{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T19:53:24Z","timestamp":1794513204348,"version":"4.9.1"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,10,2]],"date-time":"2017-10-02T00:00:00Z","timestamp":1506902400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,10,2]],"date-time":"2017-10-02T00:00:00Z","timestamp":1506902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Studies showed that manipulation of gut microbiota (GM) composition through the treatment of prebiotics could be a novel preventive measure against colorectal cancer (CRC) development. In this study, for the first time, we assessed the non-toxic doses of the triterpene saponins (ginsenoside-Rb3 and ginsenoside-Rd) \u2013 as prebiotics \u2013 that effectively reinstated the dysbiotic-gut microbial composition and intestinal microenvironment in an Apc<jats:sup>Min\/+<\/jats:sup> mice model. Rb3 and Rd effectively reduced the size and the number of the polyps that accompanied with the downregulation of oncogenic signaling molecules (iNOS, STAT3\/pSTAT3, Src\/pSrc). Both the compounds improved the gut epithelium by promoting goblet and Paneth cells population and reinstating the E-cadherin and N-Cadherin expression. Mucosal immunity remodeled with increased in anti-inflammatory cytokines and reduced in pro-inflammatory cytokines in treated mice. All these changes were correlating with the promoted growth of beneficial bacteria such as <jats:italic>Bifidobacterium<\/jats:italic> spp., <jats:italic>Lactobacillus<\/jats:italic> spp., <jats:italic>Bacteroides acidifaciens<\/jats:italic>, and <jats:italic>Bacteroides xylanisolvens<\/jats:italic>. Whereas, the abundance of cancer cachexia associated bacteria, such as <jats:italic>Dysgonomonas<\/jats:italic> spp. and <jats:italic>Helicobacter<\/jats:italic> spp., was profoundly lower in Rb3\/Rd-treated\u00a0mice. In conclusion, ginsenosides Rb3 and Rd exerted anti-cancer effects by holistically reinstating mucosal architecture, improving mucosal immunity, promoting beneficial bacteria, and down-regulating cancer-cachexia associated bacteria.<\/jats:p>","DOI":"10.1038\/s41598-017-12644-5","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T14:37:16Z","timestamp":1506436636000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Ginsenosides Rb3 and Rd reduce polyps formation while reinstate the dysbiotic gut microbiota and the intestinal microenvironment in ApcMin\/+ mice"],"prefix":"10.1038","volume":"7","author":[{"given":"Guoxin","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imran","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waikit","family":"Leong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leung Tsun","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. L. Wendy","family":"Hsiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,2]]},"reference":[{"key":"12644_CR1","unstructured":"National Cancer Institute: Surveillance, Epidemiology, and E. R. P. Cancer Stat Facts: Colon and Rectum Cancer. Available at: https:\/\/seer.cancer.gov\/statfacts\/html\/colorect.html. (Accessed: 29thAugust2017)."},{"key":"12644_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/srep29353","volume":"6","author":"D Saita","year":"2016","unstructured":"Saita, D. et al. Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation. Sci. Rep. \n                           6, 29353 (2016).","journal-title":"Sci. Rep."},{"key":"12644_CR3","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jnutbio.2016.09.016","volume":"39","author":"M Niku","year":"2017","unstructured":"Niku, M. et al. Western diet enhances intestinal tumorigenesis in Min\/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity. J. Nutr. Biochem. \n                           39, 126\u2013133 (2017).","journal-title":"J. Nutr. Biochem."},{"key":"12644_CR4","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.3945\/ajcn.112.046607","volume":"97","author":"H-M Chen","year":"2013","unstructured":"Chen, H.-M. et al. Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma. Am. J. Clin. Nutr. \n                           97, 1044\u20131052 (2013).","journal-title":"Am. J. Clin. Nutr."