Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer
2019; Elsevier BV; Volume: 158; Issue: 2 Linguagem: Inglês
10.1053/j.gastro.2019.06.048
ISSN1528-0012
AutoresMingyang Song, Andrew T. Chan, Jun Sun,
Tópico(s)Tea Polyphenols and Effects
ResumoResearchers have discovered associations between elements of the intestinal microbiome (including specific microbes, signaling pathways, and microbiota-related metabolites) and risk of colorectal cancer (CRC). However, it is unclear whether changes in the intestinal microbiome contribute to the development of sporadic CRC or result from it. Changes in the intestinal microbiome can mediate or modify the effects of environmental factors on risk of CRC. Factors that affect risk of CRC also affect the intestinal microbiome, including overweight and obesity; physical activity; and dietary intake of fiber, whole grains, and red and processed meat. These factors alter microbiome structure and function, along with the metabolic and immune pathways that mediate CRC development. We review epidemiologic and laboratory evidence for the influence of the microbiome, diet, and environmental factors on CRC incidence and outcomes. Based on these data, features of the intestinal microbiome might be used for CRC screening and modified for chemoprevention and treatment. Integrated prospective studies are urgently needed to investigate these strategies. Researchers have discovered associations between elements of the intestinal microbiome (including specific microbes, signaling pathways, and microbiota-related metabolites) and risk of colorectal cancer (CRC). However, it is unclear whether changes in the intestinal microbiome contribute to the development of sporadic CRC or result from it. Changes in the intestinal microbiome can mediate or modify the effects of environmental factors on risk of CRC. Factors that affect risk of CRC also affect the intestinal microbiome, including overweight and obesity; physical activity; and dietary intake of fiber, whole grains, and red and processed meat. These factors alter microbiome structure and function, along with the metabolic and immune pathways that mediate CRC development. We review epidemiologic and laboratory evidence for the influence of the microbiome, diet, and environmental factors on CRC incidence and outcomes. Based on these data, features of the intestinal microbiome might be used for CRC screening and modified for chemoprevention and treatment. Integrated prospective studies are urgently needed to investigate these strategies. Andrew T. ChanView Large Image Figure ViewerDownload Hi-res image Download (PPT)Jun SunView Large Image Figure ViewerDownload Hi-res image Download (PPT) Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer death in men and women in the United States, despite the increasing uptake of colonoscopy screening.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2019.CA Cancer J Clin. 2019; 69: 7-34Crossref PubMed Scopus (1638) Google Scholar In 2019, approximately 145,600 new cases of CRC and 51,020 deaths were estimated to occur. Moreover, although CRC incidence and mortality have decreased steadily in the past few decades among adults older than 65 years, an opposing trend has occurred in adults younger than 50 years,2Siegel R.L. Miller K.D. Fedewa S.A. et al.Colorectal cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 177-193Crossref PubMed Scopus (1416) Google Scholar for whom routine screening has not been recommended. The incidence of colon cancer increased by 2.4% per year in adults 20–29 years old and by 1.0% per year in adults 30–39 years old from the mid-1980s through 2013, and it has been increasing in adults 40–49 years old (1.3% per year) and 50–54 years old (0.5% per year) since the mid-1990s.2Siegel R.L. Miller K.D. Fedewa S.A. et al.Colorectal cancer statistics, 2017.CA Cancer J Clin. 2017; 67: 177-193Crossref PubMed Scopus (1416) Google Scholar A prolonged and steeper increase has been observed for rectal cancer cases. This alarming trend in young adults, coupled with the continued burden of CRC in the overall population, indicates a need to develop new prevention strategies to complement screening. Over the past few decades, migration studies and prospective cohort studies have established the important effects of diet and lifestyle in the development of CRC.3Song M. Garrett W.S. Chan A.T. Nutrients, foods, and colorectal cancer prevention.Gastroenterology. 