The Four Horsemen in Colon Cancer

Worldwide, neoplasms of the gastrointestinal tract have a very high incidence and mortality. Among these, colorectal cancer, which includes colon and rectum malignancies, representing both highest incidence and mortality. While gallbladder cancer, another neoplasm associated to gastrointestinal tract occurs less frequently. Genetic factors, inflammation and nutrition are important risk factors associated with colorectal cancer development. Likewise, pathogenic microorganisms inducing intestinal dysbiosis have become an important scope to determine the role of bacterial infection on tumorigenesis. Interestingly, in human biopsies of different types of gastrointestinal tract cancer, the presence of different bacterial strains, such as Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis and Salmonella enterica have been detected, and it has been considered as a high-risk factor to cancer development. Therefore, pathogens infection could contribute to neoplastic development through different mechanisms; including intestinal dysbiosis, inflammation, evasion of tumoral immune response and activation of pro-tumoral signaling pathways, such as β catenin. Here, we have reviewed the suggested bacterial molecular mechanisms and their possible role on development and progression of gastrointestinal neoplasms, focusing mainly on colon neoplasms, where the bacteria Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis and Salmonella enterica infect.

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16S rRNA of Mucosal Colon Microbiome and CCL2 Circulating Levels Are Potential Biomarkers in Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms221910747 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10747

Author(s):

Carmela Nardelli ◽

Ilaria Granata ◽

Marcella Nunziato ◽

Mario Setaro ◽

Fortunata Carbone ◽

...

Keyword(s):

Colorectal Cancer ◽

Escherichia Coli ◽

16S Rrna ◽

Bacteroides Fragilis ◽

Fusobacterium Nucleatum ◽

Normal Weight ◽

Western World ◽

Intestinal Dysbiosis ◽

Rrna Sequencing ◽

Circulating Levels

Colorectal cancer (CRC) is one of the most common malignancies in the Western world and intestinal dysbiosis might contribute to its pathogenesis. The mucosal colon microbiome and C-C motif chemokine 2 (CCL2) were investigated in 20 healthy controls (HC) and 20 CRC patients using 16S rRNA sequencing and immunoluminescent assay, respectively. A total of 10 HC subjects were classified as overweight/obese (OW/OB_HC) and 10 subjects were normal weight (NW_HC); 15 CRC patients were classified as OW/OB_CRC and 5 patients were NW_CRC. Results: Fusobacterium nucleatum and Escherichia coli were more abundant in OW/OB_HC than in NW_HC microbiomes. Globally, Streptococcus intermedius, Gemella haemolysans, Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were significantly increased in CRC patient tumor/lesioned tissue (CRC_LT) and CRC patient unlesioned tissue (CRC_ULT) microbiomes compared to HC microbiomes. CCL2 circulating levels were associated with tumor presence and with the abundance of Fusobacterium nucleatum, Bacteroides fragilis and Gemella haemolysans. Our data suggest that mucosal colon dysbiosis might contribute to CRC pathogenesis by inducing inflammation. Notably, Fusobacterium nucleatum, which was more abundant in the OW/OB_HC than in the NW_HC microbiomes, might represent a putative link between obesity and increased CRC risk.

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Association between colorectal cancer and Fusobacterium nucleatum and Bacteroides fragilis bacteria in Iranian patients: a preliminary study

Infectious Agents and Cancer ◽

10.1186/s13027-021-00381-4 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Aref Shariati ◽

Shabnam Razavi ◽

Ehsanollah Ghaznavi-Rad ◽

Behnaz Jahanbin ◽

Abolfazl Akbari ◽

...

Keyword(s):

