{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:16:09Z","timestamp":1783577769647,"version":"3.55.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The gut microbiome is directly involved in colorectal carcinogenesis, but much of the epidemiological evidence for the effect of the gut microbiome on colorectal cancer (CRC) risk comes from observational studies, and it is unclear whether identified microbial alterations are the cause or consequence of CRC development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Univariate Mendelian randomization (MR) analysis and multivariate MR analysis based on Bayesian model averaging were performed to comprehensively explore the microbial risk factors associated with CRC. The Network Module Structure Shift method was used to identify microbial biomarkers associated with CRC. Mediation analysis was used to explore the dietary habits-microbiota-CRC pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results of the four methods showed that 9 bacteria had a robust causal relationship with the development of CRC. Among them, <jats:italic>Streptococcus thermophilus<\/jats:italic> reduced the risk of CRC; <jats:italic>Eubacterium ventriosum<\/jats:italic> and <jats:italic>Streptococcus<\/jats:italic> were beneficial bacteria of malignant tumors of colon (CC); Erysipelotrichaceae was a protective factor for malignant tumors of rectal (CR); <jats:italic>Bacteroides ovatus<\/jats:italic> was a risk factor for benign tumors. Finally, the mediation analysis revealed 10 pathways by which dietary regulation bacteria affected the risk of CRC, including alcohol consumption increased the risk of CC by reducing the abundance of <jats:italic>Eubacterium ventriosum<\/jats:italic> (mediated proportion: 43.044%), and the mediated proportion of other pathways was 7.026%-34.22%.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings will contribute to the understanding of the different carcinogenic mechanisms of intestinal flora in the colon and rectum and the risk of tumor transformation, thereby aiding CRC prevention, early screening, and the development of future strategies to reduce CRC risk.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1224705","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T18:56:17Z","timestamp":1689792977000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Identifying and ranking causal microbial biomarkers for colorectal cancer at different cancer subsites and stages: a Mendelian randomization study"],"prefix":"10.3389","volume":"13","author":[{"given":"Hongfeng","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dashuang","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuandi","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2021.101174","article-title":"Global colorectal cancer burden in 2020 and projections to 2040","volume":"14","author":"Xi","year":"2021","journal-title":"Trans Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/DCR.0b013e31819edbd4","article-title":"Divergent oncogenic changes influence survival differences between colon and rectal adenocarcinomas","volume":"52","author":"Kalady","year":"2009","journal-title":"Dis Colon Rectum"},{"key":"B3","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1097\/DCR.0000000000000926","article-title":"The american society of colon and rectal surgeons clinical practice guidelines for the treatment of colon cancer","volume":"60","author":"Vogel","year":"2017","journal-title":"Dis Colon Rectum"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2007.122739","article-title":"Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840 149 screening colonoscopies","volume":"56","author":"Brenner","year":"2007","journal-title":"Gut"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.6238","article-title":"Screening for colorectal cancer: us preventive services task force recommendation statement","volume":"325","year":"2021","journal-title":"JAMA"},{"key":"B6","doi-asserted-by":"publisher","first-page":"6528","DOI":"10.1038\/ncomms7528","article-title":"Gut microbiome development along the colorectal adenoma-carcinoma sequence","volume":"6","author":"Feng","year":"2015","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309595","article-title":"Tumour-associated and non-tumour-associated microbiota in colorectal cancer","volume":"66","author":"Flemer","year":"2017","journal-title":"Gut"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S268943","article-title":"Progress in research on colorectal cancer-related microorganisms and metabolites","volume":"12","author":"Han","year":"2020","journal-title":"Cancer Manage Res"},{"key":"B9","doi-asserted-by":"publisher","first-page":"766","DOI":"10.15252\/msb.20145645","article-title":"Potential of fecal microbiota for early-stage detection of colorectal cancer","volume":"10","author":"Zeller","year":"2014","journal-title":"Mol Syst Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s40168-018-0451-2","article-title":"Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers","volume":"6","author":"Dai","year":"2018","journal-title":"Microbiome"},{"key":"B11","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1053\/gast.2003.50047","article-title":"Bacteroides fragilis enterotoxin induces c-myc expression and cellular proliferation","volume":"124","author":"Wu","year":"2003","journal-title":"Gastroenterology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198469","article-title":"Induction of colonic regulatory T cells by indigenous clostridium species","volume":"331","author":"Atarashi","year":"2011","journal-title":"Sci (New York N.Y.)