2015; 148: 1244-1260Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Approximately 50%–60% of incident cases of CRC in the United States are estimated to be attributable to modifiable risk factors4Islami F. Goding Sauer A. Miller K.D. et al.Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States.CA Cancer J Clin. 2018; 68: 31-54Crossref PubMed Scopus (125) Google Scholar,5Mima K. Cao Y. Chan A.T. et al.Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location.Clin Transl Gastroenterol. 2016; 7e200Crossref PubMed Scopus (0) Google Scholar such as smoking; heavy consumption of alcohol; overweight and obesity; physical inactivity; high consumption of red and processed meat; and low consumption of dietary fiber, whole grains, and other healthful nutrients. The microbiome (including bacteria, virus, fungi, etc) regulates health, and alterations can contribute to disease. Increasing data indicate that changes in the intestinal microbiome allow environmental risk factors to initiate and promote CRC.6Song M. Chan A.T. Environmental factors, gut microbiota, and colorectal cancer prevention.Clin Gastroenterol Hepatol. 2019; 17: 275-289Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,7Scott A.J. Alexander J.L. Merrifield C.A. et al.International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis.Gut. 2019; 68: 1624-1632Crossref PubMed Scopus (4) Google Scholar This could be because changes of the microbiome affect metabolism and immune function. The intestinal microbiome might therefore be modified as part of CRC prevention strategies. Studies have identified differences in the compositions of intestinal microbiomes between patients with CRC and healthy individuals, as well as individual microbes that are enriched or depleted in the microbiomes of patients with CRC. Moreover, there is evidence that changes in the gut microbiome occur during the early stages of colorectal carcinogenesis and can be used to identify individuals at risk for colorectal adenoma, the precursor lesion to CRC. Changes in the microbiome might therefore be used as biomarkers for the early detection of CRC to improve screening strategies. The intestinal microbiome can also influence the efficacy or toxicity of therapeutic agents, including immunotherapies.8Roy S. Trinchieri G. Microbiota: a key orchestrator of cancer therapy.Nat Rev Cancer. 2017; 17: 271-285Crossref PubMed Scopus (179) Google Scholar Although there have been numerous reviews of the association between the gut microbiome and CRC, most have focused on specific microbes,9Tilg H. Adolph T.E. Gerner R.R. et al.The intestinal microbiota in colorectal cancer.Cancer Cell. 2018; 33: 954-964Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar mechanistic pathways,10Dai Z. Zhang J. Wu Q. et al.The role of microbiota in the development of colorectal cancer.Int J Cancer. 2019; 145: 2032-2041Crossref PubMed Scopus (3) Google Scholar, 11Keku T.O. Dulal S. Deveaux A. et al.The gastrointestinal microbiota and colorectal cancer.Am J Physiol Gastrointest Liver Physiol. 2015; 308: G351-G363Crossref PubMed Google Scholar, 12Yang Y. Jobin C. Novel insights into microbiome in colitis and colorectal cancer.Curr Opin Gastroenterol. 2017; 33: 422-427Crossref PubMed Scopus (5) Google Scholar or individual risk factors.6Song M. Chan A.T. Environmental factors, gut microbiota, and colorectal cancer prevention.Clin Gastroenterol Hepatol. 