat. Rev. Cancer,  2004, 4(10), 781-792.
[http://dx.doi.org/10.1038/nrc1454] [PMID: 15510159] 
[49] 
Johnson, C.H.; Dejea, C.M.; Edler, D.; Hoang, L.T.; Santidrian, A.F.; Felding, B.H.; Ivanisevic, J.; Cho, K.; Wick, E.C.; Hechenbleikner, E.M.; Uritboonthai, W.; Goetz, L.; Casero, R.A., Jr.; Pardoll, D.M.; White, J.R.; Patti, G.J.; Sears, C.L.; Siuzdak, G. Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab.,  2015, 21(6), 891-897.
[http://dx.doi.org/10.1016/j.cmet.2015.04.011] [PMID: 25959674] 
[50] 
Liu, R.; Lin, X.; Li, Z.; Li, Q.; Bi, K. Quantitative metabolomics for investigating the value of polyamines in the early diagnosis and therapy of colorectal cancer. Oncotarget,  2017, 9(4), 4583-4592.
[http://dx.doi.org/10.18632/oncotarget.22885] [PMID: 29435126] 
[51] 
Hayes, C.S.; Shicora, A.C.; Keough, M.P.; Snook, A.E.; Burns, M.R.; Gilmour, S.K. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol. Res.,  2014, 2(3), 274-285.
[http://dx.doi.org/10.1158/2326-6066.CIR-13-0120-T] [PMID: 24778323] 
[52] 
Casero, R.A., Jr; Murray Stewart, T.; Pegg, A.E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer,  2018, 18(11), 681-695.
[http://dx.doi.org/10.1038/s41568-018-0050-3] [PMID: 30181570] 
[53] 
Pietrocola, F.; Pol, J.; Vacchelli, E.; Rao, S.; Enot, D.P.; Baracco, E.E.; Levesque, S.; Castoldi, F.; Jacquelot, N.; Yamazaki, T.; Senovilla, L.; Marino, G.; Aranda, F.; Durand, S.; Sica, V.; Chery, A.; Lachkar, S.; Sigl, V.; Bloy, N.; Buque, A.; Falzoni, S.; Ryffel, B.; Apetoh, L.; Di Virgilio, F.; Madeo, F.; Maiuri, M.C.; Zitvogel, L.; Levine, B.; Penninger, J.M.; Kroemer, G. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell,  2016, 30(1), 147-160.
[http://dx.doi.org/10.1016/j.ccell.2016.05.016] [PMID: 27411589] 
[54] 
Francino, M.P. Early development of the gut microbiota and immune health. Pathogens,  2014, 3(3), 769-790.
[http://dx.doi.org/10.3390/pathogens3030769] [PMID: 25438024] 
[55] 
Nakanishi, Y.; Sato, T.; Ohteki, T. Commensal Gram-positive bacteria initiates colitis by inducing monocyte/macrophage mobilization. Mucosal Immunol.,  2015, 8(1), 152-160.
[http://dx.doi.org/10.1038/mi.2014.53] [PMID: 24938744] 
[56] 
Thomas, C.M.; Versalovic, J. Probiotics-host communication: modulation of signaling pathways in the intestine. Gut Microbes,  2010, 1(3), 148-163.
[http://dx.doi.org/10.4161/gmic.1.3.11712] [PMID: 20672012] 
[57] 
Belkaid, Y.; Hand, T.W. Role of the microbiota in immunity and inflammation. Cell,  2014, 157(1), 121-141.
[http://dx.doi.org/10.1016/j.cell.2014.03.011] [PMID: 24679531] 
[58] 
Owaga, E.; Hsieh, R.H.; Mugendi, B.; Masuku, S.; Shih, C.K.; Chang, J.S. Th17 cells as potential probiotic therapeutic targets in inflammatory bowel diseases. Int. J. Mol. Sci.,  2015, 16(9), 20841-20858.
[http://dx.doi.org/10.3390/ijms160920841] [PMID: 26340622] 
[59] 
Mazmanian, S.K.; Round, J.L.; Kasper, D.L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature,  2008, 453(7195), 620-625.
[http://dx.doi.org/10.1038/nature07008] [PMID: 18509436] 
[60] 
Round, J.L.; Lee, S.M.; Li, J.; Tran, G.; Jabri, B.; Chatila, T.A.; Mazmanian, S.K. The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science,  2011, 332(6032), 974-977.
[http://dx.doi.org/10.1126/science.1206095] [PMID: 21512004] 
[61] 
Shanahan, F.; Ghosh, T.S.; O’Toole, P.W. What is the definition of a healthy gut microbiome? Gastroenterology,  2021, 160(2), 483-494.
[http://dx.doi.org/10.1053/j.gastro.2020.09.057] [PMID: 33253682] 
[62] 
Duvallet, C.; Gibbons, S.M.; Gurry, T.; Irizarry, R.A.; Alm, E.J. Meta-analysis of gut microbiome studies identifies disease-specific and shared responses. Nat. Commun.,  2017, 8(1), 1784.
[http://dx.doi.org/10.1038/s41467-017-01973-8] [PMID: 29209090] 
[63] 
Kho, Z.Y.; Lal, S.K. 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] 
[64] 
Cani, P.D.; Van Hul, M. Gut microbiota and obesity: causally linked? Expert Rev. Gastroenterol. Hepatol.,  2020, 14(6), 401-403.
[http://dx.doi.org/10.1080/17474124.2020.1758064] [PMID: 32306776] 
[65] 
Lloyd-Price, J.; Arze, C.; Ananthakrishnan, A.N.; Schirmer, M.; Avila-Pacheco, J.; Poon, T.W.; Andrews, E.; Ajami, N.J.; Bonham, K.S.; Brislawn, C.J.; Casero, D.; Courtney, H.; Gonzalez, A.; Graeber, T.G.; Hall, A.B.; Lake, K.; Landers, C.J.; Mallick, H.; Plichta, D.R.; Prasad, M.; Rahnavard, G.; Sauk, J.; Shungin, D.; Vázquez-Baeza, Y.; White, R.A., III; Braun, J.; Denson, L.A.; Jansson, J.K.; Knight, R.; Kugathasan, S.; McGovern, D.P.B.; Petrosino, J.F.; Stappenbeck, T.S.; Winter, H.S.; Clish, C.B.; Franzosa, E.A.; Vlamakis, H.; Xavier, R.J.; Huttenhower, C. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature,  2019, 569(7758), 655-662.
[http://dx.doi.org/10.1038/s41586-019-1237-9] [PMID: 31142855] 
[66] 
Khan, I.; Ullah, N.; Zha, L.; Bai, Y.; Khan, A.; Zhao, T.; Che, T.; Zhang, C. Alteration of gut Mmicrobiota in inflammatory bowel disease (IBD): cause or consequence? IBD treatment targeting the gut microbiome. Pathogens,  2019, 8, 126.
[http://dx.doi.org/10.3390/pathogens8030126] 
[67] 
Wong, S.H.; Yu, J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat. Rev. Gastroenterol. Hepatol.,  2019, 16(11), 690-704.
[http://dx.doi.org/10.1038/s41575-019-0209-8] [PMID: 31554963] 
[68] 
Sheflin, A.M.; Whitney, A.K.; Weir, T.L. Cancer-promoting effects of microbial dysbiosis. Curr. Oncol. Rep.,  2014, 16(10), 406.
[http://dx.doi.org/10.1007/s11912-014-0406-0] [PMID: 25123079] 
[69] 
Candela, M.; Turroni, S.; Biagi, E.; Carbonero, F.; Rampelli, S.; Fiorentini, C.; Brigidi, P. Inflammation and colorectal cancer, when microbiota-host mutualism breaks. World J. Gastroenterol.,  2014, 20(4), 908-922.
[http://dx.doi.org/10.3748/wjg.v20.i4.908] [PMID: 24574765] 
[70] 
Farrell, J.J.; Zhang, L.; Zhou, H.; Chia, D.; Elashoff, D.; Akin, D.; Paster, B.J.; Joshipura, K.; Wong, D.T. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut,  2012, 61(4), 582-588.
[http://dx.doi.org/10.1136/gutjnl-2011-300784] [PMID: 21994333] 
[71] 
Gong, H.L.; Shi, Y.; Zhou, L.; Wu, C.P.; Cao, P.Y.; Tao, L.; Xu, C.; Hou, D.S.; Wang, Y.Z. The composition of microbiome in larynx and the throat biodiversity between laryngeal squamous cell carcinoma patients and control population. PLoS One,  2013, 8(6), e66476.
[http://dx.doi.org/10.1371/journal.pone.0066476] [PMID: 23824228] 
[72] 
Sharma, V.; Chauhan, V.S.; Nath, G.; Kumar, A.; Shukla, V.K. Role of bile bacteria in gallbladder carcinoma. Hepatogastroenterology,  2007, 54(78), 1622-1625.
[PMID: 18019679] 
[73] 
Bhatt, A.P.; Redinbo, M.R.; Bultman, S.J. The role of the microbiome in cancer development and therapy. CA Cancer J. Clin.,  2017, 67(4), 326-344.
[http://dx.doi.org/10.3322/caac.21398] [PMID: 28481406] 
[74] 
Goodman, B.; Gardner, H. The microbiome and cancer. J. Pathol.,  2018, 244(5), 667-676.
[http://dx.doi.org/10.1002/path.5047] [PMID: 29377130] 
[75] 
Chaffer, C.L.; Weinberg, R.A. How does multistep tumorigenesis really proceed? Cancer Discov.,  2015, 5(1), 22-24.
[http://dx.doi.org/10.1158/2159-8290.CD-14-0788] [PMID: 25583800] 
[76] 
Mármol, I.; Sánchez-de-Diego, C.; Pradilla Dieste, A.; Cerrada, E.; Rodriguez Yoldi, M.J. Colorectal carcinoma: a general overview and future perspectives in colorectal cancer. Int. J. Mol. Sci.,  2017, 18(1), 197.
[http://dx.doi.org/10.3390/ijms18010197] [PMID: 28106826] 
[77] 
Zhang, L.; Shay, J.W. Multiple roles of APC and its therapeutic implications in colorectal cancer. J. Natl. Cancer Inst.,  2017, 109(8), djw332.
[http://dx.doi.org/10.1093/jnci/djw332] [PMID: 28423402] 
[78] 
McCoy, A.N.; Araújo-Pérez, F.; Azcárate-Peril, A.; Yeh, J.J.; Sandler, R.S.; Keku, T.O. Fusobacterium is associated with colorectal adenomas. PLoS One,  2013, 8(1), e53653.
