Shining a Light on Colibactin Biology

Abstract

Colibactin is a secondary metabolite encoded by the pks gene island identified in several Enterobacteriaceae, including some pathogenic Escherichia coli (E. coli) commonly enriched in mucosal tissue collected from patients with inflammatory bowel disease and colorectal cancer. E. coli harboring this biosynthetic gene cluster cause DNA damage and tumorigenesis in cell lines and pre-clinical models, yet fundamental knowledge regarding colibactin function is lacking. To accurately assess the role of pks+ E. coli in cancer etiology, the biological mechanisms governing production and delivery of colibactin by these bacteria must be elucidated. In this review, we will focus on recent advances in our understanding of colibactin’s structural mode-of-action and mutagenic potential with consideration for how this activity may be regulated by physiologic conditions within the intestine.

A Probiotic Friend

“…If infants are already frequently colonized by pks -bearing strains, if these strains are persistent over time, and if they are able to induce colorectal cancer later in life, it needs to be explained why only such a relatively small fraction of CRC tumors bear this signature. This paradox has also been noticed by others, suggesting that the presence of commensal pks + bacteria alone is likely insufficient for cancer development and such bacteria exert a carcinogenic influence only under specific conditions ( 12 ). The genotoxic activity of colibactin is observed only following direct cell-cell contact ( 6 ), plus the transcriptional activation of all clb genes of the pks island seems to be required ( 12 ).…”

“…This paradox has also been noticed by others, suggesting that the presence of commensal pks + bacteria alone is likely insufficient for cancer development and such bacteria exert a carcinogenic influence only under specific conditions ( 12 ). The genotoxic activity of colibactin is observed only following direct cell-cell contact ( 6 ), plus the transcriptional activation of all clb genes of the pks island seems to be required ( 12 ). The direct cell-cell contact of pks + strains with host epithelium cells is not only hampered by presence of mucus in the gut ( 13 ), but the intestinal barrier is even enhanced by EcN’s ability to promote mucus production and to seal the tight junctions ( 14 ).…”

“…The direct cell-cell contact of pks + strains with host epithelium cells is not only hampered by presence of mucus in the gut ( 13 ), but the intestinal barrier is even enhanced by EcN’s ability to promote mucus production and to seal the tight junctions ( 14 ). Transcriptional regulation of clb genes is influenced by many factors (e.g., metabolites), and transcription of several clb components is promoted by inflammation ( 12 ), but EcN is known to be anti-inflammatory by modulating the host immune system in multiple ways ( 14 ).…”

“…Obviously, the onset of CRC is multifactorial, to which genetic factors and diet also contribute. Additionally, DNA damage repair responses play an important role (reviewed in, for example, references 12 and 15 ). It is therefore relevant to consider the possibility that most of the DNA damage induced by colibactin would be repaired or would generally result in apoptosis.…”

Host–Microbiota Interactions in Liver Inflammation and Cancer

“…Indeed, mycotoxins, including aflatoxins, which are secondary metabolites produced by fungi, lead to microbiome dysbiosis and intestinal permeability that indirectly promotes liver cancer, as previously discussed. Additional examples of carcinogenic compounds produced by bacteria of the gut microbiome include (a) colibactin produced by the polyketide synthase (pks) island of certain E. coli species [91]; (b) a zinc-dependent metalloprotease toxin produced by enterotoxigenic Bacteroides fragilis, termed B. fragilis toxin (BTF) [92]; and (c) a carcinogenic Fusobacterium nucleatum adhesion complex encoded by FadA [93]. While these bacterial products have been demonstrated to contribute to colorectal cancer, by inducing DNA damage, stimulating STAT3 or β-catenin activation, respectively, their role in liver cancer is less well established.…”