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Gut microbiota can influence genomic stability of the host in both direct and indirect ways. Colorectal cancer stands as an example of this phenomenon. There are two indirect mechanisms. First, gut microbes can elicit a chronic inflammatory response, which may promote the release of DNA-damaging reactive oxygen species (ROS) and reactive nitrogen species (RNS). Dysbiotic microbiotas constantly provide antigens, such as components of the bacterial cell, which stimulate the host immune system, inducing chronic inflammation. Second, gut microbes can produce secondary metabolites (such as SCFAs, hydrogen sulfide, and secondary bile acids) that can impact the host genome. Specifically, SCFAs exert a protective role by suppressing inflammation, whereas hydrogen sulfide, secondary bile acids, and other molecules cause DNA damage, exerting a procarcinogenic effect. Direct mechanisms include the production of ROS and RNS or toxins by bacteria.

For example, in in vitro studies, colibactin produced by pks+ Escherichia coli was associated with the induction of DNA double-strand breaks and chromosomal aberration. Working synergistically with enterotoxigenic Bacteroides fragilis, pks+ E. coli increases DNA damage, inflammation, and tumor formation in a mouse model of colorectal cancer. Other bacterial toxins that can directly damage DNA and modulate tumorigenesis are cytolethal distending toxin and cytotoxic necrotizing factor 1. Besides E. coli and B. fragilis, Shigella dysenteriae, Actinobacillus actinomycetemcomitans, Campylobacter, Helicobacter, Salmonella typhi, and H. ducreyi have been suggested to release toxins that can cause DNA damage, cell cycle arrest, or apoptosis. Also, enteropathogenic E. coli is associated with the depletion of host proteins needed for DNA repair, leading to an increased frequency of mutations. Furthermore, chromosomal instability seems to be induced by a microbialmacrophage interaction. Specifically, by influencing macrophages, Enterococcus faecalis was associated with chromosomal instability induction and cancerogenic DNA mutations in cancer-driving genes.