[http://dx.doi.org/10.1371/journal.pone.0053653] [PMID: 23335968] 
[79] 
Castellarin, M.; Warren, R.L.; Freeman, J.D.; Dreolini, L.; Krzywinski, M.; Strauss, J.; Barnes, R.; Watson, P.; Allen-Vercoe, E.; Moore, R.A.; Holt, R.A. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res.,  2012, 22(2), 299-306.
[http://dx.doi.org/10.1101/gr.126516.111] [PMID: 22009989] 
[80] 
Zheng, J.; Meng, J.; Zhao, S.; Singh, R.; Song, W. Campylobacter-induced interleukin-8 secretion in polarized human intestinal epithelial cells requires Campylobacter-secreted cytolethal distending toxin- and Toll-like receptor-mediated activation of NF-kappaB. Infect. Immun.,  2008, 76(10), 4498-4508.
[http://dx.doi.org/10.1128/IAI.01317-07] [PMID: 18644884] 
[81] 
Bullman, S.; Pedamallu, C.S.; Sicinska, E.; Clancy, T.E.; Zhang, X.; Cai, D.; Neuberg, D.; Huang, K.; Guevara, F.; Nelson, T.; Chipashvili, O.; Hagan, T.; Walker, M.; Ramachandran, A.; Diosdado, B.; Serna, G.; Mulet, N.; Landolfi, S.; Ramon. Y.; Cajal, S.; Fasani, R.; Aguirre, A.J.; Ng, K.; Élez, E.; Ogino, S.; Tabernero, J.; Fuchs, C.S.; Hahn, W.C.; Nuciforo, P.; Meyerson, M.; Meyerson, M. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science,  2017, 358(6369), 1443-1448.
[http://dx.doi.org/10.1126/science.aal5240] [PMID: 29170280] 
[82] 
Louis, P.; Flint, H.J. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol. Lett.,  2009, 294(1), 1-8.
[http://dx.doi.org/10.1111/j.1574-6968.2009.01514.x] [PMID: 19222573] 
[83] 
Tjalsma, H.; Boleij, A.; Marchesi, J.R.; Dutilh, B.E. A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects. Nat. Rev. Microbiol.,  2012, 10(8), 575-582.
[http://dx.doi.org/10.1038/nrmicro2819] [PMID: 22728587] 
[84] 
Huycke, M.M.; Abrams, V.; Moore, D.R. Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA. Carcinogenesis,  2002, 23(3), 529-536.
[http://dx.doi.org/10.1093/carcin/23.3.529] [PMID: 11895869] 
[85] 
de Almeida, C.V.; Taddei, A.; Amedei, A. The controversial role of Enterococcus faecalis in colorectal cancer. Therap. Adv. Gastroenterol.,  2018, 11, 1756284818783606.
[http://dx.doi.org/10.1177/1756284818783606] [PMID: 30013618] 
[86] 
Toprak, N.U.; Yagci, A.; Gulluoglu, B.M.; Akin, M.L.; Demirkalem, P.; Celenk, T.; Soyletir, G. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect.,  2006, 12(8), 782-786.
[http://dx.doi.org/10.1111/j.1469-0691.2006.01494.x] [PMID: 16842574] 
[87] 
Haghi, F.; Goli, E.; Mirzaei, B.; Zeighami, H. The association between fecal enterotoxigenic B. fragilis with colorectal cancer. BMC Cancer,  2019, 19(1), 879.
[http://dx.doi.org/10.1186/s12885-019-6115-1] [PMID: 31488085] 
[88] 
Lara-Tejero, M.; Galán, J.E. Cytolethal distending toxin: limited damage as a strategy to modulate cellular functions. Trends Microbiol.,  2002, 10(3), 147-152.
[http://dx.doi.org/10.1016/S0966-842X(02)02316-8] [PMID: 11864825] 
[89] 
Ge, Z.; Rogers, A.B.; Feng, Y.; Lee, A.; Xu, S.; Taylor, N.S.; Fox, J.G. Bacterial cytolethal distending toxin promotes the development of dysplasia in a model of microbially induced hepatocarcinogenesis. Cell. Microbiol.,  2007, 9(8), 2070-2080.
[http://dx.doi.org/10.1111/j.1462-5822.2007.00939.x] [PMID: 17441986] 
[90] 
Guerra, L.; Guidi, R.; Slot, I.; Callegari, S.; Sompallae, R.; Pickett, C.L.; Åström, S.; Eisele, F.; Wolf, D.; Sjögren, C.; Masucci, M.G.; Frisan, T. Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival. J. Cell Sci.,  2011, 124(Pt 16), 2735-2742.
[http://dx.doi.org/10.1242/jcs.085845] [PMID: 21807938] 
[91] 
Martin, O.C.B.; Bergonzini, A.; D’Amico, F.; Chen, P.; Shay, J.W.; Dupuy, J.; Svensson, M.; Masucci, M.G.; Frisan, T. Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells. Cell. Microbiol.,  2019, 21(12), e13099.
[http://dx.doi.org/10.1111/cmi.13099] [PMID: 31414579] 
[92] 
Wentling, G.K.; Metzger, P.P.; Dozois, E.J.; Chua, H.K.; Krishna, M. Unusual bacterial infections and colorectal carcinoma-Streptococcus bovis and Clostridium septicum: report of three cases. Dis. Colon Rectum,  2006, 49(8), 1223-1227.
[http://dx.doi.org/10.1007/s10350-006-0576-4] [PMID: 16845563] 
[93] 
Kostic, A.D.; Chun, E.; Robertson, L.; Glickman, J.N.; Gallini, C.A.; Michaud, M.; Clancy, T.E.; Chung, D.C.; Lochhead, P.; Hold, G.L.; El-Omar, E.M.; Brenner, D.; Fuchs, C.S.; Meyerson, M.; Garrett, W.S. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe,  2013, 14(2), 207-215.
[http://dx.doi.org/10.1016/j.chom.2013.07.007] [PMID: 23954159] 
[94] 
Boleij, A.; Tjalsma, H. The itinerary of Streptococcus gallolyticus infection in patients with colonic malignant disease. Lancet Infect. Dis.,  2013, 13(8), 719-724.
[http://dx.doi.org/10.1016/S1473-3099(13)70107-5] [PMID: 23831427] 
[95] 
Marchesi, J.R.; Dutilh, B.E.; Hall, N.; Peters, W.H.; Roelofs, R.; Boleij, A.; Tjalsma, H. Towards the human colorectal cancer microbiome. PLoS One,  2011, 6(5), e20447.
[http://dx.doi.org/10.1371/journal.pone.0020447] [PMID: 21647227] 
[96] 
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] 
[97] 
Dapito, D.H.; Mencin, A.; Gwak, G.Y.; Pradere, J.P.; Jang, M.K.; Mederacke, I.; Caviglia, J.M.; Khiabanian, H.; Adeyemi, A.; Bataller, R.; Lefkowitch, J.H.; Bower, M.; Friedman, R.; Sartor, R.B.; Rabadan, R.; Schwabe, R.F. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell,  2012, 21(4), 504-516.
[http://dx.doi.org/10.1016/j.ccr.2012.02.007] [PMID: 22516259] 
[98] 
Tremaroli, V.; Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature,  2012, 489(7415), 242-249.
[http://dx.doi.org/10.1038/nature11552] [PMID: 22972297] 
[99] 
Yoshimoto, S.; Loo, T.M.; Atarashi, K.; Kanda, H.; Sato, S.; Oyadomari, S.; Iwakura, Y.; Oshima, K.; Morita, H.; Hattori, M.; Honda, K.; Ishikawa, Y.; Hara, E.; Ohtani, N. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature,  2013, 499(7456), 97-101.
[http://dx.doi.org/10.1038/nature12347] [PMID: 23803760] 
[100] 
Quante, M.; Bhagat, G.; Abrams, J.A.; Marache, F.; Good, P.; Lee, M.D.; Lee, Y.; Friedman, R.; Asfaha, S.; Dubeykovskaya, Z.; Mahmood, U.; Figueiredo, J.L.; Kitajewski, J.; Shawber, C.; Lightdale, C.J.; Rustgi, A.K.; Wang, T.C. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell,  2012, 21(1), 36-51.
[http://dx.doi.org/10.1016/j.ccr.2011.12.004] [PMID: 22264787] 
[101] 
Ridlon, J.M.; Kang, D.J.; Hylemon, P.B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res.,  2006, 47(2), 241-259.
[http://dx.doi.org/10.1194/jlr.R500013-JLR200] [PMID: 16299351] 
[102] 
Eslami.S;, Z.; Majidzadeh.A;, K.; 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] 
[103] 
Goedert, J.J.; Jones, G.; Hua, X.; Xu, X.; Yu, G.; Flores, R.; Falk, R.T.; Gail, M.H.; Shi, J.; Ravel, J.; Feigelson, H.S. Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study. J. Natl. Cancer Inst.,  2015, 107(8), djv147.
[http://dx.doi.org/10.1093/jnci/djv147] [PMID: 26032724] 
[104] 
Plottel, C.S.; Blaser, M.J. Microbiome and malignancy. Cell Host Microbe,  2011, 10(4), 324-335.
[http://dx.doi.org/10.1016/j.chom.2011.10.003] [PMID: 22018233] 
[105] 
Gloux, K.; Berteau, O.; El Oumami, H.; Béguet, F.; Leclerc, M.; Doré, J. A metagenomic β-glucuronidase uncovers a core adaptive function of the human intestinal microbiome. Proc. Natl. Acad. Sci. USA,  2011, 108(Suppl. 1), 4539-4546.
[http://dx.doi.org/10.1073/pnas.1000066107] [PMID: 20615998] 
[106] 
Dabek, M.; McCrae, S.I.; Stevens, V.J.; Duncan, S.H.; Louis, P. Distribution of beta-glucosidase and beta-glucuronidase activity and of beta-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol. Ecol.,  2008, 66(3), 487-495.
[http://dx.doi.org/10.1111/j.1574-6941.2008.00520.x] [PMID: 18537837] 
[107] 
McIntosh, F.M.; Maison, N.; Holtrop, G.; Young, P.; Stevens, V.J.; Ince, J.; Johnstone, A.M.; Lobley, G.E.; Flint, H.J.; Louis, P. Phylogenetic distribution of genes encoding β-glucuronidase activity in human colonic bacteria and the impact of diet on faecal glycosidase activities. Environ. Microbiol.,  2012, 14(8), 1876-1887.
[http://dx.doi.org/10.1111/j.1462-2920.2012.02711.x] [PMID: 22364273] 
[108] 
Rizkallah, M.R.; Saad, R.; Aziz, R.K. The Human Microbiome Project, personalized medicine and the birth of pharmacomicrobiomics. Curr. Pharmacogenomics Person. Med.,  2010, 8, 182-193.
[http://dx.doi.org/10.2174/187569210792246326] 
[109] 
Alexander, J.L.; Wilson, I.D.; Teare, J.; Marchesi, J.R.; Nicholson, J.K.; Kinross, J.M. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat. Rev. Gastroenterol. Hepatol.,  2017, 14(6), 356-365.
[http://dx.doi.org/10.1038/nrgastro.2017.20] [PMID: 28270698] 
[110] 
Roy, S.; Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer,  2017, 17(5), 271-285.
[http://dx.doi.org/10.1038/nrc.2017.13] [PMID: 28303904] 
[111] 
Nayak, R.R.; Turnbaugh, P.J. Mirror, mirror on the wall: which microbiomes will help heal them all? BMC Med.,  2016, 14, 72.
[http://dx.doi.org/10.1186/s12916-016-0622-6] [PMID: 27146150] 
[112] 
Fessler, J.L.; Gajewski, T.F. The microbiota: a new variable impacting cancer treatment outcomes. Clin. Cancer Res.,  2017, 23(13), 3229-3231.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0864] [PMID: 28446507] 
[113] 
Nauts, H.C.; Swift, W.E.; Coley, B.L. The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res.,  1946, 6, 205-216.
[PMID: 21018724] 
[114] 
McCarthy, E.F. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop. J.,  2006, 26, 154-158.
[PMID: 16789469] 
[115] 
Zbar, B.; Bernstein, I.; Tanaka, T.; Rapp, H.J. Tumor immunity produced by the intradermal inoculation of living tumor cells and living Mycobacterium bovis (strain BCG). Science,  1970, 170(3963), 1217-1218.
[http://dx.doi.org/10.1126/science.170.3963.1217] [PMID: 4920656] 
[116] 
Aso, Y.; Akazan, H. Prophylactic effect of a Lactobacillus casei preparation on the recurrence of superficial bladder cancer. Urol. Int.,  1992, 49(3), 125-129.
[http://dx.doi.org/10.1159/000282409] [PMID: 1466089] 
[117] 
Hoesl, C.E.; Altwein, J.E. The probiotic approach: an alternative treatment option in urology. Eur. Urol.,  2005, 47(3), 288-296.
[http://dx.doi.org/10.1016/j.eururo.2004.09.011] [PMID: 15716188] 
[118] 
Vivarelli, S.; Salemi, R.; Candido, S.; Falzone, L.; Santagati, M.; Stefani, S.; Torino, F.; Banna, G.L.; Tonini, G.; Libra, M. Gut microbiota and cancer: from pathogenesis to therapy. Cancers (Basel),  2019, 11(1), 38.
[http://dx.doi.org/10.3390/cancers11010038] [PMID: 30609850] 
[119] 
Stebbing, J.; Dalgleish, A.; Gifford-Moore, A.; Martin, A.; Gleeson, C.; Wilson, G.; Brunet, L.R.; Grange, J.; Mudan, S. An intra-patient placebo-controlled phase I trial to evaluate the safety and tolerability of intradermal IMM-101 in melanoma. Ann. Oncol.,  2012, 23(5), 1314-1319.
[http://dx.doi.org/10.1093/annonc/mdr363] [PMID: 21930686] 
[120] 
Dalgleish, A.G.; Stebbing, J.; Adamson, D.J.; Arif, S.S.; Bidoli, P.; Chang, D.; Cheeseman, S.; Diaz-Beveridge, R.; Fernandez-Martos, C.; Glynne-Jones, R.; Granetto, C.; Massuti, B.; McAdam, K.; McDermott, R.; Martín, A.J.; Papamichael, D.; Pazo-Cid, R.; Vieitez, J.M.; Zaniboni, A.; Carroll, K.J.; Wagle, S.; Gaya, A.; Mudan, S.S. Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. Br. J. Cancer,  2016, 115(7), 789-796.
[http://dx.doi.org/10.1038/bjc.2016.271] [PMID: 27599039] 
[121] 
Toso, J.F.; Gill, V.J.; Hwu, P.; Marincola, F.M.; Restifo, N.P.; Schwartzentruber, D.J.; Sherry, R.M.; Topalian, S.L.; Yang, J.C.; Stock, F.; Freezer, L.J.; Morton, K.E.; Seipp, C.; Haworth, L.; Mavroukakis, S.; White, D.; MacDonald, S.; Mao, J.; Sznol, M.; Rosenberg, S.A. Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J. Clin. Oncol.,  2002, 20(1), 142-152.
[http://dx.doi.org/10.1200/JCO.2002.20.1.142] [PMID: 11773163] 
[122] 
Nemunaitis, J.; Cunningham, C.; Senzer, N.; Kuhn, J.; Cramm, J.; Litz, C.; Cavagnolo, R.; Cahill, A.; Clairmont, C.; Sznol, M. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther.,  2003, 10(10), 737-744.
[http://dx.doi.org/10.1038/sj.cgt.7700634] [PMID: 14502226] 
[123] 
Kramer, M.G.; Masner, M.; Ferreira, F.A.; Hoffman, R.M. Bacterial therapy of cancer: promises, limitations, and insights for future directions. Front. Microbiol.,  2018, 9, 16.
[http://dx.doi.org/10.3389/fmicb.2018.00016] [PMID: 29472896] 
[124] 
Schwabe, R.F.; Jobin, C. The microbiome and cancer. Nat. Rev. Cancer,  2013, 13(11), 800-812.
[http://dx.doi.org/10.1038/nrc3610] [PMID: 24132111] 
[125] 
DeVita, V.T., Jr; Chu, E. A history of cancer chemotherapy. Cancer Res.,  2008, 68(21), 8643-8653.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-6611] [PMID: 18974103] 
[126] 
McGranahan, N.; Swanton, C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell,  2015, 27(1), 15-26.
[http://dx.doi.org/10.1016/j.ccell.2014.12.001] [PMID: 25584892] 
[127] 
Allison, J.P.; McIntyre, B.W.; Bloch, D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J. Immunol.,  1982, 129(5), 2293-2300.
[PMID: 6181166] 
[128] 
Toh, H.C. Cancer immunotherapy-the end of the beginning. Chin. Clin. Oncol.,  2018, 7(2), 12.
[http://dx.doi.org/10.21037/cco.2018.04.03] [PMID: 29764157] 
[129] 
Dzutsev, A.; Goldszmid, R.S.; 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] 
[130] 
Mathijssen, R.H.; van Alphen, R.J.; Verweij, J.; Loos, W.J.; Nooter, K.; Stoter, G.; Sparreboom, A. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin. Cancer Res.,  2001, 7(8), 2182-2194.
[PMID: 11489791] 
[131] 
Takasuna, K.; Hagiwara, T.; Hirohashi, M.; Kato, M.; Nomura, M.; Nagai, E.; Yokoi, T.; Kamataki, T. Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res.,  1996, 56(16), 3752-3757.
[PMID: 8706020] 
[132] 
Cheng, K.W.; Tseng, C.H.; Tzeng, C.C.; Leu, Y.L.; Cheng, T.C.; Wang, J.Y.; Chang, J.M.; Lu, Y.C.; Cheng, C.M.; Chen, I.J.; Cheng, Y.A.; Chen, Y.L.; Cheng, T.L. Pharmacological inhibition of bacterial β-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo. Pharmacol. Res.,  2019, 139, 41-49.
[http://dx.doi.org/10.1016/j.phrs.2018.10.029] [PMID: 30391354] 
[133] 
Iida, N.; Dzutsev, A.; Stewart, C.A.; Smith, L.; Bouladoux, N.; Weingarten, R.A.; Molina, D.A.; Salcedo, R.; Back, T.; Cramer, S.; Dai, R.M.; Kiu, H.; Cardone, M.; Naik, S.; Patri, A.K.; Wang, E.; Marincola, F.M.; Frank, K.M.; Belkaid, Y.; Trinchieri, G.; Goldszmid, R.S. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science,  2013, 342(6161), 967-970.
[http://dx.doi.org/10.1126/science.1240527] [PMID: 24264989] 
[134] 
Gui, Q.F.; Lu, H.F.; Zhang, C.X.; Xu, Z.R.; Yang, Y.H. Well-balanced commensal microbiota contributes to anti- cancer response in a lung cancer mouse model. Genet. Mol. Res.,  2015, 14(2), 5642-5651.
[http://dx.doi.org/10.4238/2015.May.25.16] [PMID: 26125762] 
[135] 
Viaud, S.; Saccheri, F.; Mignot, G.; Yamazaki, T.; Daillère, R.; Hannani, D.; Enot, D.P.; Pfirschke, C.; Engblom, C.; Pittet, M.J.; Schlitzer, A.; Ginhoux, F.; Apetoh, L.; Chachaty, E.; Woerther, P.L.; Eberl, G.; Bérard, M.; Ecobichon, C.; Clermont, D.; Bizet, C.; Gaboriau-Routhiau, V.; Cerf-Bensussan, N.; Opolon, P.; Yessaad, N.; Vivier, E.; Ryffel, B.; Elson, C.O.; Doré, J.; Kroemer, G.; Lepage, P.; Boneca, I.G.; Ghiringhelli, F.; Zitvogel, L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science,  2013, 342(6161), 971-976.
[http://dx.doi.org/10.1126/science.1240537] [PMID: 24264990] 
[136] 
Zitvogel, L.; Pitt, J.M.; Daillère, R.; Smyth, M.J.; Kroemer, G. Mouse models in oncoimmunology. Nat. Rev. Cancer,  2016, 16(12), 759-773.
[http://dx.doi.org/10.1038/nrc.2016.91] [PMID: 27687979] 
[137] 
Ivanov, I.I.; Frutos, R.L.; Manel, N.; Yoshinaga, K.; Rifkin, D.B.; Sartor, R.B.; Finlay, B.B.; Littman, D.R. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe,  2008, 4(4), 337-349.
[http://dx.doi.org/10.1016/j.chom.2008.09.009] [PMID: 18854238] 
[138] 
Daillère, R.; Vétizou, M.; Waldschmitt, N.; Yamazaki, T.; Isnard, C.; Poirier-Colame, V.; Duong, C.P.M.; Flament, C.; Lepage, P.; Roberti, M.P.; Routy, B.; Jacquelot, N.; Apetoh, L.; Becharef, S.; Rusakiewicz, S.; Langella, P.; Sokol, H.; Kroemer, G.; Enot, D.; Roux, A.; Eggermont, A.; Tartour, E.; Johannes, L.; Woerther, P.L.; Chachaty, E.; Soria, J.C.; Golden, E.; Formenti, S.; Plebanski, M.; Madondo, M.; Rosenstiel, P.; Raoult, D.; Cattoir, V.; Boneca, I.G.; Chamaillard, M.; Zitvogel, L. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity,  2016, 45(4), 931-943.