},{"key":"12644_CR5","doi-asserted-by":"publisher","first-page":"11070","DOI":"10.1073\/pnas.0504978102","volume":"102","author":"RE Ley","year":"2005","unstructured":"Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. USA \n                           102, 11070\u20135 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"12644_CR6","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nature12480","volume":"500","author":"A Cotillard","year":"2013","unstructured":"Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature \n                           500, 585\u2013588 (2013).","journal-title":"Nature"},{"key":"12644_CR7","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1146\/annurev-micro-102215-095513","volume":"70","author":"CA Brennan","year":"2016","unstructured":"Brennan, C. A. & Garrett, W. S. Gut Microbiota, Inflammation, and Colorectal Cancer. Annu. Rev. Microbiol. \n                           70, 395\u2013411 (2016).","journal-title":"Annu. Rev. Microbiol."},{"key":"12644_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7528","volume":"6","author":"Q Feng","year":"2015","unstructured":"Feng, Q. et al. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat. Commun. \n                           6, 6528 (2015).","journal-title":"Nat. Commun."},{"key":"12644_CR9","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1007\/s00248-013-0245-9","volume":"66","author":"N Wu","year":"2013","unstructured":"Wu, N. et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb. Ecol. \n                           66, 462\u2013470 (2013).","journal-title":"Microb. Ecol."},{"key":"12644_CR10","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20145645","volume":"10","author":"G Zeller","year":"2014","unstructured":"Zeller, G. et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol. Syst. Biol. \n                           10, 766 (2014).","journal-title":"Mol. Syst. Biol."},{"key":"12644_CR11","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s00535-014-0963-x","volume":"50","author":"L Mira-Pascual","year":"2015","unstructured":"Mira-Pascual, L. et al. Microbial mucosal colonic shifts associated with the development of colorectal cancer reveal the presence of different bacterial and archaeal biomarkers. J. Gastroenterol. \n                           50, 167\u2013179 (2015).","journal-title":"J. Gastroenterol."},{"key":"12644_CR12","doi-asserted-by":"publisher","first-page":"501","DOI":"10.3748\/wjg.v22.i2.501","volume":"22","author":"J Gagni\u00e8re","year":"2016","unstructured":"Gagni\u00e8re, J. et al. Gut microbiota imbalance and colorectal cancer. World J. Gastroenterol. \n                           22, 501\u2013518 (2016).","journal-title":"World J. Gastroenterol."},{"key":"12644_CR13","doi-asserted-by":"publisher","first-page":"6728","DOI":"10.1021\/jf204230r","volume":"60","author":"RS Macdonald","year":"2012","unstructured":"Macdonald, R. S. & Wagner, K. Influence of dietary phytochemicals and microbiota on colon cancer risk. J. Agric. Food Chem. \n                           60, 6728\u20136735 (2012).","journal-title":"J. Agric. Food Chem."},{"key":"12644_CR14","doi-asserted-by":"publisher","first-page":"8249","DOI":"10.1021\/jf301903t","volume":"60","author":"P Rupa","year":"2012","unstructured":"Rupa, P. & Mine, Y. Recent advances in the role of probiotics in human inflammation and gut health. J. Agric. Food Chem. \n                           60, 8249\u20138256 (2012).","journal-title":"J. Agric. Food Chem."},{"key":"12644_CR15","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1021\/jf803638d","volume":"57","author":"M Larrosa","year":"2009","unstructured":"Larrosa, M. et al. Effect of a low dose of dietary resveratrol on colon microbiota, inflammation and tissue damage in a DSS-induced colitis rat model. J. Agric. Food Chem. \n                           57, 2211\u20132220 (2009).","journal-title":"J. Agric. Food Chem."},{"key":"12644_CR16","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1093\/carcin\/bgr022","volume":"32","author":"NJ Kang","year":"2011","unstructured":"Kang, N. J. et al. Coffee phenolic phytochemicals suppress colon cancer metastasis by targeting MEK and TOPK. Carcinogenesis \n                           32, 921\u2013928 (2011).","journal-title":"Carcinogenesis"},{"key":"12644_CR17","doi-asserted-by":"crossref","first-page":"2580S","DOI":"10.1093\/jn\/137.11.2580S","volume":"137","author":"BL Pool-Zobel","year":"2007","unstructured":"Pool-Zobel, B. L. & Sauer, J. Overview of experimental data on reduction of colorectal cancer risk by inulin-type fructans. J. Nutr. \n                           137, 2580S\u20132584S (2007).","journal-title":"J. Nutr."