Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, Evry, France.
Published: October 2024
AI Article Synopsis
Article Abstract
Unlabelled: Colibactin, a nonribosomal peptide/polyketide produced by , is a virulence factor and putative carcinogen that damages DNA by interstrand crosslinking (ICL). While the genes for colibactin biosynthesis have been identified, studies are needed to elucidate the mechanisms regulating colibactin production and activity. Here we perform untargeted metabolomics of coli cultures to identify L-tryptophan as a candidate repressor of colibactin activity. When is grown in a minimal medium supplemented with L-tryptophan ICL of plasmid DNA is reduced by >80%. L-tryptophan does not affect the transcription of genes but protects from copper toxicity and triggers the expression of genes to export copper to the periplasm where copper can directly inhibit the ClbP peptidase domain. Thus, L-tryptophan and copper interact and repress colibactin activity, potentially reducing its carcinogenic effects in the intestine.
Importance: Colibactin is a small molecule produced by + that damages DNA, leading to oncogenic mutations in human genomes. Colibactin-producing (+) cells promote tumorigenesis in mouse models of colorectal cancer (CRC) and are elevated in abundance in CRC patient biopsies, making it important to identify the regulatory systems governing colibactin production. Here, we apply a systems biology approach to explore metabolite repression of colibactin production in + . We identify L-tryptophan as a repressor of colibactin genotoxicity that stimulates the expression of genes to export copper to the periplasm where it can inhibit ClbP, the colibactin-activating peptidase. These results work toward an antibiotic-sparing, prophylactic strategy to inhibit colibactin genotoxicity and its tumorigenic effects in the intestine.
Unlabelled: The bacterial toxin colibactin, produced primarily by the B2 phylogroup of , underlies some cases of colorectal cancers. Colibactin crosslinks DNA and induces genotoxic damage in both mammalian and bacterial cells. While the mechanisms facilitating colibactin delivery remain unclear, results from multiple studies supported a delivery model that necessitates cell-cell contact.
Various bacteria are suggested to contribute to colorectal cancer (CRC) development, including pks Escherichia coli, which produces the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells. However, it remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells to cause harm. Here, using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC, we demonstrate that the oncogenic potential of pks E.
The gastrointestinal and respiratory systems are closely linked in different ways, including from the embryological, anatomical, cellular, and physiological angles. The highest number (and various types) of microorganisms live in the large intestine/colon, and constitute the normal microbiota in healthy people. Adverse alterations of the microbiota or dysbiosis can lead to chronic inflammation.
Unlabelled: Colibactin, a nonribosomal peptide/polyketide produced by , is a virulence factor and putative carcinogen that damages DNA by interstrand crosslinking (ICL). While the genes for colibactin biosynthesis have been identified, studies are needed to elucidate the mechanisms regulating colibactin production and activity. Here we perform untargeted metabolomics of coli cultures to identify L-tryptophan as a candidate repressor of colibactin activity.
Recently, the mounting integration of probiotics into human health strategies has gathered considerable attention. Although the benefits of probiotics have been widely recognized in patients with gastrointestinal disorders, immune system modulation, and chronic-degenerative diseases, there is a growing need to evaluate their potential risks. In this context, new concerns have arisen regarding the safety of probiotics as some strains may have adverse effects in humans.
