<p>Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer development; however, it is not clear whether and how these factors interact to promote carcinogenesis. Here we used <i>Il10</i>^{−<i>/</i>−} mice colonized with bacteria previously associated with colorectal cancer: enterotoxigenic <i>Bacteroides fragilis</i>, <i>Helicobacter hepaticus</i> or colibactin-producing (polyketide synthase-positive (<i>pks</i>⁺)) <i>Escherichia coli</i> and fed either a low-carbohydrate (LC) diet deficient in soluble fibre, a high-fat and high-sugar diet, or a normal chow diet. Colonic polyposis was increased in mice colonized with <i>pks</i>⁺ <i>E. coli</i> and fed the LC diet. 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 <i>pks</i>⁺ <i>E. coli</i> 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. The <i>pks</i>⁺ <i>E. coli</i> also induced more polyps in mismatch-repair-deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the mismatch-repair-deficient model. These data reveal that diet and host genetics influence the oncogenic potential of a common bacterium.</p>