Colorectal Cancer ◽

Relative Abundance ◽

Normal Tissue ◽

Bacteroides Fragilis ◽

Fusobacterium Nucleatum ◽

Normal Mucosa ◽

Clinicopathologic Characteristics ◽

Tissue Samples ◽

Adjacent Normal Mucosa ◽

Iranian Patients

Abstract Background and aim Recent studies have proposed that commensal bacteria might be involved in the development and progression of gastrointestinal disorders such as colorectal cancer (CRC). Therefore, in this study, the relative abundance of Fusobacterium nucleatum, Bacteroides fragilis, Streptococcus bovis/gallolyticus, and Enteropathogenic Escherichia coli (EPEC) in CRC tissues, and their association with clinicopathologic characteristics of CRC was investigated in Iranian patients. Moreover, the role of these bacteria in the CRC-associated mutations including PIK3CA, KRAS, and BRAF was studied. Method To these ends, the noted bacteria were quantified in paired tumors and normal tissue specimens of 30 CRC patients, by TaqMan quantitative Real-Time Polymerase Chain Reaction (qPCR). Next, possible correlations between clinicopathologic factors and mutations in PIK3CA, KRAS, and BRAF genes were analyzed. Results In studied samples, B. fragilis was the most abundant bacteria that was detected in 66 and 60% of paired tumor and normal samples, respectively. Furthermore, 15% of the B. fragilis-positive patients were infected with Enterotoxigenic B. fragilis (ETBF) in both adenocarcinoma and matched adjacent normal samples. F. nucleatum was also identified in 23% of tumors and 13% of adjacent normal tissue samples. Moreover, the relative abundance of these bacteria determined by 2-ΔCT was significantly higher in CRC samples than in adjacent normal mucosa (p < 0.05). On the other hand, our findings indicated that S. gallolyticus and EPEC, compared to adjacent normal mucosa, were not prevalent in CRC tissues. Finally, our results revealed a correlation between F. nucleatum-positive patients and the KRAS mutation (p = 0.02), while analyses did not show any association between bacteria and mutation in PIK3CA and BRAF genes. Conclusion The present study is the first report on the analysis of different bacteria in CRC tissue samples of Iranian patients. Our findings revealed that F. nucleatum and B. fragilis might be linked to CRC. However, any link between gut microbiome dysbiosis and CRC remains unknown.

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The Intestinal Microbiota and Colorectal Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2020.615056 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yiwen Cheng ◽

Zongxin Ling ◽

Lanjuan Li

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Escherichia Coli ◽

Intestinal Microbiota ◽

Pathogenic Bacteria ◽

Large Population ◽

Fusobacterium Nucleatum ◽

Colorectal Carcinogenesis ◽

Complex Relationship ◽

Streptococcus Bovis

The intestinal microbiota, composed of a large population of microorganisms, is often considered a “forgotten organ” in human health and diseases. Increasing evidence indicates that dysbiosis of the intestinal microbiota is closely related to colorectal cancer (CRC). The roles for intestinal microorganisms that initiated and facilitated the CRC process are becoming increasingly clear. Hypothesis models have been proposed to illustrate the complex relationship between the intestinal microbiota and CRC. Recent studies have identified Streptococcus bovis, enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, Enterococcus faecalis, Escherichia coli, and Peptostreptococcus anaerobius as CRC candidate pathogens. In this review, we summarized the mechanisms involved in microbiota-related colorectal carcinogenesis, including inflammation, pathogenic bacteria, and their virulence factors, genotoxins, oxidative stress, bacterial metabolites, and biofilm. We also described the clinical values of intestinal microbiota and novel strategies for preventing and treating CRC.

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In Vitro Effects of Thymol-β-d-Glucopyranoside on Salmonella enterica Serovar Typhimurium and Escherichia coli K88†

Journal of Food Protection ◽

10.4315/0362-028x.jfp-15-360 ◽

2016 ◽

Vol 79 (2) ◽

pp. 299-303 ◽

Cited By ~ 5

Author(s):

G. LEVENT ◽

R. B. HARVEY ◽

G. CIFTCIOGLU ◽

R. C. BEIER ◽

K. J. GENOVESE ◽

...

Keyword(s):