},{"key":"12644_CR18","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.bpg.2016.02.009","volume":"30","author":"P Ambalam","year":"2016","unstructured":"Ambalam, P., Raman, M., Purama, R. K. & Doble, M. Probiotics, prebiotics and colorectal cancer prevention. Best Pract. Res. Clin. Gastroenterol. \n                           30, 119\u2013131 (2016).","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"12644_CR19","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.trecan.2016.08.001","volume":"2","author":"DVF Tauriello","year":"2017","unstructured":"Tauriello, D. V. F. & Batlle, E. Targeting the Microenvironment in Advanced Colorectal Cancer. Trends in Cancer \n                           2, 495\u2013504 (2017).","journal-title":"Trends in Cancer"},{"key":"12644_CR20","unstructured":"Compare, D. & Nardone, G. The bacteria-hypothesis of colorectal cancer: pathogenetic and therapeutic implications. Transl. Gastrointest. Cancer; Vol 3, No 1 (January 2014) Transl. Gastrointest. Cancer (2013)."},{"key":"12644_CR21","doi-asserted-by":"publisher","first-page":"31226","DOI":"10.18632\/oncotarget.8886","volume":"7","author":"L Chen","year":"2016","unstructured":"Chen, L., Brar, M. S., Leung, F. C. C. & Hsiao, W. L. W. Triterpenoid herbal saponins enhance beneficial bacteria, decrease sulfate-reducing bacteria, modulate inflammatory intestinal microenvironment and exert cancer preventive effects in ApcMin\/+ mice. Oncotarget \n                           7, 31226\u201331242 (2016).","journal-title":"Oncotarget"},{"key":"12644_CR22","doi-asserted-by":"crossref","unstructured":"Chen, L. et al. Tumor grafting induces changes of gut microbiota in athymic nude mice in the presence and absence of medicinal Gynostemma saponins. PLoS One \n                           10 (2015).","DOI":"10.1371\/journal.pone.0126807"},{"key":"12644_CR23","doi-asserted-by":"publisher","first-page":"8969","DOI":"10.1073\/pnas.91.19.8969","volume":"91","author":"R Fodde","year":"1994","unstructured":"Fodde, R. et al. A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc. Natl. Acad. Sci. USA \n                           91, 8969\u20138973 (1994).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"12644_CR24","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1189\/jlb.0412214","volume":"92","author":"IG Luzina","year":"2012","unstructured":"Luzina, I. G. et al. Regulation of inflammation by interleukin-4: a review of \u2018alternatives\u2019. J. Leukoc. Biol. \n                           92, 753\u2013764 (2012).","journal-title":"J. Leukoc. Biol."},{"key":"12644_CR25","doi-asserted-by":"publisher","first-page":"5819","DOI":"10.1074\/jbc.M111.295964","volume":"287","author":"H Xiong","year":"2012","unstructured":"Xiong, H. et al. Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J. Biol. Chem. \n                           287, 5819\u20135832 (2012).","journal-title":"J. Biol. Chem."},{"key":"12644_CR26","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1038\/ni.3233","volume":"16","author":"Q Zhang","year":"2015","unstructured":"Zhang, Q. et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat. Immunol. \n                           16, 918\u2013926 (2015).","journal-title":"Nat. Immunol."},{"key":"12644_CR27","doi-asserted-by":"publisher","first-page":"6338","DOI":"10.1158\/0008-5472.CAN-12-3544","volume":"72","author":"MA Hallett","year":"2012","unstructured":"Hallett, M. A., Venmar, K. T. & Fingleton, B. Cytokine stimulation of epithelial cancer cells: the similar and divergent functions of IL4 and IL13. Cancer Res. \n                           72, 6338\u20136343 (2012).","journal-title":"Cancer Res."},{"key":"12644_CR28","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1189\/jlb.1012512","volume":"93","author":"ML Novak","year":"2013","unstructured":"Novak, M. L. & Koh, T. J. Macrophage phenotypes during tissue repair. J. Leukoc. Biol. \n                           93, 875\u2013881 (2013).","journal-title":"J. Leukoc. Biol."},{"key":"12644_CR29","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1172\/JCI59643","volume":"122","author":"A Sica","year":"2012","unstructured":"Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. \n                           122, 787\u2013795 (2012).","journal-title":"J. Clin. Invest."},{"key":"12644_CR30","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nrgastro.2012.14","volume":"9","author":"I Mukhopadhya","year":"2012","unstructured":"Mukhopadhya, I., Hansen, R., El-Omar, E. M. & Hold, G. L. IBD-what role do Proteobacteria play? Nat. Rev. Gastroenterol. Hepatol. \n                           9, 219\u2013230 (2012).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"12644_CR31","doi-asserted-by":"publisher","first-page":"2748","DOI":"10.1128\/JB.00276-12","volume":"194","author":"D-S Kim","year":"2012","unstructured":"Kim, D.-S. et al. Genome sequence of Myroides injenensis M09-0166(T), isolated from clinical specimens. J. Bacteriol. \n                           194, 2748\u20132749 (2012).","journal-title":"J. Bacteriol."},{"key":"12644_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/srep04985","volume":"4","author":"X Liang","year":"2014","unstructured":"Liang, X., Li, H., Tian, G. & Li, S. Dynamic microbe and molecule networks in a mouse model of colitis-associated colorectal cancer. Sci. Rep. \n                           4, 4985 (2014).","journal-title":"Sci. Rep."},{"key":"12644_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1574-695X.2010.00744.x","volume":"61","author":"R Hansen","year":"2011","unstructured":"Hansen, R. et al. Could Helicobacter organisms cause inflammatory bowel disease? FEMS Immunol. Med. Microbiol. \n                           61, 1\u201314 (2011).","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"12644_CR34","doi-asserted-by":"publisher","first-page":"179","DOI":"10.7705\/biomedica.v32i2.652","volume":"32","author":"AF Henao-Martinez","year":"2012","unstructured":"Henao-Martinez, A. F., Gonzalez-Fontal, G. R. & Johnson, S. A case of community-acquired Acinetobacter junii-johnsonii cellulitis. Biomedica \n                           32, 179\u2013181 (2012).","journal-title":"Biomedica"},{"key":"12644_CR35","doi-asserted-by":"publisher","first-page":"103","DOI":"10.18388\/abp.2014_845","volume":"62","author":"IV Kushkevych","year":"2015","unstructured":"Kushkevych, I. V. Activity and kinetic properties of phosphotransacetylase from intestinal sulfate-reducing bacteria. Acta Biochim. Pol. \n                           62, 103\u2013108 (2015).","journal-title":"Acta Biochim. Pol."},{"key":"12644_CR36","doi-asserted-by":"publisher","first-page":"213 LP","DOI":"10.1111\/j.1574-6941.2009.00709.x","volume":"69","author":"PD Scanlan","year":"2009","unstructured":"Scanlan, P. D., Shanahan, F. & Marchesi, J. R. Culture-independent analysis of desulfovibrios in the human distal colon of healthy, colorectal cancer and polypectomized individuals. FEMS Microbiol. Ecol. \n                           69, 213 LP\u2013221 (2009).","journal-title":"FEMS Microbiol. Ecol."},{"key":"12644_CR37","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.anaerobe.2016.02.003","volume":"39","author":"M Li","year":"2016","unstructured":"Li, M. et al. In vitro fermentation of alginate and its derivatives by human gut microbiota. Anaerobe \n                           39, 19\u201325 (2016).","journal-title":"Anaerobe"},{"key":"12644_CR38","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1159\/000441768","volume":"93","author":"K Takahashi","year":"2016","unstructured":"Takahashi, K. et al. Reduced Abundance of Butyrate-Producing Bacteria Species in the Fecal Microbial Community in Crohn\u2019s Disease. Digestion \n                           93, 59\u201365 (2016).","journal-title":"Digestion"},{"key":"12644_CR39","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.3109\/0284186X.2015.1054949","volume":"54","author":"RM Manzat-Saplacan","year":"2015","unstructured":"Manzat-Saplacan, R. M. et al. Can we change our microbiome to prevent colorectal cancer development? Acta Oncol. \n                           54, 1085\u20131095 (2015).","journal-title":"Acta Oncol."