Tu190 - Dietary Fibre Counters the Oncogenic Potential of Colibactin-producing Escherichia coli in Colorectal Cancer

Abstract Text: Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer (CRC) development, however it is not clear whether and how these factors interact to promote carcinogenesis. Here, we used Il10-/- mice colonized with bacteria previously associated with CRC: enterotoxigenic Bacteroides fragilis, Helicobacter hepaticus, or colibactin-producing (pks+) Escherichia coli and fed either a low carbohydrate (LC) deficient in soluble fibre, a high fat-high sugar, or a normal chow diet. Colonic polyposis was increased in mice colonized with pks+ E. coli and fed the LC diet, that was dependent on colibactin. Mechanistically, mucosal inflammation was increased in the LC diet-fed mice, leading to diminished colonic PPAR-γ signalling and increased luminal nitrate levels. This promoted both pks+ E. coli growth and colibactin-induced DNA damage. PPAR-γ agonists or supplementation with dietary soluble fibre in the form of inulin reverted inflammatory and polyposis phenotypes. Since colibactin toxin produced by pks+ E. coli causes DNA adducts, interstrand DNA cross-links and double-stranded DNA breaks (DSBs), we also tested whether deficiencies in DNA repair pathways that repair DNA lesions produced by colibactin could increase susceptibility to colon carcinogenesis. Indeed, pks+ E. coli induced more polyps in mismatch repair (MMR)- deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the MMR-deficient model. These data reveal a dynamic interplay between diet and host genetics that shape the local mucosal milieu to influence the oncogenic potential of a common pathobiont.