colibactin and Carcinogenesis

Colorectal cancer (CRC) incidence is increasing in young patients without a clear etiology. Emerging data have implicated the fecal microbiome in CRC carcinogenesis. However, its impact on young onset CRC is poorly defined.. We performed a meta-analysis of fecal metagenomics sequencing data from n = 692 patients with CRC and n = 602 healthy controls from eleven studies to evaluate features of the fecal metagenome associated with CRC. We hypothesized that known carcinogenic virulence factors (colibactin, fadA) and species abundance may be differentially enriched in young CRC patients relative to older CRC patients and controls.. Summary odds ratios (OR) for CRC were increased with the presence of colibactin (OR 1.92 95% CI 1.08-3.38), fadA (OR 4.57 95% CI 1.63-12.85), and F. nucleatum (OR 6.93 95% CI 3.01-15.96) in meta-analysis models adjusted for age, gender, and body mass index. The OR for CRC for the presence of E.coli was 2.02 (0.92-4.45). An increase in the prevalence of Fusobacterium nucleatum (OR = 1.40 [1.18; 1.65]) and Escherichia coli (OR = 1.14 [1.02; 1.28]) per 10-year increase in age was observed in models including samples from both CRC and healthy controls. Species relative abundance was differentially enriched in young CRC patients for five species-Intestinimonas butyriciproducens, Holdemania filiformis, Firimicutues bacterium CAG 83, Bilophilia wadsworthia, and Alistipes putredinis.. In this study, we observed strong associations with CRC status for colibactin, fadA, and Fusobacterium nucleatum with CRC relative to controls. In addition, we identified several microbial species differentially enriched in young colorectal cancer patients. Studies targeting the young CRC patients are warranted to elucidate underlying preclinical mechanisms.

Topics: Carcinogenesis; Colorectal Neoplasms; Fusobacterium nucleatum; Humans; Metagenome; Metagenomics; Microbiota

Recent studies have shown that

Topics: Carcinogenesis; Carcinogens; Colorectal Neoplasms; Escherichia coli; Humans; Peptides; Polyketides; Risk Factors

Colibactin is a genotoxin that induces DNA double-strand breaks that may lead to carcinogenesis and is produced by Escherichia coli strains harboring the pks island. Human and animal studies have shown that colibactin-producing gut bacteria promote carcinogenesis and enhance the progression of colorectal cancer through cellular senescence and chromosomal abnormalities. In this study, we investigated the impact of prebiotics on the genotoxicity of colibactin-producing E. coli strains Nissle 1917 and NC101.. Bacteria were grown in medium supplemented with 20, 30 and 40 mg/mL of prebiotics inulin or galacto-oligosaccharide, and with or without 5 μM, 25 μM and 125 μM of ferrous sulfate. Colibactin expression was assessed by luciferase reporter assay for the clbA gene, essential for colibactin production, in E. coli Nissle 1917 and by RT-PCR in E. coli NC101. The human epithelial colorectal adenocarcinoma cell line, Caco-2, was used to assess colibactin-induced megalocytosis by methylene blue binding assay and genotoxicity by γ-H2AX immunofluorescence analysis.. Inulin and galacto-oligosaccharide enhanced the expression of clbA in pks+ E. coli. However, the addition of 125 μM of ferrous sulfate inhibited the expression of clbA triggered by oligosaccharides. In the presence of either oligosaccharide, E. coli NC101 increased dysplasia and DNA double-strand breaks in Caco-2 cells compared to untreated cells.. Our results suggest that, in vitro, prebiotic oligosaccharides exacerbate DNA damage induced by colibactin-producing bacteria. Further studies are necessary to establish whether oligosaccharide supplementation may lead to increased colorectal tumorigenesis in animal models colonized with pks+ E. coli.

Topics: Caco-2 Cells; Carcinogenesis; Cellular Senescence; Colonic Neoplasms; DNA Damage; Escherichia coli; Genomic Islands; Humans; Mutagens; Oligosaccharides; Peptides; Polyketides

The Escherichia coli strain that is known to produce the genotoxic secondary metabolite colibactin is linked to colorectal oncogenesis. Therefore, understanding the properties of such colibactin-positive E. coli and the molecular mechanism of oncogenesis by colibactin may provide us with opportunities for early diagnosis or prevention of colorectal oncogenesis. While there have been major advances in the characterization of colibactin-positive E. coli and the toxin it produces, the infection route of the clb + strain remains poorly characterized.. We examined infants and their treatments during and post-birth periods to examine potential transmission of colibactin-positive E. coli to infants. Here, analysis of fecal samples of infants over the first month of birth for the presence of a colibactin biosynthetic gene revealed that the bacterium may be transmitted from mother to infant through intimate contacts, such as natural childbirth and breastfeeding, but not through food intake.. Our finding suggests that transmission of colibactin-positive E. coli appears to be occurring at the very early stage of life of the newborn and hints at the possibility of developing early preventive measures against colorectal cancer.

Topics: Bacterial Toxins; Carcinogenesis; Carcinogens; Colorectal Neoplasms; Escherichia coli; Escherichia coli Infections; Feces; Female; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Mothers; Peptides; Polyketides

Topics: Carcinogenesis; Colonic Neoplasms; DNA Damage; Escherichia coli; Escherichia coli Proteins; HeLa Cells; Humans; Mutagens; Peptides; Phosphotransferases (Phosphate Group Acceptor); Polyketides; Virulence

Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of

Topics: Aerobiosis; Animals; Carcinogenesis; Colitis; Colorectal Neoplasms; Dextran Sulfate; Escherichia coli; Escherichia coli Infections; Female; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL; Oxygen; Peptides; Polyketides

Certain

Topics: Alkylating Agents; Alkylation; Animals; Carcinogenesis; Colorectal Neoplasms; Cyclopropanes; DNA Adducts; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Germ-Free Life; HeLa Cells; HT29 Cells; Humans; Mice; Mice, Inbred C57BL; Mutagens; Peptides; Polyketides

Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of

Topics: Adenomatous Polyposis Coli; Animals; Bacterial Toxins; Bacteroides fragilis; Biofilms; Carcinogenesis; Colon; Colonic Neoplasms; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Humans; Interleukin-17; Intestinal Mucosa; Metalloendopeptidases; Mice; Peptides; Polyketides; Precancerous Conditions

Escherichia coli strains harbouring the pks island (pks+ E. coli) are often seen in human colorectal tumours and have a carcinogenic effect independent of inflammation in an AOM/IL-10(-/-) (azoxymethane/interleukin) mouse model.. To investigate the mechanism sustaining pks+ E. coli-induced carcinogenesis.. Underlying cell processes were investigated in vitro and in vivo (xenograft model) using intestinal epithelial cells infected by pks+ E. coli or by an isogenic mutant defective for pks (pks- E. coli). The results were supported by data obtained from an AOM/DSS (azoxymethane/dextran sodium sulphate) colon cancer mouse model and from human colon cancer biopsy specimens colonised by pks+ E. coli or pks- E. coli.. Colibactin-producing E. coli enhanced tumour growth in both xenograft and AOM/DSS models. Growth was sustained by cellular senescence (a direct consequence of small ubiquitin-like modifier (SUMO)-conjugated p53 accumulation), which was accompanied by the production of hepatocyte growth factor (HGF). The underlying mechanisms involve microRNA-20a-5p, which targets SENP1, a key protein regulating p53 deSUMOylation. These results are consistent with the expression of SENP1, microRNA-20a-5p, HGF and phosphorylation of HGF receptor found in human and mouse colon cancers colonised by pks+ E. coli.. These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role.

Topics: Animals; Carcinogenesis; Cellular Senescence; Colonic Neoplasms; Cysteine Endopeptidases; Endopeptidases; Escherichia coli; Hepatocyte Growth Factor; Humans; Mice; Mutagens; Mutation; Neoplasms, Experimental; Nuclear Proteins; Peptides; Polyketides; Proto-Oncogene Proteins c-met

Topics: Animals; Carcinogenesis; Colonic Neoplasms; Escherichia coli; Humans; Peptides; Polyketides