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1053\/j.gastro.2016.11.018","article-title":"Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-\u03bab, and up-regulating expression of microrna-21","volume":"152","author":"Yang","year":"2017","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13092060","article-title":"Colibactin-producing escherichia coli induce the formation of invasive carcinomas in a chronic inflammation-associated mouse model","volume":"13","author":"Salesse","year":"2021","journal-title":"Cancers"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-313321","article-title":"Race-dependent association of sulfidogenic bacteria with colorectal cancer","volume":"66","author":"Yazici","year":"2017","journal-title":"Gut"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006944","article-title":"Genetic epidemiology and mendelian randomization for informing disease therapeutics: conceptual and methodological challenges","volume":"13","author":"Paternoster","year":"2017","journal-title":"PloS Genet"},{"key":"B17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41467-019-13870-3","article-title":"Selecting likely causal risk factors from high-throughput experiments using multivariable mendelian randomization","volume":"11","author":"Zuber","year":"2020","journal-title":"Nat Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s43588-022-00247-8","article-title":"Large-Scale microbiome data integration enables robust biomarker identification","volume":"2","author":"Xiao","year":"2022","journal-title":"Nat Comput Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00992-y","article-title":"Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch microbiome project","volume":"54","author":"Lopera-Maya","year":"2022","journal-title":"Nat Genet"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/2022.03.03.22271360","article-title":"FinnGen: unique genetic insights from combining isolated population and national health register data","author":"Kurki","year":"2023","journal-title":"BioRxiv [Preprint]"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1101\/2020.08.10.244293","article-title":"The MRC IEU OpenGWAS data infrastructure","author":"Elsworth","year":"2020","journal-title":"BioRxiv [Preprint]"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0350-x","article-title":"Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases","volume":"51","author":"Sanna","year":"2019","journal-title":"Nat Genet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00747-1","article-title":"Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome","volume":"53","author":"R\u00fchlemann","year":"2021","journal-title":"Nat Genet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz469","article-title":"PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations","volume":"35","author":"Kamat","year":"2019","journal-title":"Bioinf (Oxford England)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"B26","doi-asserted-by":"publisher","first-page":"n2233","DOI":"10.1136\/bmj.n2233","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration","volume":"375","author":"Skrivankova","year":"2021","journal-title":"BMJ"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1214\/aoms\/1177731868","article-title":"The fitting of straight lines if both variables are subject to error","volume":"11","author":"Wald","year":"1940","journal-title":"Ann Math Stat"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004383","article-title":"Bayesian Test for colocalisation between pairs of genetic association studies using summary statistics","volume":"10","author":"Giambartolomei","year":"2014","journal-title":"PloS Genet"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwt084","article-title":"Efficient design for mendelian randomization studies: subsample and 2-sample instrumental variable estimators","volume":"178","author":"Pierce","year":"2013","journal-title":"Am J Epidemiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwu283","article-title":"Multivariable mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects","volume":"181","author":"Burgess","year":"2015","journal-title":"Am J Epidemiol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-314281","article-title":"Mucosal microbiome dysbiosis in gastric carcinogenesis","volume":"67","author":"Coker","year":"2018","journal-title":"Gut"},{"key":"B34","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1146\/annurev-publhealth-032315-021402","article-title":"Mediation analysis: a practitioner\u2019s guide","volume":"37","author":"VanderWeele","year":"2016","journal-title":"Annu Rev Public Health"},{"key":"B35","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1207\/s15327906mbr3901_4","article-title":"Confidence limits for the indirect effect: distribution of the product and resampling methods","volume":"39","author":"Mackinnon","year":"2004","journal-title":"Multivariate Behav Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1186\/s12885-022-10483-w","article-title":"Mendelian randomization study of causal link from gut microbiota to colorectal cancer","volume":"22","author":"Ni","year":"2022","journal-title":"BMC Cancer"},{"key":"B37","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12916-023-02761-6","article-title":"Causal relationship between gut microbiota and cancers: a two-sample mendelian randomisation study","volume":"21","author":"Long","year":"2023","journal-title":"BMC Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2015.1039223","article-title":"Gut microbiome compositional and functional differences between tumor and non-tumor adjacent tissues from cohorts from the US and Spain","volume":"6","author":"Allali","year":"2015","journal-title":"Gut Microbes"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1053\/j.gastro.2020.09.003","article-title":"Streptococcus thermophilus inhibits colorectal tumorigenesis through secreting \u03b2-galactosidase","volume":"160","author":"Li","year":"2021","journal-title":"Gastroenterology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02214","article-title":"In vitro probiotic potential and anti-cancer activity of newly isolated folate-producing streptococcus thermophilus strains","volume":"9","author":"Tarrah","year":"2018","journal-title":"Front Microbiol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"18193","DOI":"10.1038\/s41598-022-21928-4","article-title":"Differential analysis of microbiomes in mucus and tissues obtained from colorectal cancer patients","volume":"12","author":"Tajima","year":"2022","journal-title":"Sci Rep"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31941","article-title":"Prospective study of oral microbiome and colorectal cancer risk in low-income and African American populations","volume":"144","author":"Yang","year":"2019","journal-title":"Int J Cancer"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039743","article-title":"Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer","volume":"7","author":"Chen","year":"2012","journal-title":"PloS One"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.112.046607","article-title":"Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma","volume":"97","author":"Chen","year":"2013","journal-title":"Am J Clin Nutr"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090849","article-title":"Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer","volume":"9","author":"Zhu","year":"2014","journal-title":"PloS One"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000001842","article-title":"Concomitant decrease of double-positive lymphocyte population CD4CD8\u03b1\u03b1 and faecalibacterium prausnitzii in patients with colorectal cancer","volume":"32","author":"Touchefeu","year":"2021","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah3648","article-title":"Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria","volume":"359","author":"Dejea","year":"2018","journal-title":"Sci (New York N.Y.)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/s41423-022-00871-4","article-title":"Bacteroides ovatus-mediated CD27- MAIT cell activation is associated with obesity-related T2D progression","volume":"19","author":"Li","year":"2022","journal-title":"Cell Mol Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2021.01.009","article-title":"Bacteroides ovatus promotes il-22 production and reduces trinitrobenzene sulfonic acid-driven colonic inflammation","volume":"191","author":"Ihekweazu","year":"2021","journal-title":"Am J Pathol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1016\/j.cell.2017.07.008","article-title":"Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy","volume":"170","author":"Yu","year":"2017","journal-title":"Cell"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2018.07.012","article-title":"Environmental factors, gut microbiota, and colorectal cancer prevention","volume":"17","author":"Song","year":"2019","journal-title":"Clin Gastroenterol Hepatology: Off Clin Pract J Am Gastroenterological Assoc"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/srep27923","article-title":"Ecophysiological consequences of alcoholism on human gut microbiota: implications for ethanol-related pathogenesis of colon cancer","volume":"6","author":"Tsuruya","year":"2016","journal-title":"Sci Rep"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1177\/1756283X17694832","article-title":"Insights into the role of the intestinal microbiota in colon cancer","volume":"10","author":"Oke","year":"2017","journal-title":"Ther Adv Gastroenterol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/srep06328","article-title":"Changes of the human gut microbiome induced by a fermented milk product","volume":"4","author":"Veiga","year":"2014","journal-title":"Sci Rep"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2008.176131","article-title":"Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium bacteroides ovatus","volume":"59","author":"Hamady","year":"2010","journal-title":"Gut"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1224705\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T18:58:59Z","timestamp":1689793139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1224705\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,19]]},"references-count":55,"alternative-id":["10.3389\/fonc.2023.1224705"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2023.1224705","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,19]]},"article-number":"1224705"}}