[http://dx.doi.org/10.1016/j.immuni.2016.09.009] [PMID: 27717798] 
[139] 
Jahrsdörfer, B.; Weiner, G.J. CpG oligodeoxynucleotides as immunotherapy in cancer. Update Cancer Ther.,  2008, 3(1), 27-32.
[http://dx.doi.org/10.1016/j.uct.2007.11.003] [PMID: 19255607] 
[140] 
Routy, B.; Le Chatelier, E.; Derosa, L.; Duong, C.P.M.; Alou, M.T.; Daillère, R.; Fluckiger, A.; Messaoudene, M.; Rauber, C.; Roberti, M.P.; Fidelle, M.; Flament, C.; Poirier-Colame, V.; Opolon, P.; Klein, C.; Iribarren, K.; Mondragón, L.; Jacquelot, N.; Qu, B.; Ferrere, G.; Clémenson, C.; Mezquita, L.; Masip, J.R.; Naltet, C.; Brosseau, S.; Kaderbhai, C.; Richard, C.; Rizvi, H.; Levenez, F.; Galleron, N.; Quinquis, B.; Pons, N.; Ryffel, B.; Minard- Colin, V.; Gonin, P.; Soria, J.C.; Deutsch, E.; Loriot, Y.; Ghiringhelli, F.; Zalcman, G.; Goldwasser, F.; Escudier, B.; Hellmann, M.D.; Eggermont, A.; Raoult, D.; Albiges, L.; Kroemer, G.; Zitvogel, L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science,  2018, 359(6371), 91-97.
[http://dx.doi.org/10.1126/science.aan3706] [PMID: 29097494] 
[141] 
Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; Reuben, A.; Andrews, M.C.; Karpinets, T.V.; Prieto, P.A.; Vicente, D.; Hoffman, K.; Wei, S.C.; Cogdill, A.P.; Zhao, L.; Hudgens, C.W.; Hutchinson, D.S.; Manzo, T.; Petaccia de Macedo, M.; Cotechini, T.; Kumar, T.; Chen, W.S.; Reddy, S.M.; Szczepaniak Sloane, R.; Galloway-Pena, J.; Jiang, H.; Chen, P.L.; Shpall, E.J.; Rezvani, K.; Alousi, A.M.; Chemaly, R.F.; Shelburne, S.; Vence, L.M.; Okhuysen, P.C.; Jensen, V.B.; Swennes, A.G.; McAllister, F.; Marcelo Riquelme Sanchez, E.; Zhang, Y.; Le Chatelier, E.; Zitvogel, L.; Pons, N.; Austin-Breneman, J.L.; Haydu, L.E.; Burton, E.M.; Gardner, J.M.; Sirmans, E.; Hu, J.; Lazar, A.J.; Tsujikawa, T.; Diab, A.; Tawbi, H.; Glitza, I.C.; Hwu, W.J.; Patel, S.P.; Woodman, S.E.; Amaria, R.N.; Davies, M.A.; Gershenwald, J.E.; Hwu, P.; Lee, J.E.; Zhang, J.; Coussens, L.M.; Cooper, Z.A.; Futreal, P.A.; Daniel, C.R.; Ajami, N.J.; Petrosino, J.F.; Tetzlaff, M.T.; Sharma, P.; Allison, J.P.; Jenq, R.R.; Wargo, J.A. 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] 
[142] 
Matson, V.; Fessler, J.; Bao, R.; Chongsuwat, T.; Zha, Y.; Alegre, M.L.; Luke, J.J.; Gajewski, T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science,  2018, 359(6371), 104-108.
[http://dx.doi.org/10.1126/science.aao3290] [PMID: 29302014] 
[143] 
Chen, Q.; Wang, C.; Chen, G.; Hu, Q.; Gu, Z. Delivery strategies for immune checkpoint blockade. Adv. Healthc. Mater.,  2018, 7(20), e1800424.
[http://dx.doi.org/10.1002/adhm.201800424] [PMID: 29978565] 
[144] 
Buchbinder, E.I.; Desai, A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol.,  2016, 39(1), 98-106.
[http://dx.doi.org/10.1097/COC.0000000000000239] [PMID: 26558876] 
[145] 
Vétizou, M.; Pitt, J.M.; Daillère, R.; Lepage, P.; Waldschmitt, N.; Flament, C.; Rusakiewicz, S.; Routy, B.; Roberti, M.P.; Duong, C.P.; Poirier-Colame, V.; Roux, A.; Becharef, S.; Formenti, S.; Golden, E.; Cording, S.; Eberl, G.; Schlitzer, A.; Ginhoux, F.; Mani, S.; Yamazaki, T.; Jacquelot, N.; Enot, D.P.; Bérard, M.; Nigou, J.; Opolon, P.; Eggermont, A.; Woerther, P.L.; Chachaty, E.; Chaput, N.; Robert, C.; Mateus, C.; Kroemer, G.; Raoult, D.; Boneca, I.G.; Carbonnel, F.; Chamaillard, M.; Zitvogel, L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science,  2015, 350(6264), 1079-1084.
[http://dx.doi.org/10.1126/science.aad1329] [PMID: 26541610] 
[146] 
Sivan, A.; Corrales, L.; Hubert, N.; Williams, J.B.; Aquino-Michaels, K.; Earley, Z.M.; Benyamin, F.W.; Lei, Y.M.; Jabri, B.; Alegre, M.L.; Chang, E.B.; Gajewski, T.F. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science,  2015, 350(6264), 1084-1089.
[http://dx.doi.org/10.1126/science.aac4255] [PMID: 26541606] 
[147] 
Gharaibeh, R.Z.; Jobin, C. Microbiota and cancer immunotherapy: in search of microbial signals. Gut,  2019, 68(3), 385-388.
[http://dx.doi.org/10.1136/gutjnl-2018-317220] [PMID: 30530851] 
[148] 
Limeta, A.; Ji, B.; Levin, M.; Gatto, F.; Nielsen, J. Meta- analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma. JCI Insight,  2020, 5(23), e140940.
[http://dx.doi.org/10.1172/jci.insight.140940] [PMID: 33268597] 
[149] 
Tanoue, T.; Morita, S.; Plichta, D.R.; Skelly, A.N.; Suda, W.; Sugiura, Y.; Narushima, S.; Vlamakis, H.; Motoo, I.; Sugita, K.; Shiota, A.; Takeshita, K.; Yasuma-Mitobe, K.; Riethmacher, D.; Kaisho, T.; Norman, J.M.; Mucida, D.; Suematsu, M.; Yaguchi, T.; Bucci, V.; Inoue, T.; Kawakami, Y.; Olle, B.; Roberts, B.; Hattori, M.; Xavier, R.J.; Atarashi, K.; Honda, K. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature,  2019, 565(7741), 600-605.
[http://dx.doi.org/10.1038/s41586-019-0878-z] [PMID: 30675064] 
[150] 
Mager, L.F.; Burkhard, R.; Pett, N.; Cooke, N.C.A.; Brown, K.; Ramay, H.; Paik, S.; Stagg, J.; Groves, R.A.; Gallo, M.; Lewis, I.A.; Geuking, M.B.; McCoy, K.D. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science,  2020, 369(6510), 1481-1489.
[http://dx.doi.org/10.1126/science.abc3421] [PMID: 32792462] 
[151] 
Li, Y.; Elmén, L.; Segota, I.; Xian, Y.; Tinoco, R.; Feng, Y.; Fujita, Y.; Segura Muñoz, R.R.; Schmaltz, R.; Bradley, L.M.; Ramer-Tait, A.; Zarecki, R.; Long, T.; Peterson, S.N.; Ronai, Z.A. Prebiotic-induced anti-tumor immunity attenuates tumor growth. Cell Rep.,  2020, 30(6), 1753-1766.e6.
[http://dx.doi.org/10.1016/j.celrep.2020.01.035] [PMID: 32049008] 
[152] 
Jenq, R.R.; van den Brink, M.R. Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat. Rev. Cancer,  2010, 10(3), 213-221.
[http://dx.doi.org/10.1038/nrc2804] [PMID: 20168320] 
[153] 
Zeiser, R.; Blazar, B.R. Acute graft-versus-host disease - biologic process, prevention, and therapy. N. Engl. J. Med.,  2017, 377(22), 2167-2179.
[http://dx.doi.org/10.1056/NEJMra1609337] [PMID: 29171820] 
[154] 
Peled, J.U.; Gomes, A.L.C.; Devlin, S.M.; Littmann, E.R.; Taur, Y.; Sung, A.D.; Weber, D.; Hashimoto, D.; Slingerland, A.E.; Slingerland, J.B.; Maloy, M.; Clurman, A.G.; Stein-Thoeringer, C.K.; Markey, K.A.; Docampo, M.D.; Burgos da Silva, M.; Khan, N.; Gessner, A.; Messina, J.A.; Romero, K.; Lew, M.V.; Bush, A.; Bohannon, L.; Brereton, D.G.; Fontana, E.; Amoretti, L.A.; Wright, R.J.; Armijo, G.K.; Shono, Y.; Sanchez-Escamilla, M.; Castillo Flores, N.; Alarcon Tomas, A.; Lin, R.J.; Yáñez San Segundo, L.; Shah, G.L.; Cho, C.; Scordo, M.; Politikos, I.; Hayasaka, K.; Hasegawa, Y.; Gyurkocza, B.; Ponce, D.M.; Barker, J.N.; Perales, M.A.; Giralt, S.A.; Jenq, R.R.; Teshima, T.; Chao, N.J.; Holler, E.; Xavier, J.B.; Pamer, E.G.; van den Brink, M.R.M. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N. Engl. J. Med.,  2020, 382(9), 822-834.
[http://dx.doi.org/10.1056/NEJMoa1900623] [PMID: 32101664] 
[155] 
Ingham, A.C.; Kielsen, K.; Cilieborg, M.S.; Lund, O.; Holmes, S.; Aarestrup, F.M.; Müller, K.G.; Pamp, S.J. Specific gut microbiome members are associated with distinct immune markers in pediatric allogeneic hematopoietic stem cell transplantation. Microbiome,  2019, 7(1), 131.
[http://dx.doi.org/10.1186/s40168-019-0745-z] [PMID: 31519210] 
[156] 
Zama, D.; Bossù, G.; Leardini, D.; Muratore, E.; Biagi, E.; Prete, A.; Pession, A.; Masetti, R. Insights into the role of intestinal microbiota in hematopoietic stem-cell transplantation. Ther. Adv. Hematol.,  2020, 11, 2040620719896961.
[http://dx.doi.org/10.1177/2040620719896961] [PMID: 32010434] 
[157] 
Taur, Y.; Xavier, J.B.; Lipuma, L.; Ubeda, C.; Goldberg, J.; Gobourne, A.; Lee, Y.J.; Dubin, K.A.; Socci, N.D.; Viale, A.; Perales, M.A.; Jenq, R.R.; van den Brink, M.R.; Pamer, E.G. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin. Infect. Dis.,  2012, 55(7), 905-914.
[http://dx.doi.org/10.1093/cid/cis580] [PMID: 22718773] 
[158] 
Taur, Y.; Jenq, R.R.; Perales, M.A.; Littmann, E.R.; Morjaria, S.; Ling, L.; No, D.; Gobourne, A.; Viale, A.; Dahi, P.B.; Ponce, D.M.; Barker, J.N.; Giralt, S.; van den Brink, M.; Pamer, E.G. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood,  2014, 124(7), 1174-1182.
[http://dx.doi.org/10.1182/blood-2014-02-554725] [PMID: 24939656] 
[159] 
Jenq, R.R.; Ubeda, C.; Taur, Y.; Menezes, C.C.; Khanin, R.; Dudakov, J.A.; Liu, C.; West, M.L.; Singer, N.V.; Equinda, M.J.; Gobourne, A.; Lipuma, L.; Young, L.F.; Smith, O.M.; Ghosh, A.; Hanash, A.M.; Goldberg, J.D.; Aoyama, K.; Blazar, B.R.; Pamer, E.G.; van den Brink, M.R. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med.,  2012, 209(5), 903-911.
[http://dx.doi.org/10.1084/jem.20112408] [PMID: 22547653] 
[160] 
Shono, Y.; Docampo, M.D.; Peled, J.U.; Perobelli, S.M.; Velardi, E.; Tsai, J.J.; Slingerland, A.E.; Smith, O.M.; Young, L.F.; Gupta, J.; Lieberman, S.R.; Jay, H.V.; Ahr, K.F.; Porosnicu Rodriguez, K.A.; Xu, K.; Calarfiore, M.; Poeck, H.; Caballero, S.; Devlin, S.M.; Rapaport, F.; Dudakov, J.A.; Hanash, A.M.; Gyurkocza, B.; Murphy, G.F.; Gomes, C.; Liu, C.; Moss, E.L.; Falconer, S.B.; Bhatt, A.S.; Taur, Y.; Pamer, E.G.; van den Brink, M.R.M.; Jenq, R.R. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci. Transl. Med.,  2016, 8(339), 339ra71.
[http://dx.doi.org/10.1126/scitranslmed.aaf2311] [PMID: 27194729] 
[161] 
Heimesaat, M.M.; Nogai, A.; Bereswill, S.; Plickert, R.; Fischer, A.; Loddenkemper, C.; Steinhoff, U.; Tchaptchet, S.; Thiel, E.; Freudenberg, M.A.; Göbel, U.B.; Uharek, L. MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut,  2010, 59(8), 1079-1087.
[http://dx.doi.org/10.1136/gut.2009.197434] [PMID: 20639251] 
[162] 
Eriguchi, Y.; Takashima, S.; Oka, H.; Shimoji, S.; Nakamura, K.; Uryu, H.; Shimoda, S.; Iwasaki, H.; Shimono, N.; Ayabe, T.; Akashi, K.; Teshima, T. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins. Blood,  2012, 120(1), 223-231.
[http://dx.doi.org/10.1182/blood-2011-12-401166] [PMID: 22535662] 
[163] 
Biagi, E.; Zama, D.; Nastasi, C.; Consolandi, C.; Fiori, J.; Rampelli, S.; Turroni, S.; Centanni, M.; Severgnini, M.; Peano, C.; de Bellis, G.; Basaglia, G.; Gotti, R.; Masetti, R.; Pession, A.; Brigidi, P.; Candela, M. Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT. Bone Marrow Transplant.,  2015, 50(7), 992-998.
[http://dx.doi.org/10.1038/bmt.2015.16] [PMID: 25893458] 
[164] 
Biagi, E.; Zama, D.; Rampelli, S.; Turroni, S.; Brigidi, P.; Consolandi, C.; Severgnini, M.; Picotti, E.; Gasperini, P.; Merli, P.; Decembrino, N.; Zecca, M.; Cesaro, S.; Faraci, M.; Prete, A.; Locatelli, F.; Pession, A.; Candela, M.; Masetti, R. Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders. BMC Med. Genomics,  2019, 12(1), 49.
[http://dx.doi.org/10.1186/s12920-019-0494-7] [PMID: 30845942] 
[165] 
Han, L.; Zhang, H.; Chen, S.; Zhou, L.; Li, Y.; Zhao, K.; Huang, F.; Fan, Z.; Xuan, L.; Zhang, X.; Dai, M.; Lin, Q.; Jiang, Z.; Peng, J.; Jin, H.; Liu, Q. Intestinal microbiota can predict acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant.,  2019, 25(10), 1944-1955.
[http://dx.doi.org/10.1016/j.bbmt.2019.07.006] [PMID: 31299215] 
[166] 
Mathewson, N.D.; Jenq, R.; Mathew, A.V.; Koenigsknecht, M.; Hanash, A.; Toubai, T.; Oravecz-Wilson, K.; Wu, S.R.; Sun, Y.; Rossi, C.; Fujiwara, H.; Byun, J.; Shono, Y.; Lindemans, C.; Calafiore, M.; Schmidt, T.M.; Honda, K.; Young, V.B.; Pennathur, S.; van den Brink, M.; Reddy, P. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat. Immunol.,  2016, 17(5), 505-513.
[http://dx.doi.org/10.1038/ni.3400] [PMID: 26998764] 
[167] 
Atarashi, K.; Tanoue, T.; Oshima, K.; Suda, W.; Nagano, Y.; Nishikawa, H.; Fukuda, S.; Saito, T.; Narushima, S.; Hase, K.; Kim, S.; Fritz, J.V.; Wilmes, P.; Ueha, S.; Matsushima, K.; Ohno, H.; Olle, B.; Sakaguchi, S.; Taniguchi, T.; Morita, H.; Hattori, M.; Honda, K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature,  2013, 500(7461), 232-236.
[http://dx.doi.org/10.1038/nature12331] [PMID: 23842501] 
[168] 
Liu, X.; Mao, B.; Gu, J.; Wu, J.; Cui, S.; Wang, G.; Zhao, J.; Zhang, H.; Chen, W. Blautia-a new functional genus with potential probiotic properties? Gut Microbes,  2021, 13(1), 1-21.
[http://dx.doi.org/10.1080/19490976.2021.1875796] [PMID: 33525961] 
[169] 
Jenq, R.R.; Taur, Y.; Devlin, S.M.; Ponce, D.M.; Goldberg, J.D.; Ahr, K.F.; Littmann, E.R.; Ling, L.; Gobourne, A.C.; Miller, L.C.; Docampo, M.D.; Peled, J.U.; Arpaia, N.; Cross, J.R.; Peets, T.K.; Lumish, M.A.; Shono, Y.; Dudakov, J.A.; Poeck, H.; Hanash, A.M.; Barker, J.N.; Perales, M.A.; Giralt, S.A.; Pamer, E.G.; van den Brink, M.R. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol. Blood Marrow Transplant.,  2015, 21(8), 1373-1383.
[http://dx.doi.org/10.1016/j.bbmt.2015.04.016] [PMID: 25977230] 
[170] 
D’Amico, F.; Biagi, E.; Rampelli, S.; Fiori, J.; Zama, D.; Soverini, M.; Barone, M.; Leardini, D.; Muratore, E.; Prete, A.; Gotti, R.; Pession, A.; Masetti, R.; Brigidi, P.; Turroni, S.; Candela, M. Enteral nutrition in pediatric patients undergoing hematopoietic SCT promotes the recovery of gut microbiome homeostasis. Nutrients,  2019, 11(12), 2958.
[http://dx.doi.org/10.3390/nu11122958] [PMID: 31817158] 
[171] 
Staffas, A.; Burgos da Silva, M.; Slingerland, A.E.; Lazrak, A.; Bare, C.J.; Holman, C.D.; Docampo, M.D.; Shono, Y.; Durham, B.; Pickard, A.J.; Cross, J.R.; Stein-Thoeringer, C.; Velardi, E.; Tsai, J.J.; Jahn, L.; Jay, H.; Lieberman, S.; Smith, O.M.; Pamer, E.G.; Peled, J.U.; Cohen, D.E.; Jenq, R.R.; van den Brink, M.R.M. Nutritional support from the intestinal microbiota improves hematopoietic reconstitution after bone marrow transplantation in Mice. Cell Host Microbe,  2018, 23(4), 447-457.
[http://dx.doi.org/10.1016/j.chom.2018.03.002] [PMID: 29576480] 
[172] 
Geller, L.T.; Barzily-Rokni, M.; Danino, T.; Jonas, O.H.; Shental, N.; Nejman, D.; Gavert, N.; Zwang, Y.; Cooper, Z.A.; Shee, K.; Thaiss, C.A.; Reuben, A.; Livny, J.; Avraham, R.; Frederick, D.T.; Ligorio, M.; Chatman, K.; Johnston, S.E.; Mosher, C.M.; Brandis, A.; Fuks, G.; Gurbatri, C.; Gopalakrishnan, V.; Kim, M.; Hurd, M.W.; Katz, M.; Fleming, J.; Maitra, A.; Smith, D.A.; Skalak, M.; Bu, J.; Michaud, M.; Trauger, S.A.; Barshack, I.; Golan, T.; Sandbank, J.; Flaherty, K.T.; Mandinova, A.; Garrett, W.S.; Thayer, S.P.; Ferrone, C.R.; Huttenhower, C.; Bhatia, S.N.; Gevers, D.; Wargo, J.A.; Golub, T.R.; Straussman, R. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science,  2017, 357(6356), 1156-1160.
[http://dx.doi.org/10.1126/science.aah5043] [PMID: 28912244] 
[173] 
Barrett, M.; Hand, C.K.; Shanahan, F.; Murphy, T.; O’Toole, P.W. Mutagenesis by microbe: the role of the microbiota in shaping the cancer genome. Trends Cancer,  2020, 6(4), 277-287.
[http://dx.doi.org/10.1016/j.trecan.2020.01.019] [PMID: 32209443] 
[174] 
Pleguezuelos-Manzano, C.; Puschhof, J.; Rosendahl Huber, A.; van Hoeck, A.; Wood, H.M.; Nomburg, J.; Gurjao, C.; Manders, F.; Dalmasso, G.; Stege, P.B.; Paganelli, F.L.; Geurts, M.H.; Beumer, J.; Mizutani, T.; Miao, Y.; van der Linden, R.; van der Elst, S.; Garcia, K.C.; Top, J.; Willems, R.J.L.; Giannakis, M.; Bonnet, R.; Quirke, P.; Meyerson, M.; Cuppen, E.; van Boxtel, R.; Clevers, H. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature,  2020, 580(7802), 269-273.