},{"key":"12644_CR40","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/j.jfma.2016.06.004","volume":"115","author":"C-H Chen","year":"2016","unstructured":"Chen, C.-H., Wu, S.-S. & Hsiu, R.-H. Dysgonomonas capnocytophagoides bacteremia due to liver abscesses after radiofrequency ablation in a patient with hepatocellular carcinoma. J. Formos. Med. Assoc. \n                           115, 889\u2013890 (2016).","journal-title":"J. Formos. Med. Assoc."},{"key":"12644_CR41","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1016\/j.arcmed.2006.05.002","volume":"37","author":"T Matsumoto","year":"2006","unstructured":"Matsumoto, T. et al. First isolation of Dysgonomonas mossii from intestinal juice of a patient with pancreatic cancer. Arch. Med. Res. \n                           37, 914\u2013916 (2006).","journal-title":"Arch. Med. Res."},{"key":"12644_CR42","doi-asserted-by":"publisher","first-page":"37","DOI":"10.7314\/APJCP.2016.17.1.37","volume":"17","author":"SJ Kaewpitoon","year":"2016","unstructured":"Kaewpitoon, S. J. et al. Helicobacter Species are Possible Risk Factors of Cholangiocarcinoma. Asian Pac. J. Cancer Prev. \n                           17, 37\u201344 (2016).","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"12644_CR43","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.fitote.2010.06.004","volume":"81","author":"S Man","year":"2010","unstructured":"Man, S. et al. Chemical study and medical application of saponins as anti-cancer agents. Fitoterapia \n                           81, 703\u2013714 (2010).","journal-title":"Fitoterapia"},{"key":"12644_CR44","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1158\/1940-6207.CAPR-13-0345","volume":"7","author":"NB Janakiram","year":"2014","unstructured":"Janakiram, N. B. et al. Raloxifene and antiestrogenic gonadorelin inhibits intestinal tumorigenesis by modulating immune cells and decreasing stem-like cells. Cancer Prev. Res. (Phila). \n                           7, 300\u2013309 (2014).","journal-title":"Cancer Prev. Res. (Phila)."},{"key":"12644_CR45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0014325","volume":"5","author":"MR Schneider","year":"2010","unstructured":"Schneider, M. R. et al. A key role for E-cadherin in intestinal homeostasis and Paneth cell maturation. PLoS One \n                           5, e14325 (2010).","journal-title":"PLoS One"},{"key":"12644_CR46","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1089\/jir.2014.0132","volume":"35","author":"L Wang","year":"2015","unstructured":"Wang, L. et al. Deficiency of interferon-gamma or its receptor promotes colorectal cancer development. J. Interferon Cytokine Res. \n                           35, 273\u2013280 (2015).","journal-title":"J. Interferon Cytokine Res."},{"key":"12644_CR47","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1111\/j.1745-7254.2008.00889.x","volume":"29","author":"X Wang","year":"2008","unstructured":"Wang, X. & Lin, Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol. Sin. \n                           29, 1275\u20131288 (2008).","journal-title":"Acta Pharmacol. Sin."},{"key":"12644_CR48","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1002\/jcp.24125","volume":"228","author":"T Triulzi","year":"2013","unstructured":"Triulzi, T., Tagliabue, E., Balsari, A. & Casalini, P. FOXP3 expression in tumor cells and implications for cancer progression. J. Cell. Physiol. \n                           228, 30\u201335 (2013).","journal-title":"J. Cell. Physiol."},{"key":"12644_CR49","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/nm.4086","volume":"22","author":"T Saito","year":"2016","unstructured":"Saito, T. et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat. Med \n                           22, 679\u2013684 (2016).","journal-title":"Nat. Med"},{"key":"12644_CR50","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1038\/nm.3895","volume":"21","author":"MWL Teng","year":"2015","unstructured":"Teng, M. W. L. et al. IL-12 and IL-23cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. \n                           21, 719\u2013729 (2015).","journal-title":"Nat. Med."