colibactin and Colorectal-Neoplasms

Previous studies on the association between pks+Escherichia coli and colorectal cancer (CRC) demonstrated conflicting results. Hence, we performed a meta-analysis to obtain more precise estimates.. Related literature was obtained from PubMed, ScienceDirect, Google Scholar, and Cochrane Library. Data were then extracted, summarized, and subjected to analysis using Review Manager 5.4 by computing for the pooled odds ratios at the 95% confidence interval.. Overall analysis showed that individuals carrying pks+E coli had a greater risk of developing CRC. Subgroup analysis further showed that individuals from Western countries carrying pks+E coli and individuals with pks+E coli in their tissue samples had increased risk of developing CRC.. Results of this meta-analysis suggest that individuals with pks+E coli have a greater risk of developing CRC. However, more studies are needed to confirm our claims.

Topics: Colorectal Neoplasms; Escherichia coli; Humans; Peptides; Polyketides

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

The impact of bacterial members of the microbiota on the development of colorectal cancer (CRC) has become clear in recent years. However, exactly how bacteria contribute to the development of cancer is often still up for debate. The impact of bacteria-derived metabolites, which can influence the development of CRC either in a promoting or inhibiting manner, is undeniable. Here, we discuss the effects of the most well-studied bacteria-derived metabolites associated with CRC, including secondary bile acids, short-chain fatty acids, trimethylamine-N-oxide and indoles. We show that the effects of individual metabolites on CRC development are often nuanced and dose- and location-dependent. In the coming years, the array of metabolites involved in CRC development will undoubtedly increase further, which will emphasize the need to focus on causation and mechanisms and the clearly defined roles of bacterial species within the microbiota.

Topics: Animals; Bacteria; Bile Acids and Salts; Colorectal Neoplasms; Fatty Acids, Volatile; Gastrointestinal Microbiome; Humans; Hydrogen Sulfide; Indoles; Polyamines; Reactive Oxygen Species

Recent studies have shown that

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

Microbiota can significantly contribute to colorectal cancer initiation and development. It was described that E. coli harbouring polyketide synthase (pks) genes can synthetize bacterial toxin colibactin, which was first described by Nougayrede's group in 2006. E. coli positive for pks genes were overrepresented in colorectal cancer biopsies and, therefore, prevalence and the effect of pks positive bacteria as a risk factor in colorectal cancer development is in our interest. Interestingly, pks gene cluster in E. coli shares a striking 100% sequence identity with K. pneumoniae, suggesting that their function and regulation are conserved. Moreover, K. pneumoniae can express a variety of virulence factors, including capsules, siderophores, iron-scavenging systems, adhesins and endotoxins. It was reported that pks cluster and thereby colibactin is also related to the hypervirulence of K. pneumoniae. Acquisition of the pks locus is associated with K. pneumoniae gut colonisation and mucosal invasion. Colibactin also increases the likelihood of serious complications of bacterial infections, such as development of meningitis and potentially tumorigenesis. Even though K. pneumoniae is undoubtedly a gut colonizer, the role of pks positive K. pneumoniae in GIT has not yet been investigated. It seems that CRC-distinctive microbiota is already present in the early stages of cancer development and, therefore, microbiome analysis could help to discover the early stages of cancer, which are crucial for effectiveness of anticancer therapy. We hypothesize, that pks positive K. pneumoniae can be a potential biomarker of tumour prevalence and anticancer therapy response.

Topics: Bacterial Toxins; Colorectal Neoplasms; Escherichia coli; Humans; Klebsiella pneumoniae; Peptides; Polyketides

Colibactin is a genotoxic molecule, produced primarily by Escherichia coli. Colibactin causes DNA damage that may lead to colorectal cancer. Here we review recent advances in the study of colibactin and propose a focus on patients with inflammatory bowel diseases (IBD) who have higher levels of colibactin-producing bacteria in their intestines.

Topics: Animals; Colorectal Neoplasms; DNA Damage; Escherichia coli; Escherichia coli Infections; Humans; Peptides; Polyketides

To the multiple factors that may eventually result in colorectal cancer (CRC), strains of E. coli have now been added, in particular strains producing colibactin from their polyketide synthesis (pks) locus. The evidence and mechanistic explanations for this unfortunate effect of what is in most cases a harmless commensal are discussed in the first part of this review. In the second part, observations are presented and discussed that do not fit with the hypothesis that colibactin-producing E. coli produce CRC. The last part of this review is reserved for an alternative explanation of the function of this enigmatic colibactin, a toxin that has not yet been isolated. It is hypothesized that E. coli preferentially colonizes cancerous lesions as an effect rather than a cause and that colibactin production provides a selective advantage to compete with other bacteria.