[http://dx.doi.org/10.1038/s41586-020-2080-8] [PMID: 32106218] 
[175] 
Brennan, C.A.; Garrett, W.S. Fusobacterium nucleatum - symbiont, opportunist and oncobacterium. Nat. Rev. Microbiol.,  2019, 17(3), 156-166.
[http://dx.doi.org/10.1038/s41579-018-0129-6] [PMID: 30546113] 
[176] 
Sepich-Poore, G.D.; Zitvogel, L.; Straussman, R.; Hasty, J.; Wargo, J.A.; Knight, R. The microbiome and human cancer. Science,  2021, 371(6536), eabc4552.
[http://dx.doi.org/10.1126/science.abc4552] [PMID: 33766858] 
[177] 
Nejman, D.; Livyatan, I.; Fuks, G.; Gavert, N.; Zwang, Y.; Geller, L.T.; Rotter-Maskowitz, A.; Weiser, R.; Mallel, G.; Gigi, E.; Meltser, A.; Douglas, G.M.; Kamer, I.; Gopalakrishnan, V.; Dadosh, T.; Levin-Zaidman, S.; Avnet, S.; Atlan, T.; Cooper, Z.A.; Arora, R.; Cogdill, A.P.; Khan, M.A.W.; Ologun, G.; Bussi, Y.; Weinberger, A.; Lotan-Pompan, M.; Golani, O.; Perry, G.; Rokah, M.; Bahar-Shany, K.; Rozeman, E.A.; Blank, C.U.; Ronai, A.; Shaoul, R.; Amit, A.; Dorfman, T.; Kremer, R.; Cohen, Z.R.; Harnof, S.; Siegal, T.; Yehuda-Shnaidman, E.; Gal-Yam, E.N.; Shapira, H.; Baldini, N.; Langille, M.G.I.; Ben-Nun, A.; Kaufman, B.; Nissan, A.; Golan, T.; Dadiani, M.; Levanon, K.; Bar, J.; Yust-Katz, S.; Barshack, I.; Peeper, D.S.; Raz, D.J.; Segal, E.; Wargo, J.A.; Sandbank, J.; Shental, N.; Straussman, R. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science,  2020, 368(6494), 973-980.
[http://dx.doi.org/10.1126/science.aay9189] [PMID: 32467386] 
[178] 
Poore, G.D.; Kopylova, E.; Zhu, Q.; Carpenter, C.; Fraraccio, S.; Wandro, S.; Kosciolek, T.; Janssen, S.; Metcalf, J.; Song, S.J.; Kanbar, J.; Miller-Montgomery, S.; Heaton, R.; Mckay, R.; Patel, S.P.; Swafford, A.D.; Knight, R. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature,  2020, 579(7800), 567-574.
[http://dx.doi.org/10.1038/s41586-020-2095-1] [PMID: 32214244] 
[179] 
Errington, J. Cell wall-deficient, L-form bacteria in the 21st century: a personal perspective. Biochem. Soc. Trans.,  2017, 45(2), 287-295.
[http://dx.doi.org/10.1042/BST20160435] [PMID: 28408469] 
[180] 
Parhi, L.; Alon-Maimon, T.; Sol, A.; Nejman, D.; Shhadeh, A.; Fainsod-Levi, T.; Yajuk, O.; Isaacson, B.; Abed, J.; Maalouf, N.; Nissan, A.; Sandbank, J.; Yehuda-Shnaidman, E.; Ponath, F.; Vogel, J.; Mandelboim, O.; Granot, Z.; Straussman, R.; Bachrach, G. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nat. Commun.,  2020, 11(1), 3259.
[http://dx.doi.org/10.1038/s41467-020-16967-2] [PMID: 32591509] 
[181] 
Yu, T.; Guo, F.; Yu, Y.; Sun, T.; Ma, D.; Han, J.; Qian, Y.; Kryczek, I.; Sun, D.; Nagarsheth, N.; Chen, Y.; Chen, H.; Hong, J.; Zou, W.; Fang, J.Y. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell,  2017, 170(3), 548-563.
[http://dx.doi.org/10.1016/j.cell.2017.07.008] [PMID: 28753429] 
[182] 
Riquelme, E.; Zhang, Y.; Zhang, L.; Montiel, M.; Zoltan, M.; Dong, W.; Quesada, P.; Sahin, I.; Chandra, V.; San Lucas, A.; Scheet, P.; Xu, H.; Hanash, S.M.; Feng, L.; Burks, J.K.; Do, K.A.; Peterson, C.B.; Nejman, D.; Tzeng, C.D.; Kim, M.P.; Sears, C.L.; Ajami, N.; Petrosino, J.; Wood, L.D.; Maitra, A.; Straussman, R.; Katz, M.; White, J.R.; Jenq, R.; Wargo, J.; McAllister, F. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell,  2019, 178(4), 795-806.
[http://dx.doi.org/10.1016/j.cell.2019.07.008] [PMID: 31398337] 
[183] 
Falzone, L.; Salomone, S.; Libra, M. Evolution of cancer pharmacological treatments at the turn of the third millennium. Front. Pharmacol.,  2018, 9, 1300.
[http://dx.doi.org/10.3389/fphar.2018.01300] [PMID: 30483135] 
[184] 
Helmink, B.A.; Khan, M.A.W.; Hermann, A.; Gopalakrishnan, V.; Wargo, J.A. The microbiome, cancer, and cancer therapy. Nat. Med.,  2019, 25(3), 377-388.
[http://dx.doi.org/10.1038/s41591-019-0377-7] [PMID: 30842679] 
[185] 
Parida, S.; Sharma, D. The microbiome and cancer: creating friendly neighborhoods and removing the foes within. Cancer Res.,  2021, 81(4), 790-800.
[http://dx.doi.org/10.1158/0008-5472.CAN-20-2629] [PMID: 33148661] 
[186] 
Kaźmierczak-Siedlecka, K.; Daca, A.; Fic, M.; van de Wetering, T.; Folwarski, M.; Makarewicz, W. Therapeutic methods of gut microbiota modification in colorectal cancer management - fecal microbiota transplantation, prebiotics, probiotics, and synbiotics. Gut Microbes,  2020, 11(6), 1518-1530.
[http://dx.doi.org/10.1080/19490976.2020.1764309] [PMID: 32453670] 
[187] 
Gibson, G.R.; Hutkins, R.; Sanders, M.E.; Prescott, S.L.; Reimer, R.A.; Salminen, S.J.; Scott, K.; Stanton, C.; Swanson, K.S.; Cani, P.D.; Verbeke, K.; Reid, G. 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] 
[188] 
Vandeputte, D.; Falony, G.; Vieira-Silva, S.; Wang, J.; Sailer, M.; Theis, S.; Verbeke, K.; Raes, J. Prebiotic inulin- type fructans induce specific changes in the human gut microbiota. Gut,  2017, 66(11), 1968-1974.
[http://dx.doi.org/10.1136/gutjnl-2016-313271] [PMID: 28213610] 
[189] 
Cunningham, M.; Azcarate-Peril, M.A.; Barnard, A.; Benoit, V.; Grimaldi, R.; Guyonnet, D.; Holscher, H.D.; Hunter, K.; Manurung, S.; Obis, D.; Petrova, M.I.; Steinert, R.E.; Swanson, K.S.; van Sinderen, D.; Vulevic, J.; Gibson, G.R. Shaping the future of probiotics and prebiotics. Trends Microbiol,  2021, 29(8), 667-685.
[http://dx.doi.org/10.1016/j.tim.2021.01.003] 
[190] 
Deehan, E.C.; Yang, C.; Perez-Muñoz, M.E.; Nguyen, N.K.; Cheng, C.C.; Triador, L.; Zhang, Z.; Bakal, J.A.; Walter, J. Precision microbiome modulation with discrete dietary fiber structures directs short-chain fatty acid production. Cell Host Microbe,  2020, 27(3), 389-404.
[http://dx.doi.org/10.1016/j.chom.2020.01.006] [PMID: 32004499] 
[191] 
Sasidharan, B.K.; Ramadass, B.; Viswanathan, P.N.; Samuel, P.; Gowri, M.; Pugazhendhi, S.; Ramakrishna, B.S. A phase 2 randomized controlled trial of oral resistant starch supplements in the prevention of acute radiation proctitis in patients treated for cervical cancer. J. Cancer Res. Ther.,  2019, 15(6), 1383-1391.
[http://dx.doi.org/10.4103/jcrt.JCRT_152_19] [PMID: 31898677] 
[192] 
Xie, X.; He, Y.; Li, H.; Yu, D.; Na, L.; Sun, T.; Zhang, D.; Shi, X.; Xia, Y.; Jiang, T.; Rong, S.; Yang, S.; Ma, X.; Xu, G. Effects of prebiotics on immunologic indicators and intestinal microbiota structure in perioperative colorectal cancer patients. Nutrition,  2019, 61, 132-142.
[http://dx.doi.org/10.1016/j.nut.2018.10.038] [PMID: 30711862] 
[193] 
García-Peris, P.; Velasco, C.; Lozano, M.A.; Moreno, Y.; Paron, L.; de la Cuerda, C.; Bretón, I.; Camblor, M.; García-Hernández, J.; Guarner, F.; Hernández, M. Effect of a mixture of inulin and fructo-oligosaccharide on Lactobacillus and Bifidobacterium intestinal microbiota of patients receiving radiotherapy: a randomised, double-blind, placebo-controlled trial. Nutr. Hosp.,  2012, 27(6), 1908-1915.
[PMID: 23588438] 
[194] 
Criscuolo, A.A.; Sesti, F.; Piccione, E.; Mancino, P.; Belloni, E.; Gullo, C.; Ciotti, M. Therapeutic efficacy of a Coriolus versicolor-based vaginal gel in women with cervical uterine high-risk HPV Infection: a retrospective observational study. Adv. Ther.,  2021, 38(2), 1202-1211.
[http://dx.doi.org/10.1007/s12325-020-01594-6] [PMID: 33367986] 
[195] 
Hill, C.; Guarner, F.; Reid, G.; Gibson, G.R.; Merenstein, D.J.; Pot, B.; Morelli, L.; Canani, R.B.; Flint, H.J.; Salminen, S.; Calder, P.C.; Sanders, M.E. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol.,  2014, 11(8), 506-514.
[http://dx.doi.org/10.1038/nrgastro.2014.66] [PMID: 24912386] 
[196] 
Suez, J.; Zmora, N.; Segal, E.; Elinav, E. The pros, cons, and many unknowns of probiotics. Nat. Med.,  2019, 25(5), 716-729.
[http://dx.doi.org/10.1038/s41591-019-0439-x] [PMID: 31061539] 
[197] 
Liu, C.T.; Chu, F.J.; Chou, C.C.; Yu, R.C. Antiproliferative and anticytotoxic effects of cell fractions and exopolysaccharides from Lactobacillus casei 01. Mutat. Res.,  2011, 721(2), 157-162.