2019; 17: 275-289Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar We review the interactions among the gut microbiome, environmental risk factors, and CRC based on findings from epidemiologic and laboratory research. We also discuss the potential of integrating analyses of the gut microbiome into CRC screening, chemoprevention, and treatment. The number of microbial species in human intestine is estimated to exceed 2000.13Almeida A. Mitchell A.L. Boland M. et al.A new genomic blueprint of the human gut microbiota.Nature. 2019; 568: 499-504Crossref PubMed Scopus (39) Google Scholar The human intestinal microbiome primarily comprises Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria. Intestinal microbes metabolize indigestible ingredients from food, synthesize nutrients such as vitamins, detoxify metabotypes, modulate the immune response, provide signals for epithelial cell renewal and maintenance of mucosal integrity, and secrete antimicrobial products.14Sun J. Chang E.B. Exploring gut microbes in human health and disease: pushing the envelope.Genes Dis. 2014; 1: 132-139Crossref PubMed Scopus (0) Google Scholar Dysbiosis is defined as pathogenic changes in microbiome profile and function. Alterations in the abundance of healthy intestinal microbes can promote chronic inflammatory conditions and the production of carcinogenic metabolites, leading to neoplasia. Patients with CRC have a less diverse microbiome than healthy individuals.15Ahn J. Sinha R. Pei Z. et al.Human gut microbiome and risk for colorectal cancer.J Natl Cancer Inst. 2013; 105: 1907-1911Crossref PubMed Scopus (306) Google Scholar However, a meta-analysis of metagenomic data from different cohorts and populations found higher richness in the microbiomes of patients with CRC than control individuals, partly due to expansions of species typically derived from the oral cavity.16Thomas A.M. Manghi P. Asnicar F. et al.Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation.Nat Med. 2019; 25: 667-678Crossref PubMed Scopus (8) Google Scholar,17Sze M.A. Schloss P.D. Leveraging existing 16S rRNA gene surveys to identify reproducible biomarkers in individuals with colorectal tumors.MBio. 2018; 9 (e00630-18)Crossref Scopus (6) Google Scholar Differences in the abundance of individual microbes have been observed in comparisons of tumor and adjacent nontumor mucosa and between stool specimens collected from patients with CRC vs control individuals. Specific changes in the microbiome and metabolome occur during different stages of colorectal neoplasia, from adenomatous polyps, to early-stage cancer, to metastatic disease, supporting an etiologic and diagnostic role for the microbiome.18Feng Q. Liang S. Jia H. et al.Gut microbiome development along the colorectal adenoma-carcinoma sequence.Nat Commun. 2015; 6: 6528Crossref PubMed Scopus (240) Google Scholar, 19Nakatsu G. Li X. Zhou H. et al.Gut mucosal microbiome across stages of colorectal carcinogenesis.Nat Commun. 2015; 6: 8727Crossref PubMed Scopus (257) Google Scholar, 20Yachida S. Mizutani S. Shiroma H. et al.Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer.Nat Med. 2019; 25: 968-976Crossref PubMed Scopus (11) Google Scholar We summarize the results from epidemiologic studies of microbes that have been associated with CRC (Tables 1 and 2).Table 1Association of the Intestinal Microbiome With CRCAuthor, YearCountryStudy designSample sizeBiospecimen typeSequencing methodMain findings comparing cases to controlsScanlan et al, 2008211Scanlan P.D. Shanahan F. Clune Y. et al.Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis.Environ Microbiol. 2008; 10: 789-798Crossref PubMed Scopus (0) Google ScholarBelgiumCase-control20 cancers, 20 polyps, 20 controlsStool16s rRNA sequencing↑ Diversity of the Clostridium leptum and Clostridium coccoides subgroupsSobhani et al, 2011212Sobhani I. Tap J. Roudot-Thoraval F. et al.Microbial dysbiosis in colorectal cancer (CRC) patients.PLoS One. 2011; 6e16393Crossref PubMed Scopus (0) Google ScholarFranceCase-control60 cancers, 119 controlsStool16s rRNA sequencing↑ Bacteroides/PrevotellaCastellarin et al, 201221Castellarin M. Warren R.L. Freeman J.D. et al.Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.Genome Res. 2012; 22: 299-306Crossref PubMed Scopus (646) Google ScholarCanadaCase-control11 cancers with adjacent normal tissueTissueRNA sequencing↑ FusobacteriumKostic et al, 201222Kostic A.D. Gevers D. Pedamallu C.S. et al.Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.Genome Res. 2012; 22: 292-298Crossref PubMed Scopus (721) Google ScholarUnited StatesCase-control95 cancers with adjacent normal tissueTissue16s rRNA sequencing↑ FusobacteriumSanapareddy et al, 2012213Sanapareddy N. Legge R.M. Jovov B. et al.Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans.ISME J. 2012; 6: 1858-1868Crossref PubMed Scopus (96) Google ScholarUnited StatesCase-control33 adenomas, 38 controlsTissue16s rRNA sequencing↑ Bacteria from 87 taxa, including potential pathogens such as Pseudomonas, Helicobacter, and Acinetobacter; ↓ bacteria from 5 taxaChen et al, 2012214Chen W. Liu F. Ling Z. et al.Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer.PLoS One. 2012; 7e39743Crossref PubMed Scopus (0) Google ScholarWang et al, 201245Wang T. Cai G. Qiu Y. et al.Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.ISME J. 2012; 6: 320-329Crossref PubMed Scopus (424) Google ScholarChinaCase-control46 cancers, 56 controlsTissue, stool, and swab16s rRNA sequencing↓ Diversity; ↑ Bacteroides fragilis, Lactobacillales, Fusobacterium, Porphyromonas, Peptostreptococcus, and Mogibacterium; ↓ Bifidobacterium, Faecalibacterium, Blautia butyrate-producing bacteriaAhn et al, 201315Ahn J. Sinha R. Pei Z. et al.Human gut microbiome and risk for colorectal cancer.J Natl Cancer Inst. 2013; 105: 1907-1911Crossref PubMed Scopus (306) Google ScholarUnited StatesCase-control47 cancers, 94 controlsStool16s rRNA sequencing↓ Diversity; ↓ Clostridia; ↑ Fusobacterium, PorphyromonasDejea et al, 2014215Dejea C.M. Wick E.C. Hechenbleikner E.M. et al.Microbiota organization is a distinct feature of proximal colorectal cancers.Proc Natl Acad Sci U S A. 2014; 111: 18321-18326Crossref PubMed Scopus (222) Google ScholarUnited StatesCase-control23 cancers, 2 adenomas with paired normal tissues, 22 controlsTissue16s rRNA sequencing↑ Fusobacterium; difference by biofilm statusZackular et al, 201435Zackular J.P. Rogers M.A. Ruffin M.T.I.V. et al.The human gut microbiome as a screening tool for colorectal cancer.Cancer Prev Res (Phila). 2014; 7: 1112-1121Crossref PubMed Scopus (0) Google ScholarUnited StatesCase-control30 cancers, 30 adenomas, 30 controlsStool16s rRNA sequencing↑ Bacteroides fragilis, Fusobacterium, Porphyromonas; ↓ butyrate-producing bacteriaZeller et al, 201436Zeller G. Tap J. Voigt A.Y. et al.Potential of fecal microbiota for early-stage detection of colorectal cancer.Mol Syst Biol. 2014; 10: 766Crossref PubMed Scopus (269) Google ScholarFranceCase-control91 cancers, 42 adenomas, 358 controlsStoolMetagenomic sequencing↑ Bacteroidetes, Fusobacteria, and Proteobacteria; ↓ Actinobacteria and FirmicutesBurns et al, 2015216Burns M.B. Lynch J. Starr T.K. et al.Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment.Genome Med. 2015; 7: 55Crossref PubMed Scopus (62) Google ScholarUnited StatesCase-control44 cancers with adjacent normal tissueTissue16s rRNA sequencing↑ Diversity, Fusobacterium and Providencia; ↑ virulence-related genesFeng et al, 201518Feng Q. Liang S. Jia H. et al.Gut microbiome development along the colorectal adenoma-carcinoma sequence.Nat Commun. 2015; 6: 6528Crossref PubMed Scopus (240) Google ScholarAustriaCase-control41 cancers, 42 adenomas, 55 controlsStoolMetagenomic sequencing↑ Bacteroides dorei, Bacteroides vulgatus, Escherichia coli, Fusobacterium;↓ Lactobacillus and BifidobacteriumLu et al, 2016217Lu Y. Chen J. Zheng J. et al.Mucosal adherent bacterial dysbiosis in patients with colorectal adenomas.Sci Rep. 2016; 6: 26337Crossref PubMed Scopus (17) Google ScholarChinaCase-control31 adenomas, 20 controlsTissue16s rRNA sequencing↑ Diversity; ↑Lactococcus and Pseudomonas; ↓ Enterococcus, Bacillus, and Solibacillus; similar composition between adenomatous