},{"key":"12644_CR51","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/ni.3153","volume":"16","author":"CA Hunter","year":"2015","unstructured":"Hunter, C. A. & Jones, S. A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. \n                           16, 448\u2013457 (2015).","journal-title":"Nat. Immunol."},{"key":"12644_CR52","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.tibtech.2015.06.011","volume":"33","author":"N-R Shin","year":"2015","unstructured":"Shin, N.-R., Whon, T. W. & Bae, J.-W. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. \n                           33, 496\u2013503 (2015).","journal-title":"Trends Biotechnol."},{"key":"12644_CR53","first-page":"1190","volume":"12","author":"Z Shen","year":"2016","unstructured":"Shen, Z. et al. Novel Helicobacter species H.japonicum isolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL\/129 IL10\u2212\/\u2212 mice. Carcinogenesis \n                           12, 1190\u20131198 (2016).","journal-title":"Carcinogenesis"},{"key":"12644_CR54","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1111\/j.1600-0463.2005.apm1130313.x","volume":"113","author":"PS Hansen","year":"2005","unstructured":"Hansen, P. S., Jensen, T. G. & Gahrn-Hansen, B. Dysgonomonas capnocytophagoides bacteraemia in a neutropenic patient treated for acute myeloid leukaemia. APMIS \n                           113, 229\u2013231 (2005).","journal-title":"APMIS"},{"key":"12644_CR55","doi-asserted-by":"publisher","DOI":"10.1186\/1750-9378-8-11","volume":"8","author":"J Cummins","year":"2013","unstructured":"Cummins, J. & Tangney, M. Bacteria and tumours: causative agents or opportunistic inhabitants? Infect. Agent. Cancer \n                           8, 11 (2013).","journal-title":"Infect. Agent. Cancer"},{"key":"12644_CR56","doi-asserted-by":"publisher","DOI":"10.1186\/1749-8090-6-137","volume":"6","author":"P Apostolou","year":"2011","unstructured":"Apostolou, P. et al. Bacterial and fungal microflora in surgically removed lung cancer samples. J. Cardiothorac. Surg. \n                           6, 137 (2011).","journal-title":"J. Cardiothorac. Surg."},{"key":"12644_CR57","doi-asserted-by":"publisher","first-page":"271","DOI":"10.18632\/oncotarget.264","volume":"2","author":"MB Rogers","year":"2011","unstructured":"Rogers, M. B. Mycoplasma and cancer: in search of the link. Oncotarget \n                           2, 271\u2013273 (2011).","journal-title":"Oncotarget"},{"key":"12644_CR58","doi-asserted-by":"publisher","first-page":"4498","DOI":"10.1128\/IAI.01317-07","volume":"76","author":"J Zheng","year":"2008","unstructured":"Zheng, J. et al. 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. \n                           76, 4498\u20134508 (2008).","journal-title":"Infect. Immun."},{"key":"12644_CR59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0070803","volume":"8","author":"TL Weir","year":"2013","unstructured":"Weir, T. L. et al. Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PLoS One \n                           8, e70803 (2013).","journal-title":"PLoS One"},{"key":"12644_CR60","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/nrgastro.2016.4","volume":"13","author":"RE Ley","year":"2016","unstructured":"Ley, R. E. Gut microbiota in 2015: Prevotella in the gut: choose carefully. Nat. Rev. Gastroenterol. Hepatol. \n                           13, 69\u201370 (2016).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"12644_CR61","first-page":"4","volume":"59","author":"E Lowicka","year":"2007","unstructured":"Lowicka, E. & Beltowski, J. Hydrogen sulfide (H2S) - the third gas of interest for pharmacologists. Pharmacol. Rep. \n                           59, 4\u201324 (2007).","journal-title":"Pharmacol. Rep."},{"key":"12644_CR62","doi-asserted-by":"publisher","first-page":"13582","DOI":"10.1073\/pnas.1312524110","volume":"110","author":"FE Rey","year":"2013","unstructured":"Rey, F. E. et al. Metabolic niche of a prominent sulfate-reducing human gut bacterium. Proc. Natl. Acad. Sci. USA \n                           110, 13582\u201313587 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"12644_CR63","doi-asserted-by":"publisher","DOI":"10.1186\/1743-7075-7-79","volume":"7","author":"SE Lakhan","year":"2010","unstructured":"Lakhan, S. E. & Kirchgessner, A. Gut inflammation in chronic fatigue syndrome. Nutr. Metab. (Lond). \n                           7, 79 (2010).","journal-title":"Nutr. Metab. (Lond)."