Topics: Animals; Colorectal Neoplasms; Escherichia coli; Escherichia coli Infections; Humans; Peptides; Polyketides

A significant challenge toward studies of the human microbiota involves establishing causal links between bacterial metabolites and human health and disease states. Certain strains of commensal Escherichia coli harbor the 54-kb clb gene cluster which codes for small molecules named precolibactins and colibactins. Several studies suggest colibactins are genotoxins and support a role for clb metabolites in colorectal cancer formation. Significant advances toward elucidating the structures and biosynthesis of the precolibactins and colibactins have been made using genetic approaches, but their full structures remain unknown. In this Perspective we describe recent synthetic efforts that have leveraged biosynthetic advances and shed light on the mechanism of action of clb metabolites. These studies indicate that deletion of the colibactin peptidase ClbP, a modification introduced to promote accumulation of precolibactins, leads to the production of non-genotoxic pyridone-based isolates derived from the diversion of linear biosynthetic intermediates toward alternative cyclization pathways. Furthermore, these studies suggest the active genotoxins (colibactins) are unsaturated imines that are potent DNA damaging agents, thereby confirming an earlier mechanism of action hypothesis. Although these imines have very recently been detected in bacterial extracts, they have to date confounded isolation. As the power of "meta-omics" approaches to natural products discovery further advance, we anticipate that chemical synthetic and biosynthetic studies will become increasingly interdependent.

Topics: Animals; Colorectal Neoplasms; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Humans; Imines; Mutagens; Peptide Hydrolases; Peptides; Polyketides

Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin. Colibactin-producing E. coli promote colorectal cancer (CRC) in preclinical models, and in vitro induce a specific mutational signature that is also detected in human CRC genomes. Yet, how colibactin exposure affects the mutational landscape of CRC in vivo remains unclear. Here we show that colibactin-producing E. coli-driven colonic tumors in mice have a significantly higher SBS burden and a larger percentage of these mutations can be attributed to a signature associated with mismatch repair deficiency (MMRd; SBS15), compared to tumors developed in the presence of colibactin-deficient E. coli. We found that the synthetic colibactin 742 but not an inactive analog 746 causes DNA damage and induces transcriptional activation of p53 and senescence signaling pathways in non-transformed human colonic epithelial cells. In MMRd colon cancer cells (HCT 116), chronic exposure to 742 resulted in the upregulation of BRCA1, Fanconi anemia, and MMR signaling pathways as revealed by global transcriptomic analysis. This was accompanied by increased T>N single-base substitutions (SBS) attributed to the proposed pks

Topics: Animals; Colonic Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair; Escherichia coli; Humans; Mice; Mutagens; Mutation

Colorectal cancer (CRC) is the third most prevalent cause of tumorigenesis and several pathogenic bacteria have been correlated with aggressive cases of cancer i.e., genotoxin (colibactin) producing Escherichia coli (E. coli). This study was designed to investigate the genetic diversity of clb+clb+ E. coli strains and their association with CRC. Pathogenic E. coli isolates from colorectal biopsies were characterized based on phylotypes, antibiotic resistance pattern, and (Enterobacterial Repetitive Intergenic Consensus Sequence-based Polymerase Chain Reaction) ERIC-PCR. Furthermore, isolates were screened for the presence of the Pks (polyketide synthase) Island specifically targeting colibactin genes A and Q. The selective clb+clb+ isolates were subjected to cytotoxicity assay using Human embryonic kidney (HEK) cell lines. We revealed that 43.47% of the cancer-associated E. coli isolates were from phylogroup B2 comparatively more pathogenic than rest while in the case of healthy controls no isolate was found from B2. Moreover, 90% were found positive for colibactin and pks (polyketide synthase) island, while none of the healthy controls were found positive for colibactin genes. All healthy and cancer-associated isolates were tested against 15 antibiotic agents, we observed that cancer-associated isolates showed a wide range of resistance from 96% against Nalidixic acid to 48% against Doxycycline. Moreover, E. coli isolates were further genotyped using ERIC-PCR, and selected clb+clb+ E. coli isolates were subjected to cytotoxicity assay. We recorded the significant cytotoxic activity of clb+clb+ E. coli phylogroup B2 isolates that might have contributed towards the progression of CRC or dysbiosis of healthy gut microbiota protecting against CRC pathogenesis. Our results revealed a significant p<0.023 association of dietary habits and hygiene p<0.001with CRC. This is the first study to report the prevalence of E. coli phylogroups and the role of colibactin most virulent phylogroup B2 among Pakistani individuals from low socioeconomic setup.

