Studio in vitro su inositolo esafosfato e metalloproteasi

L'inositolo esafosfato (IP6), anche detto acido fitico, è una delle isoforme dei fitati, e viene anche comunemente chiamato vitamina B7. Lo ritroviamo anch'esso in alimenti

come i cereali integrali, i legumi, i semi e la frutta a guscio, oltre che in molti di origine animale.

Studi in vitro hanno mostrato gli effetti preventivi di questa molecola nei confronti del cancro, ed in particolare del CRC. Questo, attraverso la sua capacità di inibire l'espressione delle metalloproteasi (MMP), ben riconosciute per la loro attività di distruzione della matrice extracellulare, fenomeno che svolge un ruolo importante nella invasività di un tumore e nella formazione di metastasi [194].

E' risaputo che l'infiammazione cronica è un rischio per la genesi di un tumore e i mediatori infiammatori ne sono gli effettori [195]; tra questi IL-1, IL-6, IL-8, TNF-α, partecipano attivamente alla progressione del tumore [196]. In particolare, IL-1 influenza l'espressione di geni metastatici e angiogenici; in diversi modelli sperimentali e in pazienti con cancro, si è visto come l'aumento locale di IL-1 fosse correlato all'invasività del tumore [197]. Questi mediatori insieme alla crescita del tumore stesso e ad una eventuale formazione di metastasi, sono da ricollegare alla migrazione cellulare e alla digestione proteolitica della ECM, cosa che viene portata a termine in particolar modo dalle MMPs, una famiglia di endopeptidasi zinco-dipendenti [198]. Numerosi studi hanno dimostrato che esiste un legame tra la sovra espressione delle MMPs nei tessuti maligni rispetto a quanto avviene nei tessuti sani adiacenti [199].

Uno studio in vitro in particolare, ha esaminato l'influenza di IP-6 nella trascrizione dei geni per le metalloproteasi in cellule cancerose di colon umano sotto l'influenza della citochina proinfiammatoria IL-1β, misurando i livelli di mRNA dei suddetti geni (Figure

Figure 24, 25 Espressione dei geni per MMP-2, MMP-9, MMP-1, MMP-13 determinati con RT-PCR. Paragone tra il numero di mRNA delle metalloproteasi nelle cellule cancerose trattate con IP6 2,5 mM e IL-1β 1 ng/ml per 6, 12 e 24 ore.

Figure 26, 27 Espressione dei geni per MMP-3, MMP-10, TIMP-1, TIMP-2 determinati con RT-PCR. Paragone tra il numero di mRNA delle metalloproteasi e dei loro inibitori nelle cellule cancerose trattate con IP6 2,5 mM e IL-1β 1 ng/ml per 6, 12 e 24 ore.

Come mostrato nelle figure, si nota che IP6 alla concentrazione di 2,5 mM è in grado di ridurre il numero di alcune MMPs indotte da IL-1β, suggerendo come IP6 possa svolgere un ruolo preventivo nei confronti della crescita tumorale secondo il meccanismo illustrato in Figura 28, che utilizza le vie di segnale MAPK, PKC e PI3/Akt, fino a diminuzione dell'espressione dei geni per la sintesi di MMPs e aumento di quella dei TIMPs, ossia specifici inibitori tissutali delle metalloproteasi stesse [200].

Sembra dunque possibile un effetto positivo di IP6 nel combattere le cellule tumorali, ma sono certamente necessari altri studi specifici in questo campo [201].

CONCLUSIONE

In conclusione è opportuno evidenziare come il cancro del colon retto (CRC) sia una patologia strettamente collegata all'alimentazione.

Tale nesso si può riscontrare essenzialmente in due circostanze.

La prima coinvolge la nutrizione del microbiota intestinale: quando quest’ultimo è nutrito correttamente (ad esempio con un adeguato apporto di carboidrati complessi fermentabili dal medesimo), esso produce molecole utili e favorevoli ad un buono stato di salute intestinale; qualora invece questo non sia nutrito correttamente, si sviluppa nell’intestino un ambiente disbiotico, che favorisce l’insorgenza del cancro del colon retto.

La seconda si riferisce a certi specifici nutrienti (come ad esempio i fitati) che sembrano avere promettenti effetti diretti sulle cellule dell'organismo umano nel prevenire o bloccare l'ulteriore crescita del CRC.

E’ doveroso ricordare che la frequenza con cui vengono pubblicati nuovi studi, che possono confermare o smentire i precedenti, richiede allo studioso aggiornamenti continui.

Infine va rammentato che gli studi esposti permettono di stabilire che la differenza più significativa in nutrizione è la diversificazione degli alimenti nella propria dieta nonché il mantenimento di porzioni adeguate al fabbisogno del singolo e adeguate al tipo di alimento, come del resto espresso nelle tabelle dei LARN del SINU.

La dieta che, ancora una volta, si distingue per le sue caratteristiche positive in merito alla prevenzione di numerose patologie è la Dieta Mediterranea, come espressa nella piramide alimentare in Figura 29.

Figura 29 Piramide Alimentare della Dieta Mediterranea proposta per la popolazione italiana come dieta preventiva nei confronti di CVD, il diabete di tipo II, anche di CRC. “Nutrire il pianeta, nutrirlo in salute. Equilibri nutrizionali di una sana alimentazione”. Quaderni della Salute, 2015.

BIBLIOGRAFIA

[1] Juan José Granados-Romero1, Alan Isaac Valderrama-Treviño2, Ericka Hazzel Contreras-Flores3, Baltazar Barrera-Mera4, Miguel Herrera Enríquez2, Karen Uriarte-Ruíz3, Jesús Carlos Ceballos-Villalva3, Aranza Guadalupe Estrada-Mata3, Cristopher Alvarado Rodríguez3, Gerardo Arauz-Peña3, “Colorectal cancer: a review”, International Journal of Research in Medical Sciences Granados- Romero JJ et al. Int J Res Med Sci. 2017 Nov;5(11):4667-4676

[2] Gastroenterology Rev 2019; 14 (2): 89–103; DOI: https://doi.org/10.5114/pg.2018.81072

[3] Galano R, Rodríguez Z, Casáus A. Cancer de colon: Seguimiento posoperatorio. Revista Cubana de Cirugía. 1997;36(1):59-63 [4] Calva AM, Acevedo Tirado MT. Revisión y actualización general en cancer colorrectal. Revista de Radiología México. 2009;1:99- 115

[5] Mitchel SC. From Colonic Polyps to Colon Cancer: Pathophysiology, Clinical Presentation and Diagnosis. Clin Lab Med. 2005;25:135-77

[6] Kelsen D, Daly J, Kern S, Levin B, Tepper J, Van Cutsem E. Principles and Practice of Gastrointestinal Oncology. 2nd Editon. Lippincott Williams and Wilkins; 2008

[7] DeVita V, Lawrence T, Rosenberg S. Cancer: Principles and practice of Oncol. 9th Editon Lippincott Williams and Wilkins; 2011 [8] Siegel RL, Ward EM, Jemal A. Trends in colorectal cancer incidence rates in the United States by tumor location and stage, 1992- 2008. Cancer Epidemiol Biomarkers Prev. 2012;21:411-6

[9] Juárez-Vázquez C, Rosales-Reynoso M. Cancer colorrectal (CCR): alteraciones genéticas y moleculares. Gaceta Médica de México. 2014;150:154-64

[10] Oliveira C, Velho S, Moutinho C, Ferreira A, Preto A, Domingo E, et al. KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene. 2007;26(1):158-63

[11] Yang YH, Lim SB, Kim MJ, Chung HJ, Yoo HW, Byeon JS, et al. Three novel mutations of the APC gene in Korean patients with familial adenomatous polyposis. Cancer Genet Cytogenet. 2010; 200(1):34-9

[12] MacDonald B, Tamai K, He X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9-26 [13] Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, Rowan A, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007;39:1315

[14] Nissar S, Sameer AS, Rasool R, Chowdri NA, Rashid F. Polymorphism of the DNA Repair Gene XRCC1 (Arg194Trp) and its role in Colorectal Cancer in Kashmiri Population: a Case Control Study. Asian Pac J Cancer Prev. 2015;16(15):6385-90

[15] Moya P, Esteban S, Fernandez-Suarez A, Maestro M, Morente M, Sánchez-Carbayo M. KiSS-1 methylation and protein expression patterns contribute to diagnostic and prognostic assessments in tissue specimens for colorectal cancer. Tumour Biol. 2013;34(1):471-9

[16] Gala M, Chung DC. Hereditary colon cancer syndromes. Seminars in Oncology. 2011;38:490-9

[17] Zhang K, Civan J, Mukherjee S, Patel F, Yang H. Genetic variations in colorectal cancer risk and clinical outcome. World J Gastroenterol. 2014;20 (15):4167-77

[18] Li H, Zhu F, Boardman LA, Wang L, Oi N, Lui K, et al. Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression. EBioMedicine. 2005;2(5):447-55

[19] Sánchez AR, Martín FM, Palma MS, López PB, Bermejo LM, Gómez CC. Fiber-type indication among different pathologies. Nutr Hosp. 2015; 31(6):237-83

[20] National Comprehensive Cancer Network Guidelines (NCCN Guidelines). Colorectal Cancer Screening. Washington: NCCN Guidelines; 2014

[21] Ballian N, Liu SH, Brunicardi FC. Transcription factor PDX-1 in human colorectal adenocarcinoma: A potential tumor marker? World J Gastroenterol. 2008;14:5823-6

[22] Cheng-jin Z, Shuang-kuan D, Xing-bo D, Min G. Expression of Paxillin is Correlated with Clinical Prognosis in Colorectal Cancer Patients. Med Sci Monit. 2015;21:1989-95

[23] Song L, Li Y. SEPT9: A Specific Circulating Biomarker for Colorectal Cancer. Adv Clin Chem. 2015;72:171-204

[24] Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer Treatment and Survivorship Statistics, 2016. Ca Cancer J Clin. 2016;66:271-89

[25] Gori Stefania, I numeri del cancro in Italia 2019, Intermedia Editore ( https://www.aiom.it/wp- content/uploads/2019/09/2019_Numeri_Cancro-operatori-web.pdf )

[26] Zhu C, Takasu C, Morine Y, Bando Y, Ikemoto T, Saito Y, et al. KISS1 Associates with Better Outcome via Inhibiting Matrix Metalloproteinase-9 in Colorectal Liver Metastasis. Ann Surg Oncol. 2015;22(3):1516-23

[27] Leenders M, Siersma PD, Overvad K, Tjonneland A, Oslen A, Boutron-Ruault MC, et al. Subtypes of fruit and vegetables, variety in consumption and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2015;1;137(11):2705-14

[28] Chao MW, Wang LT, Lai CY, Yang XM, Cheng YW, Lee KH, et al. eIF4E binding protein 1 expression is associated with clinical survival outcomes in colorectal cancer. Oncotarget. 2015; 15;6(27):24092-104

[29] Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244:254-9

[30] Arribas-Martin A, Díaz-Pizarro-Graf JI, Muñoz-Hinojosa JD, Valdés-Castañeda A, Cruz-Ramírez O, Bertrand MM. Laparoscopic versus open surgery for colorectal cancer. A comparative study. Cir Cir. 2014;82(3):274-81

[31] Herbert H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N Engl J Med. 2004; 2335-42

[32] Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-76

[33] Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841-4

[34] Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145-7

[35] Kabbinavar F, Hurwitz H, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60-5

[36] Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorrectal cancer. Cancer Res. 2006;66(8):3992-5

[37] Knijn N, Mekenkamp LJ, Klomp M, Vink-Börger ME, Teerenstra S, Meijer JW, et al. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer. 2011; 104(6):1020-6

[38] Johan Gagnière, Jennifer Raisch, Julie Veziant, Nicolas Barnich, Richard Bonnet, Emmanuel Buc,

Marie-Agnès Bringer, Denis Pezet, Mathilde Bonnet, Gut microbiota imbalance and colorectal cancer, World J Gastroenterol 2016 January 14; 22(2): 501-518

[39] Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology 2009; 136: 65-80

[40] Dominguez-Bello MG, Blaser MJ, Ley RE, Knight R. Development of the human gastrointestinal microbiota and insights from highthroughput sequencing. Gastroenterology 2011; 140: 1713-1719

[41] Stanghellini V, Barbara G, Cremon C, Cogliandro R, Antonucci A, Gabusi V, Frisoni C, De Giorgio R, Grasso V, Serra M, Corinaldesi R. Gut microbiota and related diseases: clinical features. Intern Emerg

Med 2010; 5 Suppl 1: S57-S63

[42] Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, Stanton C, van Sinderen D, O’Connor M, Harnedy N, O’Connor K, Henry C, O’Mahony D, Fitzgerald AP, Shanahan F, Twomey C, Hill C, Ross RP, O’Toole PW. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA 2011; 108 Suppl 1: 4586-4591

[43] Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010; 90: 859-904

[44] Chen W, Liu F, Ling Z, Tong X, Xiang C. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS One 2012; 7: e39743

[45] Arthur JC, Jobin C. The struggle within: microbial influences on colorectal cancer. Inflamm Bowel Dis 2011; 17: 396-409 [46] Hopkins MJ, Sharp R, Macfarlane GT. Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut 2001; 48: 198-205

[47] Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 2008; 3: 417-427

[48] Mariat, D., Firmesse, O., Levenez, F. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 9, 123 (2009) doi:10.1186/1471-2180-9-123

[49] Boleij A, Tjalsma H. Gut bacteria in health and disease: a survey on the interface between intestinal microbiology and colorectal cancer.

Biol Rev Camb Philos Soc 2012; 87: 701-730

[50] Xu J, Gordon JI. Honor thy symbionts. Proc Natl Acad Sci USA 2003; 100: 10452-10459

[51] Shanahan F. The host-microbe interface within the gut. Best Pract Res Clin Gastroenterol 2002; 16: 915-931

[52] Laparra JM, Sanz Y. Interactions of gut microbiota with functional food components and nutraceuticals. Pharmacol Res 2010; 61: 219-225

[53] Stecher B, Hardt WD. The role of microbiota in infectious disease. Trends Microbiol 2008; 16: 107-114 [54] Alexander DD, Cushing CA, Lowe KA, Sceurman B, Roberts MA. Meta-analysis of animal fat or animal protein intake and colorectal cancer. Am J Clin Nutr 2009; 89: 1402-1409

[55] Knudson A. Alfred Knudson and his two-hit hypothesis. (Interview by Ezzie Hutchinson). Lancet Oncol 2001; 2: 642-645 [56] Collins D, Hogan AM, Winter DC. Microbial and viral pathogens in colorectal cancer. Lancet Oncol 2011; 12: 504-512 [57] Proctor LM. The Human Microbiome Project in 2011 and beyond. Cell Host Microbe 2011; 10: 287-291

[58] Li Y, Kundu P, Seow SW, de Matos CT, Aronsson L, Chin KC, Kärre K, Pettersson S, Greicius G. Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice. Carcinogenesis 2012; 33: 1231-1238

[59] Sears CL, Garrett WS. Microbes, microbiota, and colon cancer. Cell Host Microbe 2014; 15: 317-328

[60] Couturier-Maillard A, Secher T, Rehman A, Normand S, De Arcangelis A, Haesler R, Huot L, Grandjean T, Bressenot A, Delanoye-Crespin A, Gaillot O, Schreiber S, Lemoine Y, Ryffel B, Hot D, Nùñez G, Chen G, Rosenstiel P, Chamaillard M. NOD2- mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest 2013; 123: 700-711

[61] Hu B, Elinav E, Huber S, Strowig T, Hao L, Hafemann A, Jin C, Wunderlich C, Wunderlich T, Eisenbarth SC, Flavell RA. Microbiota- induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc Natl Acad Sci USA 2013; 110: 9862-9867

[62] Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer 2013; 13: 800-812

[63] Hajishengallis G, Darveau RP, Curtis MA. The keystone-pathogen hypothesis. Nat Rev Microbiol 2012; 10: 717-725

[64] Ahn J, Sinha R, Pei Z, Dominianni C, Wu J, Shi J, Goedert JJ, Hayes RB, Yang L. Human gut microbiome and risk for colorectal cancer. J Natl Cancer Inst 2013; 105: 1907-1911

[65] Wu N, Yang X, Zhang R, Li J, Xiao X, Hu Y, Chen Y, Yang F, Lu N, Wang Z, Luan C, Liu Y, Wang B, Xiang C, Wang Y, Zhao F, Gao GF, Wang S, Li L, Zhang H, Zhu B. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol 2013; 66: 462-470 [66] Wang T, Cai G, Qiu Y, Fei N, Zhang M, Pang X, Jia W, Cai S, Zhao L. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J 2012; 6: 320-329

[67] Jones M, Helliwell P, Pritchard C, Tharakan J, Mathew J. Helicobacter pylori in colorectal neoplasms: is there an aetiological relationship? World J Surg Oncol 2007; 5: 51

[68] Mirza NN, McCloud JM, Cheetham MJ. Clostridium septicum sepsis and colorectal cancer - a reminder. World J Surg Oncol 2009; 7:

73

[69] McCoy AN, Araújo-Pérez F, Azcárate-Peril A, Yeh JJ, Sandler RS, Keku TO. Fusobacterium is associated with colorectal adenomas. PLoS One 2013; 8: e53653

[70] Arthur JC, Perez-Chanona E, Mühlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB, Rhodes JM, Stintzi A, Simpson KW, Hansen JJ, Keku TO, Fodor AA, Jobin C. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 2012; 338: 120-123

[71] Le Gall T, Clermont O, Gouriou S, Picard B, Nassif X, Denamur E, Tenaillon O. Extraintestinal virulence is a coincidental byproduct

of commensalism in B2 phylogenetic group Escherichia coli strains. Mol Biol Evol 2007; 24: 2373-2384

[72] Han YW, Ikegami A, Rajanna C, Kawsar HI, Zhou Y, Li M, Sojar HT, Genco RJ, Kuramitsu HK, Deng CX. Identification and characterization of a novel adhesin unique to oral fusobacteria. J Bacteriol 2005; 187: 5330-5340

[73] Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 2013; 14: 195-206

[74] Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, Higashi H, Musashi M, Iwabuchi K, Suzuki M, Yamada G, Azuma T, Hatakeyama M. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci USA 2008; 105: 1003-1008

[75] Goodwin AC, Destefano Shields CE, Wu S, Huso DL, Wu X, Murray-Stewart TR, Hacker-Prietz A, Rabizadeh S, Woster PM, Sears CL, Casero RA. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci USA 2011; 108: 15354-15359

[76] Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009; 15: 1016-1022

[77] Cuevas-Ramos G, Petit CR, Marcq I, Boury M, Oswald E, Nougayrède JP. Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc Natl Acad Sci USA 2010; 107: 11537-11542

[78] Smith JL, Bayles DO. The contribution of cytolethal distending toxin to bacterial pathogenesis. Crit Rev Microbiol 2006; 32: 227- 248

[79] Nesić D, Hsu Y, Stebbins CE. Assembly and function of a bacterial genotoxin. Nature 2004; 429: 429-433

[80] Garrett WS, Gallini CA, Yatsunenko T, Michaud M, DuBois A, Delaney ML, Punit S, Karlsson M, Bry L, Glickman JN, Gordon JI, Onderdonk AB, Glimcher LH. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe 2010; 8: 292-300

[81] Dutilh BE, Backus L, van Hijum SA, Tjalsma H. Screening metatranscriptomes for toxin genes as functional drivers of human colorectal cancer. Best Pract Res Clin Gastroenterol 2013; 27: 85-99

[82] Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 2014; 12: 661-672

[83] Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer 2013; 13: 800-812

[84] Barrasa JI, Olmo N, Lizarbe MA, Turnay J. Bile acids in the colon, from healthy to cytotoxic molecules. Toxicol In Vitro 2013; 27: 964-977

[85] Yoshimoto S, Loo TM, 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: 97-101

[86] Kim DH, Jin YH. Intestinal bacterial beta-glucuronidase activity of patients with colon cancer. Arch Pharm Res 2001; 24: 564-567 [87] Nyangale EP, Mottram DS, Gibson GR. Gut microbial activity, implications for health and disease: the potential role of metabolite analysis. J Proteome Res 2012; 11: 5573-5585

