Tackling the Threat of Cancer Due to Pathobionts Producing Colibactin: Is Mesalamine the Magic Bullet?

Min Tang-Fichaux,Jean-Philippe Nougayrède,Eric Oswald,Priscilla Branchu

doi:10.3390/toxins13120897

Abstract

Colibactin is a genotoxin produced primarily by Escherichia coli harboring the genomic pks island (pks+ E. coli). Pks+ E. coli cause host cell DNA damage, leading to chromosomal instability and gene mutations. The signature of colibactin-induced mutations has been described and found in human colorectal cancer (CRC) genomes. An inflamed intestinal environment drives the expansion of pks+ E. coli and promotes tumorigenesis. Mesalamine (i.e., 5-aminosalycilic acid), an effective anti-inflammatory drug, is an inhibitor of the bacterial polyphosphate kinase (PPK). This drug not only inhibits the production of intestinal inflammatory mediators and the proliferation of CRC cells, but also limits the abundance of E. coli in the gut microbiota and diminishes the production of colibactin. Here, we describe the link between intestinal inflammation and colorectal cancer induced by pks+ E. coli. We discuss the potential mechanisms of the pleiotropic role of mesalamine in treating both inflammatory bowel diseases and reducing the risk of CRC due to pks+ E. coli.

Highlights

Escherichia coli is a ubiquitous intestinal commensal and one of the most frequently isolated organisms from clinical specimens
We have recently shown that mesalamine directly reduces colibactin production by pks+ E. coli in a polyphosphate kinase (PPK)-dependent/ independent manner [44]
We describe the association of pks+ E. coli and intestinal inflammation in the development of colorectal cancer (CRC), and we discuss the pleiotropic role of mesalamine in the prevention of CRC due to bacteria producing colibactin

Summary

Introduction

Escherichia coli is a ubiquitous intestinal commensal and one of the most frequently isolated organisms from clinical specimens. Colibactin directly damages host DNA both in vitro [10,11,12] and in vivo [5,13,14,15,16,17,18,19] This genotoxin is linked to the virulence of pathogenic E. coli [15,17,20], 4.0/). We describe the association of pks+ E. coli and intestinal inflammation in the development of CRC, and we discuss the pleiotropic role of mesalamine in the prevention of CRC due to bacteria producing colibactin. 2. Pks+ E. coli Induce DNA Damage and Have a Mutational Impact in Colorectal Cancer. Pks+ E. coli Induce DNA Damage and Have a Mutational Impact in Colorectal Cancer Unlike other genotoxins such as CDT, colibactin is not a proteinaceous “exotoxin” [45]. DNA damages potentially can result in gene mutations which may trigger carcinogenesis

Intestinal Inflammation Contributes to Colorectal Cancer

Effects of Mesalamine on the Host

Findings

Conclusions