},{"key":"12644_CR64","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1053\/j.gastro.2006.08.035","volume":"131","author":"R Schicho","year":"2006","unstructured":"Schicho, R. et al. Hydrogen sulfide is a novel prosecretory neuromodulator in the Guinea-pig and human colon. Gastroenterology \n                           131, 1542\u20131552 (2006).","journal-title":"Gastroenterology"},{"key":"12644_CR65","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000003342","volume":"95","author":"D Liu","year":"2016","unstructured":"Liu, D. et al. Effects of Probiotics on Intestinal Mucosa Barrier in Patients With Colorectal Cancer after Operation: Meta-Analysis of Randomized Controlled Trials. Medicine (Baltimore). \n                           95, e3342 (2016).","journal-title":"Medicine (Baltimore)."},{"key":"12644_CR66","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020447","volume":"6","author":"JR Marchesi","year":"2011","unstructured":"Marchesi, J. R. et al. Towards the human colorectal cancer microbiome. PLoS One \n                           6, e20447 (2011).","journal-title":"PLoS One"},{"key":"12644_CR67","doi-asserted-by":"publisher","first-page":"7199","DOI":"10.1158\/0008-5472.CAN-13-0827","volume":"73","author":"Y Zhan","year":"2013","unstructured":"Zhan, Y. et al. Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. Cancer Res. \n                           73, 7199\u20137210 (2013).","journal-title":"Cancer Res."},{"key":"12644_CR68","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2016.00096","volume":"6","author":"LF Mager","year":"2016","unstructured":"Mager, L. F., Wasmer, M.-H., Rau, T. T. & Krebs, P. Cytokine-Induced Modulation of Colorectal Cancer. Front. Oncol. \n                           6, 96 (2016).","journal-title":"Front. Oncol."},{"key":"12644_CR69","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1038\/nri3896","volume":"15","author":"NR West","year":"2015","unstructured":"West, N. R., McCuaig, S., Franchini, F. & Powrie, F. Emerging cytokine networks in colorectal cancer. Nat. Rev. Immunol. \n                           15, 615\u2013629 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"12644_CR70","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1093\/bioinformatics\/btu616","volume":"31","author":"PJ McMurdie","year":"2015","unstructured":"McMurdie, P. J. & Holmes, S. Shiny-phyloseq: Web application for interactive microbiome analysis with provenance tracking. Bioinformatics \n                           31, 282\u2013283 (2015).","journal-title":"Bioinformatics"},{"key":"12644_CR71","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1093\/bioinformatics\/btg412","volume":"20","author":"E Paradis","year":"2004","unstructured":"Paradis, E., Claude, J. & Strimmer, K. APE: Analyses of phylogenetics and evolution in R language. Bioinformatics \n                           20, 289\u2013290 (2004).","journal-title":"Bioinformatics"},{"key":"12644_CR72","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1111\/j.1654-1103.2003.tb02228.x","volume":"14","author":"P Dixon","year":"2003","unstructured":"Dixon, P. VEGAN, a package of R functions for community ecology. J. Veg. Sci. \n                           14, 927\u2013930 (2003).","journal-title":"J. Veg. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12644-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12644-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12644-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T11:32:01Z","timestamp":1671795121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12644-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,2]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["12644"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-12644-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,2]]},"assertion":[{"value":"26 May 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 September 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 October 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"12552"}}