[http://dx.doi.org/10.1016/j.mrgentox.2011.01.005] [PMID: 21262385] 
[198] 
Reis, S.A.D.; da Conceição, L.L.; Peluzio, M.D.C.G. Intestinal microbiota and colorectal cancer: changes in the intestinal microenvironment and their relation to the disease. J. Med. Microbiol.,  2019, 68(10), 1391-1407.
[http://dx.doi.org/10.1099/jmm.0.001049] [PMID: 31424382] 
[199] 
Molska, M.; Reguła, J. Potential mechanisms of probiotics action in the prevention and treatment of colorectal cancer. Nutrients,  2019, 11(10), 2453.
[http://dx.doi.org/10.3390/nu11102453] [PMID: 31615096] 
[200] 
Lu, K.; Dong, S.; Wu, X.; Jin, R.; Chen, H. Probiotics in cancer. Front. Oncol.,  2021, 11, 638148.
[http://dx.doi.org/10.3389/fonc.2021.638148] [PMID: 33791223] 
[201] 
Hassan, Z. Anti-cancer and biotherapeutic potentials of probiotic bacteria. J. Cancer Sci. Ther.,  2019, 11, 9-13.
[http://dx.doi.org/10.4172/1948-5956.1000575] 
[202] 
Singh, B.; Mal, G.; Marotta, F. Designer probiotics: paving the way to living therapeutics. Trends Biotechnol.,  2017, 35(8), 679-682.
[http://dx.doi.org/10.1016/j.tibtech.2017.04.001] [PMID: 28483159] 
[203] 
Legesse Bedada, T.; Feto, T.K.; Awoke, K.S.; Garedew, A.D.; Yifat, F.T.; Birri, D.J. Probiotics for cancer alternative prevention and treatment. Biomed. Pharmacother.,  2020, 129, 110409.
[http://dx.doi.org/10.1016/j.biopha.2020.110409] [PMID: 32563987] 
[204] 
Hibberd, A.A.; Lyra, A.; Ouwehand, A.C.; Rolny, P.; Lindegren, H.; Cedgård, L.; Wettergren, Y. Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention. BMJ Open Gastroenterol.,  2017, 4(1), e000145.
[http://dx.doi.org/10.1136/bmjgast-2017-000145] [PMID: 28944067] 
[205] 
Consoli, M.L.; da Silva, R.S.; Nicoli, J.R.; Bruña-Romero, O.; da Silva, R.G.; de Vasconcelos Generoso, S.; Correia, M.I. Randomized clinical trial: impact of oral administration of Saccharomyces boulardii on gene expression of intestinal cytokines in patients undergoing colon resection. JPEN J. Parenter. Enteral Nutr.,  2016, 40(8), 1114-1121.
[http://dx.doi.org/10.1177/0148607115584387] [PMID: 25917895] 
[206] 
Naito, S.; Koga, H.; Yamaguchi, A.; Fujimoto, N.; Hasui, Y.; Kuramoto, H.; Iguchi, A.; Kinukawa, N. Kyushu University Urological Oncology Group. Prevention of recurrence with epirubicin and Lactobacillus casei after transurethral resection of bladder cancer. J. Urol.,  2008, 179(2), 485-490.
[http://dx.doi.org/10.1016/j.juro.2007.09.031] [PMID: 18076918] 
[207] 
Seely, D.; Ennis, J.E.; McDonell, E.; Fazekas, A.; Zhao, L.; Asmis, T.; Auer, R.C.; Fergusson, D.; Kanji, S.; Maziak, D.E.; Ramsay, T.; Chamberland, P.; Spooner, C.; Threader, J.; Seely, A. Intervention development process for a pragmatic randomized controlled trial: the thoracic peri-operative integrative surgical care evaluation trial. J. Altern. Complement. Med.,  2019, 25(S1), S112-S123.
[http://dx.doi.org/10.1089/acm.2018.0419] [PMID: 30870012] 
[208] 
U.S. department of health and human services, food and drug administration guidance for industry. Early clinical trials with live biotherapeutic products: chemistry, manufacturing, and control information. 2016. Available from: www.fda.gov/downloads/Biologi%E2%80%A6/UCM292704.pdf
[209] 
Charbonneau, M.R.; Isabella, V.M.; Li, N.; Kurtz, C.B. Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat. Commun.,  2020, 11(1), 1738.
[http://dx.doi.org/10.1038/s41467-020-15508-1] [PMID: 32269218] 
[210] 
O’Toole, P.W.; Marchesi, J.R.; Hill, C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat. Microbiol.,  2017, 2, 17057.
[http://dx.doi.org/10.1038/nmicrobiol.2017.57] [PMID: 28440276] 
[211] 
Ulsemer, P.; Henderson, G.; Toutounian, K.; Löffler, A.; Schmidt, J.; Karsten, U.; Blaut, M.; Goletz, S. Specific humoral immune response to the Thomsen-Friedenreich tumor antigen (CD176) in mice after vaccination with the commensal bacterium Bacteroides ovatus D-6. Cancer Immunol. Immunother.,  2013, 62(5), 875-887.
[http://dx.doi.org/10.1007/s00262-013-1394-x] [PMID: 23381581] 
[212] 
Ulsemer, P.; Toutounian, K.; Kressel, G.; Goletz, C.; Schmidt, J.; Karsten, U.; Hahn, A.; Goletz, S. Impact of oral consumption of heat-treated Bacteroides xylanisolvens DSM 23964 on the level of natural TFα-specific antibodies in human adults. Benef. Microbes,  2016, 7(4), 485-500.
[http://dx.doi.org/10.3920/BM2015.0143] [PMID: 27048836] 
[213] 
Ho, C.L.; Tan, H.Q.; Chua, K.J.; Kang, A.; Lim, K.H.; Ling, K.L.; Yew, W.S.; Lee, Y.S.; Thiery, J.P.; Chang, M.W. Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention. Nat. Biomed. Eng.,  2018, 2(1), 27-37.
[http://dx.doi.org/10.1038/s41551-017-0181-y] [PMID: 31015663] 
[214] 
Arthur, J.C.; Gharaibeh, R.Z.; Uronis, J.M.; Perez-Chanona, E.; Sha, W.; Tomkovich, S.; Mühlbauer, M.; Fodor, A.A.; Jobin, C. VSL#3 probiotic modifies mucosal microbial composition but does not reduce colitis-associated colorectal cancer. Sci. Rep.,  2013, 3, 2868.
[http://dx.doi.org/10.1038/srep02868] [PMID: 24100376] 
[215] 
Veiga, P.; Suez, J.; Derrien, M.; Elinav, E. Moving from probiotics to precision probiotics. Nat. Microbiol.,  2020, 5(7), 878-880.
[http://dx.doi.org/10.1038/s41564-020-0721-1] [PMID: 32393856] 
[216] 
Sotoudegan, F.; Daniali, M.; Hassani, S.; Nikfar, S.; Abdollahi, M. Reappraisal of probiotics’ safety in human. Food Chem. Toxicol.,  2019, 129, 22-29.
[http://dx.doi.org/10.1016/j.fct.2019.04.032] [PMID: 31009735] 
[217] 
Cammarota, G.; Ianiro, G.; Tilg, H.; Rajilić-Stojanović, M.; Kump, P.; Satokari, R.; Sokol, H.; Arkkila, P.; Pintus, C.; Hart, A.; Segal, J.; Aloi, M.; Masucci, L.; Molinaro, A.; Scaldaferri, F.; Gasbarrini, G.; Lopez-Sanroman, A.; Link, A.; de Groot, P.; de Vos, W.M.; Högenauer, C.; Malfertheiner, P.; Mattila, E.; Milosavljević, T.; Nieuwdorp, M.; Sanguinetti, M.; Simren, M.; Gasbarrini, A. European consensus conference on faecal microbiota transplantation in clinical practice. Gut,  2017, 66(4), 569-580.
[http://dx.doi.org/10.1136/gutjnl-2016-313017] [PMID: 28087657] 
[218] 
Ianiro, G.; Mullish, B.H.; Kelly, C.R.; Kassam, Z.; Kuijper, E.J.; Ng, S.C.; Iqbal, T.H.; Allegretti, J.R.; Bibbò, S.; Sokol, H.; Zhang, F.; Fischer, M.; Costello, S.P.; Keller, J.J.; Masucci, L.; van Prehn, J.; Quaranta, G.; Quraishi, M.N.; Segal, J.; Kao, D.; Satokari, R.; Sanguinetti, M.; Tilg, H.; Gasbarrini, A.; Cammarota, G. Reorganisation of faecal microbiota transplant services during the COVID-19 pandemic. Gut,  2020, 69(9), 1555-1563.
[http://dx.doi.org/10.1136/gutjnl-2020-321829] [PMID: 32620549] 
[219] 
Gupta, A.; Saha, S.; Khanna, S. Therapies to modulate gut microbiota: past, present and future. World J. Gastroenterol.,  2020, 26(8), 777-788.
[http://dx.doi.org/10.3748/wjg.v26.i8.777] [PMID: 32148376] 
[220] 
Rezasoltani, S.; Yadegar, A.; Asadzadeh Aghdaei, H.; Reza Zali, M. Modulatory effects of gut microbiome in cancer immunotherapy: a novel paradigm for blockade of immune checkpoint inhibitors. Cancer Med.,  2021, 10(3), 1141-1154.
[http://dx.doi.org/10.1002/cam4.3694] [PMID: 33369247] 
[221] 
Baruch, E.N.; Youngster, I.; Ben-Betzalel, G.; Ortenberg, R.; Lahat, A.; Katz, L.; Adler, K.; Dick-Necula, D.; Raskin, S.; Bloch, N.; Rotin, D.; Anafi, L.; Avivi, C.; Melnichenko, J.; Steinberg-Silman, Y.; Mamtani, R.; Harati, H.; Asher, N.; Shapira-Frommer, R.; Brosh-Nissimov, T.; Eshet, Y.; Ben-Simon, S.; Ziv, O.; Khan, M.A.W.; Amit, M.; Ajami, N.J.; Barshack, I.; Schachter, J.; Wargo, J.A.; Koren, O.; Markel, G.; Boursi, B. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science,  2021, 371(6529), 602-609.