and adjacent nonadenoma tissuesVogtmann et al, 201637Vogtmann E. Hua X. Zeller G. et al.Colorectal cancer and the human gut microbiome: reproducibility with whole-genome shotgun sequencing.PLoS One. 2016; 11e0155362Crossref PubMed Scopus (54) Google ScholarUnited States, FranceCase-control52 cancers, 52 controlsStoolMetagenomic sequencing↑ Fusobacterium, Porphyromonas, ClostridiaBaxter et al, 2016187Baxter N.T. Ruffin M.T.I.V. Rogers M.A. et al.Microbiota-based model improves the sensitivity of fecal immunochemical test for detecting colonic lesions.Genome Med. 2016; 8: 37Crossref PubMed Scopus (69) Google ScholarUSA, CanadaCase-control120 cancers, 198 adenomas, 172 no colonic lesionsStool16s rRNA sequencing↑ Porphyromonas asaccharolytica, Peptostreptococcus stomatis, Parvimonas micra, and Fusobacterium nucleatum; ↓LachnospiraceaeHale et al, 2017218Hale V.L. Chen J. Johnson S. et al.Shifts in the fecal microbiota associated with adenomatous polyps.Cancer Epidemiol Biomarkers Prev. 2017; 26: 85-94Crossref PubMed Scopus (39) Google ScholarUnited StatesCase-control233 adenomas, 547 controlsStool16s rRNA sequencing↑ Bilophila, Desulfovibrio, inflammatory bacteria in the genus Mogibacterium;↓ Veillonella, Clostridia order, and Bifidobacteriales familyYu, 2017224Yu J. Feng Q. Wong S.H. et al.Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer.Gut. 2017; 66: 70-78Crossref PubMed Scopus (163) Google ScholarDenmark, France, AustriaCase-control74 cancers, 54 controlsStoolMetagenomic sequencing↑ Peptostreptococcus stomatis, Fusobacterium nucleatum, Parvimonas micra, Solobacterium mooreiLiang et al, 201739Liang Q. Chiu J. Chen Y. et al.Fecal bacteria act as novel biomarkers for noninvasive diagnosis of colorectal cancer.Clin Cancer Res. 2017; 23: 2061-2070Crossref PubMed Scopus (127) Google ScholarChinaCase-control203 cancers, 236 controlsStool16s rRNA sequencing↑ Fusobacterium nucleatum, Clostridium hathewayi↓ Bacteroides clarusFlemer et al, 201855Flemer B. Warren R.D. Barrett M.P. et al.The oral microbiota in colorectal cancer is distinctive and predictive.Gut. 2018; 67: 1454-1463Crossref PubMed Scopus (48) Google ScholarIrelandCase-control43 cancers, 37 controlsStool and tissue16s rRNA sequencing↓ Lachnospiraceae incertae sedis and CoprococcusNOTE. Only studies with at least 10 cases (either CRC or precursors) are included. Pooled analyses of published individual studies are not included. Open table in a new tab Table 2Microbes Associated With Increased or Reduced Risk of CRCMicrobeEpidemiologic evidencePotential mechanismsReferenceAssociated with higher risk of CRC Fusobacterium nucleatumEnriched tumor tissue; higher fecal abundance in patients with colorectal neoplasia than control individuals; associated with advanced cancer stage, lower infiltration by T cells, higher risk of recurrence, and poorer patient survival; correlated with the molecular characteristics of the serrated pathwayPromotion of a tumor-permissive microenvironment through recruitment of myeloid-derived suppressor cells and inhibition of antitumor defense by NK or T cells; modulation of E-cadherin/β-catenin21Castellarin M. Warren R.L. Freeman J.D. et al.Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.Genome Res. 2012; 22: 299-306Crossref PubMed Scopus (646) Google Scholar,22Kostic A.D. Gevers D. Pedamallu C.S. et al.Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.Genome Res. 2012; 22: 292-298Crossref PubMed Scopus (721) Google Scholar,140Mehta R.S. Nishihara R. Cao Y. et al.Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue.JAMA Oncol. 2017; 3: 921-927Crossref PubMed Scopus (73) Google Scholar,219Brennan C.A. Garrett W.S. Fusobacterium nucleatum — symbiont, opportunist and oncobacterium.Nat Rev Microbiol. 