Written by | November
Colibactin is a chemically unstable small molecule genotone produced by several different bacteria, including human gut microbes, whose synthesis relies on a 54 kb-size ribosomal polypeptide synthase-polyketone synthase biosynthetic gene cluster, known as pks Island (Figure 1) [1, 2]. Colibactin has been extensively studied in humans, etc., because this metabolite induces crosslinking between DNA strands in vitro, causes cell cycle blockage in eukaryotic cell culture, and promotes tumor formation in mouse models of colorectal cancer [3]. But compared to its effects on eukaryotes, the effect of Colibactin on the microbial community is unknown.
Figure 1 Genotoxin Colibactin and pks Island
Recently, the Emily P. Balskus research group of Harvard University in the United States published an article on Nature The bacterial toxin colibactin triggers prophage induction, which found that the gene toxin Colibactin will trigger the production of microbial original phages, but non-genetoxin producing bacteria will produce resistance and protection, thereby protecting bacteria from the genotoxin. The resistance genes of Colibactin and the mechanism by which microbial products affect the microbial community were determined.
The study began with multiple evidences of DNA damage mediated by Colibactin gene toxins. Different mechanisms of self-resistance are encoded in bacteria, suggesting that Colibactin is as harmful to other bacteria as many toxic bacterial natural products. But by mixing Colibactin-producing bacteria 1:1 with Colibactin-producing bacteria, the authors found that the growth of Colibactin-producing bacteria was not significantly affected. So what is the effect of the genotone Colibactin on other microbial communities? The authors speculate that it may be protophage induction, as studies have shown that ultraviolet light, along with chemical agents, causes the activation of bacteriophages in bacteria, thereby killing cells and creating harm in a wider microbial community [4]. Prophages are a latent form of phage infection that integrates phage nucleic acids into bacteria. So the authors wondered if Colibactin would affect the bacterial community by activating protophages. To test this possibility, the authors infected wild-type E. coli with phages and co-cultured them with pks+ or pks-E. coli. The results showed that Colibactin specifically affects bacteria by inducing protophages, and this process relies on mutual contact between cells and phage receptor genes in bacteria.
The authors then wanted to further expand the detection of the genotoxic effects of Colibactin, so pks+ or pks-E. co-cultured with a variety of intestinal strains carrying protophages. The authors found that Colibactin induces an associated prophage response in humans, both in vitro co-culture environments and in environments close to the gut microbiome in vivo. In addition, the authors' results showed that strains of pks- produced Colibactin resistance, and the authors wanted to know the specific molecular mechanisms in it. Through bioinformatics, the authors found that the self-resistant protein ClbS in E. coli provides bacteria with an umbrella against Colibactin, and the specific mechanism of this resistance process is to promote the silencing of the phage genome.
Colibactin, a complex natural product produced by gut bacteria, has a wide range of biological targets as well as pathogenic results. But the effects of this gene toxin on the microbiome have not been clear. By inducing prophage activity of Colibactin-producing bacteria on other bacteria, the authors revealed a new mechanism: that natural products in bacteria such as Colibactin that may destroy DNA have a shaping effect on the microbial community. In addition, this mechanism provides a unique idea for the treatment of multiple tumors, because resistance mechanisms are created in non-Colibactin-producing strains to protect the microbial community, which lays the foundation for further study of how bacterial metabolites regulate bacteriophage behavior and affect human diseases.
Original link:
https://doi.org/10.1038/s41586-022-04444-3
Model Maker: Eleven
bibliography
1. Nougayrède, J.-P. et al. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313, 848–851 (2006).
2. Auvray, F. et al. Insights into the acquisition of the pks island and production of colibactin in the Escherichia coli population. Microb. Genomics 7, 000579 (2021).
3. Dougherty, M. W. & Jobin, C. Shining a light on colibactin biology. Toxins 13, 346 (2021).
4. Ofir, G. & Sorek, R. Contemporary phage biology: from classic models to new insights. Cell 172, 1260–1270 (2018)
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