[http://dx.doi.org/10.1126/science.abb5920] [PMID: 33303685] 
[222] 
Davar, D.; Dzutsev, A.K.; McCulloch, J.A.; Rodrigues, R.R.; Chauvin, J.M.; Morrison, R.M.; Deblasio, R.N.; Menna, C.; Ding, Q.; Pagliano, O.; Zidi, B.; Zhang, S.; Badger, J.H.; Vetizou, M.; Cole, A.M.; Fernandes, M.R.; Prescott, S.; Costa, R.G.F.; Balaji, A.K.; Morgun, A.; Vujkovic-Cvijin, I.; Wang, H.; Borhani, A.A.; Schwartz, M.B.; Dubner, H.M.; Ernst, S.J.; Rose, A.; Najjar, Y.G.; Belkaid, Y.; Kirkwood, J.M.; Trinchieri, G.; Zarour, H.M. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science,  2021, 371(6529), 595-602.
[http://dx.doi.org/10.1126/science.abf3363] [PMID: 33542131] 
[223] 
Zhang, T.; Lu, G.; Zhao, Z.; Liu, Y.; Shen, Q.; Li, P.; Chen, Y.; Yin, H.; Wang, H.; Marcella, C.; Cui, B.; Cheng, L.; Ji, G.; Zhang, F. Washed microbiota transplantation vs. manual fecal microbiota transplantation: clinical findings, animal studies and in vitro screening. Protein Cell,  2020, 11(4), 251-266.
[http://dx.doi.org/10.1007/s13238-019-00684-8] [PMID: 31919742] 
[224] 
Zhang, T.; Ding, X.; Dai, M.; Zhang, H.; Xiao, F.; He, X.; Zhang, F.; Zhang, X. Washed microbiota transplantation in patients with respiratory spreading diseases: practice recommendations. Med. Microecol.,  2021, 7, 100024.
[http://dx.doi.org/10.1016/j.medmic.2020.100024] [PMID: 34046562] 
[225] 
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), 2021-2031.
[http://dx.doi.org/10.1002/ijc.32003] [PMID: 30458058] 
[226] 
Zhu, X.; Goldberg, A. Introduction to semi-supervised learning. Morgan Claypool Publishers, 2009. 
[http://dx.doi.org/10.2200/S00196ED1V01Y200906AIM006] 
[227] 
Moreno-Indias, I.; Lahti, L.; Nedyalkova, M.; Elbere, I.; Roshchupkin, G.; Adilovic, M.; Aydemir, O.; Bakir-Gungor, B.; Santa Pau, E.C.; D’Elia, D.; Desai, M.S.; Falquet, L.; Gundogdu, A.; Hron, K.; Klammsteiner, T.; Lopes, M.B.; Marcos-Zambrano, L.J.; Marques, C.; Mason, M.; May, P.; Pašić, L.; Pio, G.; Pongor, S.; Promponas, V.J.; Przymus, P.; Saez-Rodriguez, J.; Sampri, A.; Shigdel, R.; Stres, B.; Suharoschi, R.; Truu, J.; Truică, C.O.; Vilne, B.; Vlachakis, D.; Yilmaz, E.; Zeller, G.; Zomer, A.L.; Gómez-Cabrero, D.; Claesson, M.J. Statistical and machine learning techniques in human microbiome studies: contemporary challenges and solutions. Front. Microbiol.,  2021, 12, 635781.
[http://dx.doi.org/10.3389/fmicb.2021.635781] [PMID: 33692771] 
[228] 
Bonetta, R.; Valentino, G. Machine learning techniques for protein function prediction. Proteins,  2020, 88(3), 397-413.
[http://dx.doi.org/10.1002/prot.25832] [PMID: 31603244] 
[229] 
Vamathevan, J.; Clark, D.; Czodrowski, P.; Dunham, I.; Ferran, E.; Lee, G.; Li, B.; Madabhushi, A.; Shah, P.; Spitzer, M.; Zhao, S. Applications of machine learning in drug discovery and development. Nat. Rev. Drug Discov.,  2019, 18(6), 463-477.
[http://dx.doi.org/10.1038/s41573-019-0024-5] [PMID: 30976107] 
[230] 
McCarthy, J.F.; Marx, K.A.; Hoffman, P.E.; Gee, A.G.; O’Neil, P.; Ujwal, M.L.; Hotchkiss, J. Applications of machine learning and high-dimensional visualization in cancer detection, diagnosis, and management. Ann. N. Y. Acad. Sci.,  2004, 1020, 239-262.
[http://dx.doi.org/10.1196/annals.1310.020] [PMID: 15208196] 
[231] 
Kerlikowske, K.; Scott, C.G.; Mahmoudzadeh, A.P.; Ma, L.; Winham, S.; Jensen, M.R.; Wu, F.F.; Malkov, S.; Pankratz, V.S.; Cummings, S.R.; Shepherd, J.A.; Brandt, K.R.; Miglioretti, D.L.; Vachon, C.M. Automated and clinical breast imaging reporting and data system density measures predict risk for screen-detected and interval cancers: a case-control study. Ann. Intern. Med.,  2018, 168(11), 757-765.
[http://dx.doi.org/10.7326/M17-3008] [PMID: 29710124] 
[232] 
Nam, J.G.; Park, S.; Hwang, E.J.; Lee, J.H.; Jin, K.N.; Lim, K.Y.; Vu, T.H.; Sohn, J.H.; Hwang, S.; Goo, J.M.; Park, C.M. Development and validation of deep learning-based automatic detection algorithm for malignant pulmonary nodules on chest radiographs. Radiology,  2019, 290(1), 218-228.
[http://dx.doi.org/10.1148/radiol.2018180237] [PMID: 30251934] 
[233] 
Pantuck, A.J.; Lee, D.K.; Kee, T.; Wang, P.; Lakhotia, S.; Silverman, M.H.; Mathis, C.; Drakaki, A.; Belldegrun, A.S.; Ho, C.M.; Ho, D. Modulating BET bromodomain inhibitor ZEN-3694 and enzalutamide combination dosing in a metastatic prostate cancer patient using CURATE.AI, an artificial intelligence platform. Adv. Therap.,  2018, 1, 1800104.
[http://dx.doi.org/10.1002/adtp.201800104] 
[234] 
Ngiam, K.Y.; Khor, I.W. Big data and machine learning algorithms for health-care delivery. Lancet Oncol.,  2019, 20(5), e262-e273.
[http://dx.doi.org/10.1016/S1470-2045(19)30149-4] [PMID: 31044724] 
[235] 
Marcos-Zambrano, L.J.; Karaduzovic-Hadziabdic, K.; Loncar Turukalo, T.; Przymus, P.; Trajkovik, V.; Aasmets, O.; Berland, M.; Gruca, A.; Hasic, J.; Hron, K.; Klammsteiner, T.; Kolev, M.; Lahti, L.; Lopes, M.B.; Moreno, V.; Naskinova, I.; Org, E.; Paciência, I.; Papoutsoglou, G.; Shigdel, R.; Stres, B.; Vilne, B.; Yousef, M.; Zdravevski, E.; Tsamardinos, I.; Carrillo de Santa Pau, E.; Claesson, M.J.; Moreno-Indias, I.; Truu, J. Applications of machine learning in human microbiome studies: a review on feature selection, biomarker identification, disease prediction and treatment. Front. Microbiol.,  2021, 12, 634511.
[http://dx.doi.org/10.3389/fmicb.2021.634511] [PMID: 33737920] 
[236] 
Ai, D.; Pan, H.; Han, R.; Li, X.; Liu, G.; Xia, L.C. Using decision tree aggregation with random forest model to identify gut microbes associated with colorectal cancer. Genes (Basel),  2019, 10(2), 112.
[http://dx.doi.org/10.3390/genes10020112] [PMID: 30717284] 
[237] 
Gupta, A.; Dhakan, D.B.; Maji, A.; Saxena, R.; Prasoodanan, P.K.V.; Mahajan, S.; Pulikkan, J.; Kurian, J.; Gomez, A.M.; Scaria, J.; Amato, K.R.; Sharma, A.K.; Sharma, V.K. Association of Flavonifractor plautii, a flavonoid-degrading bacterium, with the gut microbiome of colorectal cancer patients in India. mSystems,  2019, 4(6), e00438-e19.
[http://dx.doi.org/10.1128/mSystems.00438-19] [PMID: 31719139] 
[238] 
Jang, B.S.; Chang, J.H.; Chie, E.K.; Kim, K.; Park, J.W.; Kim, M.J.; Song, E.J.; Nam, Y.D.; Kang, S.W.; Jeong, S.Y.; Kim, H.J. Gut microbiome composition is associated with a pathologic response after preoperative chemoradiation in patients with rectal cancer. Int. J. Radiat. Oncol. Biol. Phys.,  2020, 107(4), 736-746.
[http://dx.doi.org/10.1016/j.ijrobp.2020.04.015] [PMID: 32315676] 
[239] 
Kharrat, N.; Assidi, M.; Abu-Elmagd, M.; Pushparaj, P.N.; Alkhaldy, A.; Arfaoui, L.; Naseer, M.I.; El Omri, A.; Messaoudi, S.; Buhmeida, A.; Rebai, A. Data mining analysis of human gut microbiota links Fusobacterium spp. with colorectal cancer onset. Bioinformation,  2019, 15(6), 372-379.
[http://dx.doi.org/10.6026/97320630015372] [PMID: 31312073] 
[240] 
Zimmermann, M.; Zimmermann-Kogadeeva, M.; Wegmann, R.; Goodman, A.L. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature,  2019, 570(7762), 462-467.
[http://dx.doi.org/10.1038/s41586-019-1291-3] [PMID: 31158845] 
[241] 
Sharma, A.K.; Jaiswal, S.K.; Chaudhary, N.; Sharma, V.K. A novel approach for the prediction of species-specific biotransformation of xenobiotic/drug molecules by the human gut microbiota. Sci. Rep.,  2017, 7(1), 9751.
[http://dx.doi.org/10.1038/s41598-017-10203-6] [PMID: 28852076] 
[242] 
Maier, L.; Pruteanu, M.; Kuhn, M.; Zeller, G.; Telzerow, A.; Anderson, E.E.; Brochado, A.R.; Fernandez, K.C.; Dose, H.; Mori, H.; Patil, K.R.; Bork, P.; Typas, A. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature,  2018, 555(7698), 623-628.
[http://dx.doi.org/10.1038/nature25979] [PMID: 29555994] 
[243] 
Zimmermann, M.; Patil, K.R.; Typas, A.; Maier, L. Towards a mechanistic understanding of reciprocal drug-microbiome interactions. Mol. Syst. Biol.,  2021, 17(3), e10116.
[http://dx.doi.org/10.15252/msb.202010116] [PMID: 33734582] 
Rights & Permissions Print Cite
Article Metrics
66
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867329666220105121754	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Host Microbiomes in Tumor Precision Medicine: How far are we?

Abstract

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Current Medicinal Chemistry

Host Microbiomes in Tumor Precision Medicine: How far are we?

Abstract

Call for Papers in Thematic Issues

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Related Journals

Related Books

Related Articles