2019; 17: 156-166Crossref PubMed Scopus (0) Google Scholar Enterotoxigenic Bacteroides fragilis (ETBF)Enriched in tumor tissue and fecal samples of patients with CRC; associated with advanced cancer stage and proximal colon tumorDNA damage40Boleij A. Hechenbleikner E.M. Goodwin A.C. et al.The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients.Clin Infect Dis. 2015; 60: 208-215Crossref PubMed Scopus (139) Google Scholar,220Sears C.L. Pardoll D.M. Perspective: alpha-bugs, their microbial partners, and the link to colon cancer.J Infect Dis. 2011; 203: 306-311Crossref PubMed Scopus (99) Google Scholar,221Chung L. Orberg E.T. Geis A.L. et al.Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells.Cell Host Microbe. 2018; 23: 421Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar pks+ Escherichia coliMore frequently detected in individuals with than without CRC, more frequently in tumors than in normal flanking tissue, and more frequently in late-stage tumors than in early-stage tumorsPromotion of intestinal inflammation49Arthur J.C. Perez-Chanona E. Muhlbauer M. et al.Intestinal inflammation targets cancer-inducing activity of the microbiota.Science. 2012; 338: 120-123Crossref PubMed Scopus (800) Google Scholar,222Wilson M.R. Jiang Y. Villalta P.W. et al.The human gut bacterial genotoxin colibactin alkylates DNA.Science. 2019; 363: eaar7785Crossref PubMed Scopus (28) Google ScholarAssociated with lower risk of CRC SCFA-producing bacteriaLower abundance in patients with CRC than control individuals; higher abundance in Native Americans with a low CRC incidence; associated with improved immune response and better metabolic parametersMetabolic and immune modulation of SCFAs that protect against CRC124Makki K. Deehan E.C. Walter J. et al.The impact of dietary fiber on gut microbiota in host health and disease.Cell Host Microbe. 2018; 23: 705-715Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,128So D. Whelan K. Rossi M. et al.Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis.Am J Clin Nutr. 2018; 107: 965-983Crossref PubMed Scopus (5) Google Scholar,223Donohoe D.R. Holley D. Collins L.B. et al.A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner.Cancer Discov. 2014; 4: 1387-1397Crossref PubMed Scopus (0) Google Scholar Open table in a new tab NOTE. Only studies with at least 10 cases (either CRC or precursors) are included. Pooled analyses of published individual studies are not included. Two independent studies reported increased levels of Fusobacterium DNA and RNA sequences in tumor compared with nontumor specimens.21Castellarin M. Warren R.L. Freeman J.D. et al.Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.Genome Res. 2012; 22: 299-306Crossref PubMed Scopus (646) Google Scholar,22Kostic A.D. Gevers D. Pedamallu C.S. et al.Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.Genome Res. 2012; 22: 292-298Crossref PubMed Scopus (721) Google Scholar Numerous studies of multiple cohorts of patients with CRC worldwide have found similar associations.23Flanagan L. Schmid J. Ebert M. et al.Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome.Eur J Clin Microbiol Infect Dis. 2014; 33: 1381-1390Crossref PubMed Scopus (135) Google Scholar, 24Ito M. Kanno S. Nosho K. et al.Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway.Int J Cancer. 2015; 137: 1258-1268Crossref PubMed Scopus (87) Google Scholar, 25Li Y.Y. Ge Q.X. Cao J. et al.Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients.World J Gastroenterol. 2016; 22: 3227-3233Crossref PubMed Scopus (0) Google Scholar, 26Mima K. Nishihara R. Qian Z.R. et al.Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut. 2016; 65: 1973-1980Crossref PubMed Scopus (162) Google Scholar, 27Tahara T. Yamamoto E. Suzuki H. et al.Fusobacterium in colonic flora and molecular features of colorectal carcinoma.Cancer Res. 2014; 74: 1311-1318Crossref PubMed Scopus (169) Google Scholar In support of the colorectal carcinogenic effect of Fusobacterium nucleatum, a higher abundance of F nucleatum (present in approximately 10%–15% of tumors) has been associated with advanced disease stage, higher risk of recurrence, and shorter patient survival times.23Flanagan L. Schmid J. Ebert M. et al.Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome.Eur J Clin Microbiol Infect Dis. 2014; 33: 1381-1390Crossref PubMed Scopus (135) Google Scholar,26Mima K. Nishihara R. Qian Z.R. et al.Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut. 2016; 65: 1973-1980Crossref PubMed Scopus (162) Google Scholar,28Yu T. Guo F. Yu Y. et al.Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy.Cell. 2017; 170: 548-563Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Moreover, levels of F nucleatum in tumor tissue have been associated with lower infiltration by T cells,29Nosho K. Sukawa Y. Adachi Y. et al.Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer.World J Gastroenterol. 2016; 22: 557-566Crossref PubMed Scopus (78) Google Scholar,30Mima K. Sukawa Y. Nishihara R. et al.Fusobacterium nucleatum and T cells in colorectal carcinoma.JAMA Oncol. 2015; 1: 653-661Crossref PubMed Scopus (152) Google Scholar supporting studies reporting that F nucleatum reduces the antitumor immune response. Epidemiologic studies of patients with CRC or premalignant lesions have associated F nucleatum with specific clinical and molecular features, such as right-sided anatomic location, mutations in BRAF, and hypermutation with microsatellite instability.24Ito M. Kanno S. Nosho K. et al.Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway.Int J Cancer. 2015; 137: 1258-1268Crossref PubMed Scopus (87) Google Scholar, 25Li Y.Y. Ge Q.X. Cao J. et al.Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients.World J Gastroenterol. 2016; 22: 3227-3233Crossref PubMed Scopus (0) Google Scholar, 26Mima K. Nishihara R. Qian Z.R. et al.Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis.Gut. 2016; 65: 1973-1980Crossref PubMed Scopus (162) Google Scholar, 27Tahara T. Yamamoto E. Suzuki H. et al.Fusobacterium in colonic flora and molecular features of colorectal carcinoma.Cancer Res. 2014; 74: 1311-1318Crossref PubMed Scopus (169) Google Scholar Given that these features characterize serrated neoplasia,31Rashtak S. Rego R. Sweetser S.R. et al.Sessile serrated polyps and colon cancer prevention.Cancer Prev Res (Phila). 2017; 10: 270-278Crossref PubMed Scopus (5) Google Scholar F nucleatum might contribute to the serrated pathway of CRC development. A study associated F nucleatum with the consensus molecular subtype 1 of CRC,32Purcell R.V. Visnovska M. Biggs P.J. et al.Distinct gut microbiome patterns associate with consensus molecular subtypes of colorectal cancer.Sci Rep. 2017; 7: 11590Crossref PubMed Scopus (29) Google Scholar which is characterized by microsatellite instability and up-regulation of immune pathways.33Guinney J. Dienstmann R. Wang X. et al.The consensus molecular subtypes of colorectal cancer.Nat Med. 2015; 21: 1350-1356Crossref PubMed Scopus (1086) Google Scholar More recently, among patients with CRC with distant metastases, nearly identical, viable strains of Fusobacterium were found at similar relative abundances in paired primary tumors and metastases. Therefore, Fusobacterium appears to be an important component of the tumor microenvironment.34Bullman S. Pedamallu C.S. Sicinska E. et al.Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer.Science. 2017; 358: 1443-1448Crossref PubMed Scopus (23) Google Scholar In addition to studies of tumor tissues, studies of fecal microbiomes that used either 16s ribosomal RNA (rRNA) or shotgun metagenomic sequencing found F nucleatum to be increased in fecal samples from patients with CRC or adenoma compared with control individuals (Table 1).15Ahn J. Sinha R. Pei Z. et al.Human gut microbiome and risk for colorectal cancer.J Natl Cancer Inst. 2013; 105: 1907-1911Crossref PubMed Scopus (306) Google Scholar,18Feng Q. Liang S. Jia H. et al.Gut microbiome development along the colorectal adenoma-carcinoma sequence.Nat Commun. 2015; 6: 6528Crossref PubMed Scopus (240) Google Scholar,35Zackular J.P. Rogers M.A. Ruffin M.T.I.V. et al.The human gut microbiome as a screening tool for colorectal cancer.Cancer Prev Res (Phila). 2014; 7: 1112-1121Crossref PubMe
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