[88] Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, Anderson SE, Flint HJ. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res 2013; 57: 523-535

[89] Attene-Ramos MS, Nava GM, Muellner MG, Wagner ED, Plewa MJ, Gaskins HR. DNA damage and toxicogenomic analyses of hydrogen sulfide in human intestinal epithelial FHs 74 Int cells. Environ Mol Mutagen 2010; 51: 304-314

[90] Homann N, Tillonen J, Salaspuro M. Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency. Int J Cancer 2000; 86: 169-173

[91] Cario E. Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut 2005; 54: 1182-1193 [92] Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5: 749-759

[93] Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol 2012; 9: 599-608 [94] Raisch J, Rolhion N, Dubois A, Darfeuille-Michaud A, Bringer MA. Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression. Lab Invest 2015; 95: 296-307

[95] Irrazábal T, Belcheva A, Girardin SE, Martin A, Philpott DJ. The multifaceted role of the intestinal microbiota in colon cancer. Mol Cell 2014; 54: 309-320

[96] Huycke MM, Moore DR. In vivo production of hydroxyl radical by Enterococcus faecalis colonizing the intestinal tract using aromatic hydroxylation. Free Radic Biol Med 2002; 33: 818-826

[97] Evans MD, Dizdaroglu M, Cooke MS. Oxidative DNA damage and disease: induction, repair and significance. Mutat Res 2004; 567: 1-61

[98] Lundberg JO, Weitzberg E, Cole JA, Benjamin N. Nitrate, bacteria and human health. Nat Rev Microbiol 2004; 2: 593-602 [99] Sobko T, Huang L, Midtvedt T, Norin E, Gustafsson LE, Norman M, Jansson EA, Lundberg JO. Generation of NO by probiotic bacteria in the gastrointestinal tract. Free Radic Biol Med 2006; 41: 985-991

[100] Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol 2010; 38: 96- 109

[101] Peltomäki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 2003; 21: 1174-1179 [102] Mangerich A, Knutson CG, Parry NM, Muthupalani S, Ye W, Prestwich E, Cui L, McFaline JL, Mobley M, Ge Z, Taghizadeh K, Wishnok JS, Wogan GN, Fox JG, Tannenbaum SR, Dedon PC. Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer. Proc Natl Acad Sci USA 2012; 109: E1820-E1829

[103] Maddocks OD, Scanlon KM, Donnenberg MS. An Escherichia coli effector protein promotes host mutation via depletion of DNA mismatch repair proteins. MBio 2013; 4: e00152-e00113

[104] Belcheva A, Irrazabal T, Robertson SJ, Streutker C, Maughan H, Rubino S, Moriyama EH, Copeland JK, Kumar S, Green B, Geddes K, Pezo RC, Navarre WW, Milosevic M, Wilson BC, Girardin SE, Wolever TM, Edelmann W, Guttman DS, Philpott DJ, Martin A. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 2014; 158: 288-299

[105] Khazaie K, Zadeh M, Khan MW, Bere P, Gounari F, Dennis K, Blatner NR, Owen JL, Klaenhammer TR, Mohamadzadeh M. Abating colon cancer polyposis by Lactobacillus acidophilus deficient in lipoteichoic acid. Proc Natl Acad Sci USA 2012; 109: 10462-10467 [106] Lightfoot YL, Yang T, Sahay B, Mohamadzadeh M. Targeting aberrant colon cancer-specific DNA methylation with lipoteichoic acid-deficient Lactobacillus acidophilus. Gut Microbes 2013; 4: 84-88

[107] Ghadimi D, Helwig U, Schrezenmeir J, Heller KJ, de Vrese M. Epigenetic imprinting by commensal probiotics inhibits the IL-23/ IL-17 axis in an in vitro model of the intestinal mucosal immune system. J Leukoc Biol 2012; 92: 895-911

[108] Viljoen KS, Dakshinamurthy A, Goldberg P, Blackburn JM. Quantitative profiling of colorectal cancer-associated bacteria reveals associations between fusobacterium spp., enterotoxigenic Bacteroides fragilis (ETBF) and clinicopathological features of colorectal