Microbiota and colorectal cancer: colibactin makes its mark

  title={Microbiota and colorectal cancer: colibactin makes its mark},
  author={Janelle C. Arthur},
  journal={Nature Reviews Gastroenterology \& Hepatology},
  • J. Arthur
  • Published 21 April 2020
  • Biology, Medicine
  • Nature Reviews Gastroenterology & Hepatology
Colibactin-producing bacteria are abundant in the gut microbiota of colorectal cancer tumours and promote colon tumorigenesis in mouse models. Now, a new study demonstrates a direct link between exposure of human intestinal epithelial cells to colibactin and two unique mutational fingerprints found in human colorectal tumours. 

Evolution of Polymyxin Resistance Regulates Colibactin Production in Escherichia coli.

It is demonstrated that polymyxin B, a last resort antibiotic, influences the production of the genotoxic metabolite colibactin from adherent-invasive Escherichia coli (AIEC) NC101, and this study establishes a key link between the polymyXin B stress response and colibACTin production in pks+ E. coli.

Exploring the Inflammatory Pathogenesis of Colorectal Cancer

This review will explore the roles of obesity and diet, smoking, diabetes, the microbiome, the mycobiome and exosomes in colorectal cancer, with a specific focus on the underlying inflammatory and metabolic pathways involved.

Microenvironmental Factors that Shape Bacterial Metabolites in Inflammatory Bowel Disease

How changes in host inflammation status, metal availability, interbacterial community structure, and xenobiotics all play an important role in shaping gut microbial ecology is outlined, with a specific focus on IBD-associated Enterobacteriaceae metabolites.

Cholecystectomy promotes the development of colorectal cancer by the alternation of bile acid metabolism and the gut microbiota

This review discussed how bile acid metabolism, gut microbiota, and the interaction between the two factors influence the development of CRC, and summarized the underlying mechanisms of the alterations in bile Acid metabolism after cholecystectomy including cellular level, molecular level, and signaling pathways.

Alterations in the Gut Microbiota and Their Metabolites in Colorectal Cancer: Recent Progress and Future Prospects

Gut microbiota and their metabolites influence the progression and causation of CRC, and the association analysis of metabolomics and gut microbiome will provide novel strategies for the prevention, diagnosis, and therapy of CRC.

Recent advances in microbial toxin-related strategies to combat cancer.

Which bacterial toxins are worthy of validation as markers in colorectal cancer screening? A critical review.

In this review, colibactin and Bacteroides fragilis toxin are the best candidates, possibly complemented by the cytotoxic necrotizing factor (CNF) and recommended for prospective evaluation of their true ability to increase the sensitivity of FOBT when combined during general population screening.

Molecular Underpinnings and Environmental Drivers of Spontaneous Loss of Heterozygosity in Drosophila Intestinal Stem Cells

A mechanistic understanding of mitotic recombination in stem cells in vivo, an important mediator of LOH, is provided using whole-genome sequencing of somatic LOH events to demonstrate that they arise primarily via mitosis recombination.

TaxiBGC: a Taxonomy-guided Approach for the Identification of Experimentally Verified Microbial Biosynthetic Gene Clusters in Shotgun Metagenomic Data

Biosynthetic gene clusters (BGCs) in microbial genomes encode for the production of bioactive secondary metabolites (SMs). Given the well-recognized importance of SMs in microbe-microbe and

Detection of pks Island mRNAs Using Toehold Sensors in Escherichia coli

‘Helper RNAs’ are introduced that can enhance the functionality of toehold switch sensors by mitigating the effect of secondary structures around a target site by employing the helper RNAs.



Mutational signature in colorectal cancer caused by genotoxic pks+E. coli

A distinct mutational signature in colorectal cancer is described and it is implied that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

Molecular Basis of Gut Microbiome-Associated Colorectal Cancer: A Synthetic Perspective.

These studies indicate that deletion of the colibactin peptidase ClbP leads to the production of non-genotoxic pyridone-based isolates derived from the diversion of linear biosynthetic intermediates toward alternative cyclization pathways, and suggest the active genotoxins (colibactins) are unsaturated imines that are potent DNA damaging agents, thereby confirming an earlier mechanism of action hypothesis.

The human gut bacterial genotoxin colibactin alkylates DNA

Interestingly, the isolation and structural characterization of metabolites from mutant strains of pks+ E. coli revealed that colibactin likely contains a cyclopropane ring, a reactive structural motif found in DNA alkylating natural products, which led to hypothesize that colIBactin may covalently modify DNA.

Colibactin DNA damage signature indicates causative role in colorectal cancer

Interestingly, genomic contexts of DSBs were enriched for AT-rich penta-/hexameric sequence motifs, exhibiting a particularly narrow minor groove width and extremely negative electrostatic potential, which corresponded with the binding characteristics of colibactin to double-stranded DNA, as elucidated by docking and molecular dynamics simulations.

Structure elucidation of colibactin and its DNA cross-links

The structure of colibactin is revealed, which accounts for the entire gene cluster encoding its biosynthesis, a goal that has remained beyond reach for more than a decade.

The landscape of somatic mutation in normal colorectal epithelial cells

Probably driver mutations were present in ∼1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colOREctal epithelium.

Escherichia coli Induces DNA Double-Strand Breaks in Eukaryotic Cells

Discovery of hybrid peptide-polyketide genotoxins in E. coli will change the view on pathogenesis and commensalism and open new biotechnological applications.

The repertoire of mutational signatures in human cancer

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet- base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota

High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10–deficient (Il10−/−) mice, suggesting that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities.