The microbiome-product colibactin hits unique cellular targets mediating host–microbe interaction

Abstract

The human microbiota produces molecules that are evolved to interact with the diverse cellular machinery of both the host and microbes, mediating health and diseases. One of the most puzzling microbiome molecules is colibactin, a genotoxin encoded in some commensal and extraintestinal microbes and is implicated in initiating colorectal cancer. The colibactin cluster was discovered more than 15 years ago, and most of the research studies have been focused on revealing the biosynthesis and precise structure of the cryptic encoded molecule(s) and the mechanism of carcinogenesis. In 2022, the Balskus group revealed that colibactin not only hits targets in the eukaryotic cell machinery but also in the prokaryotic cell. To that end, colibactin crosslinks the DNA resulting in activation of the SOS signaling pathway, leading to prophage induction from bacterial lysogens and modulation of virulence genes in pathogenic species. These unique activities of colibactin highlight its ecological role in shaping gut microbial communities and further consequences that impact human health. This review dives in-depth into the molecular mechanisms underpinning colibactin cellular targets in eukaryotic and prokaryotic cells, aiming to understand the fine details of the role of secreted microbiome chemistry in mediating host–microbe and microbe–microbe interactions. This understanding translates into a better realization of microbiome potential and how this could be advanced to future microbiome-based therapeutics or diagnostic biomarkers.

Gut commensals and their metabolites in health and disease

“…Colibactin is a genotoxic gut metabolite produced by a hybrid non-ribosomal peptide synthetase-polyketide synthase assembly line encoded by the pks genomic island (also known as clb gene cluster). pks genomic islands are present in Enterobacteriaceae that belong to the phylogenetic group B (Mousa, 2022). The structure of colibactin is given in Supplementary Figure S7.…”

“…Although the pks + E. coli 's genotoxicity and its ability to cause DNA double-strand breaks in cultured epithelial cells was identified a decade ago, the chemical species responsible for these effects wasn't identified. This was because the isolation and structural elucidation of colibactin was challenged due to its contact-dependent synthesis, minimal expression, and chemical instability (Mousa, 2022). Metabolomic studies identified that colibactin was contributing to pks + E. coli's genotoxic effects with its ability to cause double-strand DNA breaks, eukaryotic cell cycle arrest, and chromosome aberrations (Mousa, 2022;Silpe et al, 2022).…”

“…This was because the isolation and structural elucidation of colibactin was challenged due to its contact-dependent synthesis, minimal expression, and chemical instability (Mousa, 2022). Metabolomic studies identified that colibactin was contributing to pks + E. coli's genotoxic effects with its ability to cause double-strand DNA breaks, eukaryotic cell cycle arrest, and chromosome aberrations (Mousa, 2022;Silpe et al, 2022). These studies suggested that colibactin has a pseudodimeric structure, with a reactive cyclopropane warhead at each end which could account for its characteristic DNA-alkylating ability (Silpe et al, 2022).…”

“…This creates a second electrophilic center that further reacts with DNA to form a crosslink. Cross-linked DNA adducts trigger multiple DNA repair signaling pathways which result in the formation of double-stranded breaks and further, carcinogenesis (Mousa, 2022).…”

“…A study which observed a shift in gut microorganisms during inflammation (with unknown directionality of DNA damage leading to tumor and inflammatory cytokines and cells promoting tumourgenesis by creating a microenvironment that enables more DNA damage) was characterized by enrichment in genera of E. coli. This microbial shift could be associated with inflammation (Mousa, 2022). A cell-line study revealed that the expression of mucin genes which form the mucous layer on the intestinal epithelia decreased the genotoxic effect of colibactin.…”