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. 2023 Mar 16;15(1):2185028. doi: 10.1080/19490976.2023.2185028

Figure 1.

Figure 1.

Carcinogenic mechanisms of intestinal bacteria. a) pks+ Escherichia coli produce a genotoxin known as colibactin, that induces interstrand crosslinks in host cells resulting in a defined mutational signature detected in colorectal cancer (CRC) genomes. The right panel shows several microbial genotoxins with nonspecific DNA degrading activity, including the cytolethal distending toxin (CDT) found in the human enteric pathogen Campylobacter jejuni, UshA in the murine bacteria Citrobacter rodentium, and indolimines isolated from a commenstal strain of Morganella morganii obtained from patients with inflammatory bowel disease. b) Enterotoxigenic bacteroides fragilis (ETBF) secretes a toxin known as the bacteroides fragilis toxin (BFT), that degrades E-cadherin promoting nuclear translocation of β-Catenin and the activation of proliferative signaling pathways to promote tumor formation. Fusobacterium nucleatum produces a membrane-bound Fusobacterium adhesin A (FadA) protein that binds to E-cadherin to upregulate expression of the Annexin A1/β-Catenin complex to activate proliferative signaling pathways. AvrA is a virulence factor produced by Salmonella spp. promoting epithelial adherence and persistent colonization in the gastrointestinal tract, while simultaneously activating AKT serine/threonine kinase 1 (AKT)-mediated β-Catenin phosphorylation, facilitating nuclear translocation and the activation of signaling pathways to promote proliferation and cell survival. Peptostreptococcus anaerobius are selectively enriched in CRC tissue, facilitated in part by the binding of an outer membrane protein putative cell wall binding repeat 2 (PCWBR2) to α2/β1 integrins overexpressed in cancer cells. This interaction promotes phosphoinositide 3-kinase (P13K) and AKT phosphorylation to promote cell proliferation. c) A superoxide producing strain (OG1RF) of the human pathogen Enterococcus faecalis causes chromosomal instability after infection in cell lines and intestinal ligation models, resulting from the production of reactive oxygen species (ROS). Alternatively, OG1RF infected macrophages elicit similar effects in human cell lines. On the right, infection with ETBF upregulates expression of a spermine oxidase that generates ROS and DNA damage in colonic epithelial cells. d) F. nucleatum produces short-chain fatty acids (SCFA) that bind to Free Fatty Acid Receptor 2 (Ffar2) receptors on T helper 17 (Th17) macrophages or an undetermined intermediate dendritic cell to stimulate interleukin 17 (IL-17) production. The human pathogens Enterotoxigenic Bacteroides fragilis (ETBF) and Clostridioides difficile (C. difficile) secrete toxins (the Bacteroides fragilis toxin, BFT, and Clostridioides difficile toxin B, TcdB, respectively) that promote signal transducer and activator of transcription 3 (STAT3) phosphorylation and the recruitment of IL-17 producing Th17 cells. In both cases, these microbes promote IL-17 mediated inflammation that contributes to neoplastic transformation. e) ETBF infection promotes hypermethylation in ApcMin/+BRAFV600ELgr5Cre mice, resulting in the formation of proximal tumors and activation of IFNγ gene signatures. F. nucleatum infection downregulates methyltransferase 3 (METTL3) expression in a Yes1 associated transcriptional regulator (YAP)-dependent manner to inhibit m6A RNA methylation, altering mRNA translation to promote cancer metastasis.