Topics: Colorectal Neoplasms; Escherichia coli; Escherichia coli Infections; Genetic Variation; Humans; Pakistan; Polyketide Synthases; Polyketides

Gut colonization by colibactin-producing bacteria is associated with colorectal cancer. A mutational signature of this genotoxin in human cancer indicates causality but only partially accounts for cell transformation. Instead, the failure of adequately resolving DNA damage causes genomic aberrations and chromosomal instability, constituting the main starting point for colibactin-driven cancer.

Topics: Cell Transformation, Neoplastic; Chromosome Aberrations; Colorectal Neoplasms; DNA Damage; Humans; Mutation; Peptides; Polyketides

Genotoxic colibactin-producing pks+ Escherichia coli induce DNA double-strand breaks, mutations, and promote tumor development in mouse models of colorectal cancer (CRC). Colibactin's distinct mutational signature is reflected in human CRC, suggesting a causal link. Here, we investigate its transformation potential using organoids from primary murine colon epithelial cells. Organoids recovered from short-term infection with pks+ E. coli show characteristics of CRC cells, e.g., enhanced proliferation, Wnt-independence, and impaired differentiation. Sequence analysis of Wnt-independent organoids reveals an enhanced mutational burden, including chromosomal aberrations typical of genomic instability. Although we do not find classic Wnt-signaling mutations, we identify several mutations in genes related to p53-signaling, including miR-34a. Knockout of Trp53 or miR-34 in organoids results in Wnt-independence, corroborating a functional interplay between the p53 and Wnt pathways. We propose larger chromosomal alterations and aneuploidy as the basis of transformation in these organoids, consistent with the early appearance of chromosomal instability in CRC.

Topics: Animals; Chromosome Aberrations; Colon; Colonic Neoplasms; Colorectal Neoplasms; DNA Damage; Epithelial Cells; Escherichia coli; Genomics; Male; Mice; Mice, Knockout; Mutation; Organoids; Peptides; Polyketides

Changes in the microbiome are associated with the development of colorectal cancer, but causal explanations have been lacking. We recently demonstrated that pks

Topics: Cells, Cultured; Colon; Colorectal Neoplasms; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Host Microbial Interactions; Humans; INDEL Mutation; Mutation; Organoids; Peptides; Polyketides; Polymorphism, Single Nucleotide; Transcriptome

Some E. coli strains that synthesize the toxin colibactin within the 54-kb pks island are being implicated in colorectal cancer (CRC) development. Here, the prevalence of pks. A realtime qPCR protocol was developed to quantify uidA, clbB, clbN, and clbA genes in formalin fixed paraffin embedded colorectal tissues. The number of malignant tumors (44/62; 71%) positive for the uidA gene was not significantly different (p = 0.3428) from benign (38/62; 61%) tumors. Significantly higher number of benign samples (p < 0.05) were positive for all three colibactin genes (clbB, clbN, and clbA) compared with malignant samples. There was also higher prevalence of pks. Hence, pks

Topics: Colorectal Neoplasms; Disease Susceptibility; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Humans; Neoplasm Grading; Neoplasm Staging; Peptides; Polyketides; Polymerase Chain Reaction

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

Various species of the intestinal microbiota have been associated with the development of colorectal cancer

Topics: Coculture Techniques; Cohort Studies; Colorectal Neoplasms; Consensus Sequence; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Genomic Islands; Humans; Mutagenesis; Mutation; Organoids; Peptides; Polyketides

The

Topics: Colorectal Neoplasms; DNA Damage; Escherichia coli; Humans; Peptides; Polyketides

Topics: Colorectal Neoplasms; DNA Damage; Escherichia coli; Humans; Microbiota; Peptides; Polyketides

The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin

Topics: Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; DNA Breaks, Double-Stranded; DNA Damage; Epithelial Cells; Escherichia coli; Humans; Mutation; Nucleotide Motifs; Peptides; Polyketides

Topics: Adenoma; Adenomatous Polyposis Coli; Carcinoma; Cohort Studies; Colorectal Neoplasms; Genes, APC; Humans; Mosaicism; Mutation; Peptides; Polyketides

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

In a recent issue of Science, Wilson et al. (2019) provide direct evidence that the bacterial-produced colibactin alkylates DNA in vivo, resulting in DNA adducts, which mediates its genotoxic effect. This work reinforces the role of colibactin-producing bacteria in colon cancer pathogenesis.

Topics: Colorectal Neoplasms; DNA Adducts; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Humans; Mutagens; Mutation; Peptides; Polyketides

While high-colibactin-producing Escherichia coli is thought to be associated with colorectal oncogenesis, this study is complicated part due to an inability to isolate colibactin adequately. Here, we created fluorescent probes activated by ClbP, the colibactin-maturing peptidase, to identify high-colibactin-producing strains. Our probe served as a valuable clinical diagnostic tool that allowed simple high-throughput diagnostic screening of clinical samples. Furthermore, the probe also allowed identification of high-colibactin producers that would help advance our understanding of colibactin biosynthesis.

Topics: Colorectal Neoplasms; Escherichia coli; Escherichia coli Proteins; Fluorescent Dyes; Humans; Molecular Structure; Peptides; Polyketides

Colorectal cancers (CRCs) are frequently colonised by colibactin toxin-producing Escherichia coli bacteria that induce DNA damage in host cells and exhibit protumoural activities. Our objective was to identify small molecules inhibiting the toxic effects induced by these colibactin-producing bacteria.. A structural approach was adopted for the identification of a putative ligand for the ClbP enzyme involved in the synthesis of colibactin. Intestinal epithelial cells and a CRC mouse model were used to assess the activity of the selected compounds in vitro and in vivo.. Docking experiments identified two boron-based compounds with computed ligand efficiency values (-0.8 and -0.9 kcal/mol/atom) consistent with data expected for medicinal chemistry leads. The crystalline structure of ClbP in complex with the compounds confirmed that the compounds were binding to the active site of ClbP. The two compounds (2 mM) suppressed the genotoxic activity of colibactin-producing E coli both in vitro and in vivo. The mean degree of suppression of DNA damage for the most efficient compound was 98±2% (95% CI). This compound also prevented cell proliferation and colibactin-producing E coli-induced tumourigenesis in mice. In a CRC murine model colonised by colibactin-producing E coli, the number of tumours decreased by 3.5-fold in animals receiving the compound in drinking water (p<0.01).. These results demonstrate that targeting colibactin production controls the genotoxic and protumoural effects induced by this toxin.

Topics: Animals; Boronic Acids; Calcium-Binding Proteins; Colorectal Neoplasms; DNA Damage; Escherichia coli; Ligands; Mice; Mice, Inbred BALB C; Mutagens; Peptides; Polyketides

Most cases of colorectal cancer (CRC) are sporadic, and numerous studies have suggested that gut microbiota may play a crucial role in CRC development. Escherichia coli is a member of the gut microbiota frequently associated with colorectal tumors. CRC-associated E. coli strains frequently harbor the pks genomic island. This genomic island is responsible for the synthesis of colibactin genotoxin, which increases tumor numbers in CRC mouse models. We recently showed that targeting ClbP, a key enzyme involved in colibactin synthesis, blocks the deleterious effect of this toxin in vitro and leads to a significant decrease in tumor numbers in vivo. Altogether, our results suggest that the personalized treatment of CRC should also take into consideration the bacteria associated with the tumor in order to limit their deleterious effects.

Topics: Animals; Anti-Bacterial Agents; Colorectal Neoplasms; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Genomic Islands; Humans; Mice; Peptide Hydrolases; Peptides; Polyketides; Precision Medicine

Numerous studies support a role for the intestinal microbiota in colorectal tumorigenesis. Although colon cancer has not yet been epidemiologically linked to specific bacterial species, recent results suggest that certain toxigenic commensal bacteria may be oncogenic Strains of Escherichia coli, a ubiquitous member of the colonic flora, synthesize a genotoxin called colibactin. These bacteria induce DNA double-strand breaks in intestinal cells and trigger chromosomal instability, gene mutations and cell transformation. Thus, long-term colonization of the colon by rogue commensal bacteria capable of causing chronic DNA damage could contribute to the development of sporadic colorectal cancer.

Topics: Colorectal Neoplasms; Escherichia coli; Humans; Intestines; Metagenome; Mutagens; Peptides; Polyketides