Escherichia Coli ◽

Gastrointestinal Tract ◽

Pure Culture ◽

Salmonella Enterica ◽

Salmonella Enterica Serovar Typhimurium ◽

Lower Gastrointestinal Tract ◽

Serovar Typhimurium ◽

In Vitro Effects ◽

Porcine Feces

ABSTRACT Although thymol is bactericidal against many pathogens in vitro, its in vivo effectiveness against pathogens in the lower gastrointestinal tract is limited because of its rapid absorption in the proximal gut. Thymol-β-d-glucopyranoside (β-thymol), a conjugated form of thymol, can deliver thymol to the lower gastrointestinal tract and has shown antibacterial effects. In the present study, we examined the in vitro effects of β-thymol on Salmonella enterica serovar Typhimurium (ST) and Escherichia coli K88 (K88). We inoculated one-half strength Mueller-Hinton broth with 5.8 ± 0.09 log CFU/ml novobiocin- and naladixic acid–resistant (NN) ST (NVSL 95-1776) and 5.1 ± 0.09 log CFU ml−1 NN-resistant K88, with or without porcine feces (0.1% [wt/vol]) (fecal incubations). The resultant bacterial suspensions were distributed under N2 to triplicate sets of tubes to achieve initial concentrations of 0, 3, 6, and 12 mM for ST treatments and 0, 3, 12, and 30 mM for K88 treatments. Samples were incubated at 39°C and then plated onto NN-containing brilliant green agar and NN-containing MacConkey agar; ST and K88 CFU concentrations were determined via 10-fold dilutions, and viable cell counts were performed at 0, 6, and 24 h. No differences in ST CFU counts were observed in β-thymol–treated tubes without the added porcine feces (i.e., pure culture) at 6 or 24 h. However, in tubes that contained fecal incubations, ST CFU counts were reduced (P < 0.05) from controls at 6 h in tubes treated with 6 and 12 mM β-thymol, whereas in tubes treated with 3, 6, and 12 mM β-thymol the CFU counts were reduced (P < 0.05) at 24 h. No differences were observed in K88 CFU counts in pure culture or in fecal incubations at 6 h, but K88 CFU counts were reduced (P < 0.05) in both pure and fecal incubations at 24 h. The results from this study demonstrate that β-thymol, in the presence of fecal suspensions, has anti-Salmonella and anti–E. coli effects, suggesting a role of β-glycoside–hydrolyzing microbes for the release of bactericidal thymol from β-thymol.

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Antibacterial Effect of Aloe Vera Gel Extract on Escherichia coli and Salmonella enterica Isolated from the Gastrointestinal Tract of Guinea Fowls.

Journal of World's Poultry Research ◽

10.36380/scil.2019.wvj21 ◽

2019 ◽

Vol 9 (3) ◽

pp. 166-173

Author(s):

Frederick Adzitey ◽

AnthonyAmisson Agbolosu ◽

Udoji James Udoka

Keyword(s):

Escherichia Coli ◽

Gastrointestinal Tract ◽

Salmonella Enterica ◽

Antibacterial Effect ◽

Aloe Vera ◽

Aloe Vera Gel

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Conversion from epithelial to partial-EMT phenotype by Fusobacterium nucleatum infection promotes invasion of oral cancer cells

Scientific Reports ◽

10.1038/s41598-021-94384-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wenhua Shao ◽

Natsumi Fujiwara ◽

Yasuhiro Mouri ◽

Satoru Kisoda ◽

Kayo Yoshida ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Fusobacterium Nucleatum ◽

Cancer Development ◽

Mesenchymal Transition ◽

Epithelial Phenotype ◽

Oral Cancer Cells ◽

Metastatic Risk

Abstract The ability of cancer cells to undergo partial-epithelial mesenchymal transition (p-EMT), rather than complete EMT, poses a higher metastatic risk. Although Fusobacterium nucleatum mainly inhabits in oral cavity, attention has been focused on the F. nucleatum involvement in colorectal cancer development. Here we examined the p-EMT regulation by F. nucleatum in oral squamous cell carcinoma (OSCC) cells. We cultured OSCC cells with epithelial, p-EMT or EMT phenotype with live or heat-inactivated F. nucleatum. Expression of the genes involved in epithelial differentiation, p-EMT and EMT were examined in OSCC cells after co-culture with F. nucleatum by qPCR. Cell growth and invasion of OSCC cells were also examined. Both live and heat-inactivated F. nucleatum upregulated the expression of p-EMT-related genes in OSCC cells with epithelial phenotype, but not with p-EMT or EMT phenotype. Moreover, F. nucleatum promoted invasion of OSCC cells with epithelial phenotype. Co-culture with other strains of bacteria other than Porphyromonas gingivalis did not alter p-EMT-related genes in OSCC cells with epithelial phenotype. F. nucleatum infection may convert epithelial to p-EMT phenotype via altering gene expression in OSCC. Oral hygiene managements against F. nucleatum infection may contribute to reduce the risk for an increase in metastatic ability of OSCC.

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The Role of Fecal Fusobacterium nucleatum and pks+ Escherichia coli as Early Diagnostic Markers of Colorectal Cancer

Disease Markers ◽

10.1155/2021/1171239 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Kaixi Liu ◽

Xinran Yang ◽

Mi Zeng ◽

Yumeng Yuan ◽

Jianhong Sun ◽

...

Keyword(s):

Colorectal Cancer ◽

Escherichia Coli ◽

Characteristic Curve ◽

Fusobacterium Nucleatum ◽

Diagnostic Value ◽

Diagnostic Efficiency ◽

Serum Samples ◽

Accurate Analysis ◽

E Coli

Background. Accurate analysis of intestinal microbiota will facilitate establishment of an evaluating system for assessing colorectal cancer (CRC) risk and prognosis. This study evaluates the potential role of Fusobacterium nucleatum (F. nucleatum) and Escherichia coli with a pks gene (pks+ E. coli) in early CRC diagnosis. Methods. We recruited 139 patients, including CRC ( n = 60 ), colorectal adenomatous polyposis (CAP) ( n = 37 ), and healthy individuals ( n = 42 ) based on their colonoscopy examinations. We collected stool and serum samples from the participants and measured the relative abundance of F. nucleatum and pks+ E. coli in fecal samples by quantitative PCR. Receiver operating characteristic curve (ROC) analyses were used to analyze the diagnostic value of single or combined biomarkers. Results. Fecal F. nucleatum and pks+ E. coli levels were higher in the CRC group in either the CAP group or healthy controls ( P = 0.02 ; 0.01). There was no statistical difference in the distribution of F. nucleatum and pks+ E. coli in patients with different tumor sites ( P > 0.05 ). The combination of F. nucleatum+pks+ E. coli+CEA+CA19-9+FOBT was chosen as the optimal panel in differentiating both CRC and CAP from the controls. The combination of F. nucleatum, pks+ E. coli, and FOBT improved diagnostic efficiency. However, there was difficulty in differentiating CRC from CAP. Conclusion. Our results suggested that combining bacterial markers with conventional tumor markers improves the diagnostic efficiency for noninvasive diagnosis of CRC.

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A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study

BMC Medicine ◽

10.1186/s12916-021-02123-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lian-Jing Cao ◽

Xiao-Lin Peng ◽

Wen-Qiong Xue ◽

Rong Zhang ◽

Jiang-Bo Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Healthy Subjects ◽

Validation Cohort ◽

External Validation ◽

Area Under The Curve ◽

Fusobacterium Nucleatum ◽

Accurate Method ◽

Advanced Adenoma ◽

Fecal Samples ◽

Incidence And Mortality

Abstract Background Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). Methods Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. Results The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. Conclusions The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test.

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Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00026.2016 ◽

2016 ◽

Vol 310 (11) ◽

pp. G1081-G1090 ◽

Cited By ~ 29

Author(s):

Yvette J. Merga ◽

Adrian O'Hara ◽

Michael D. Burkitt ◽

Carrie A. Duckworth ◽

Christopher S. Probert ◽

...

Keyword(s):

Colorectal Cancer ◽

Gastrointestinal Tract ◽

Signaling Pathway ◽

Current Knowledge ◽

Common Factor ◽

Cancer Development ◽

Gastrointestinal Malignancies ◽

Activation Pathway ◽

Inflammatory Bowel

Chronic inflammation is a common factor in the development of many gastrointestinal malignancies. Examples include inflammatory bowel disease predisposing to colorectal cancer, Barrett's esophagus as a precursor of esophageal adenocarcinoma, and Helicobacter pylori-induced gastric cancer. The classical activation pathway of NF-κB signaling has been identified as regulating several sporadic and inflammation-associated gastrointestinal tract malignancies. Emerging evidence suggests that the alternative NF-κB signaling pathway also exerts a distinct influence on these processes. This review brings together current knowledge of the role of the alternative NF-κB signaling pathway in the gastrointestinal tract, with a particular emphasis on inflammation-associated cancer development.

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