Background <p>Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. While the gut microbiota has been shown to influence CRC development, the specific contribution of bacteria to DNA methylation and carcinogenesis remains underexplored.</p> Results <p>We colonize two groups of GF <i>Apc</i>^<i>Min/</i>+ mice with two consortia, one harboring a <i>pks</i>⁺ <i>E. coli</i> strain with "low-<i>pks</i>" activity (DSMZ) and the second with a clinical isolate exhibiting "high-<i>pks</i>" activity (UM149). These colonized mice are exposed to DSS-induced colitis, and analyzed for tumor burden, DNA methylation, and transcriptional changes. We find that colonization with C13-UM149 leads to more tumors, increased cell proliferation, and higher DNA damage compared to C13-DSMZ (<i>p</i> &lt; 0.05). Methylation analyses show that C13-DSMZ causes extensive promoter hypermethylation and altered gene expression. Differential DNA methylation in mice colonized with either C13-DSMZ or C13-UM149 is associated with changes in pathways controlling tumor suppression, cell proliferation, inflammation, and <i>Wnt</i> signaling. In C13-DSMZ mice, hypermethylation is associated with gene expression involved in tumor suppression in both tumors and normal tissue, whereas hypomethylation is linked to expression of genes promoting <i>Wnt</i> signaling. In C13-UM149 mice, methylation changes were connected to genes involved in epithelial proliferation, extracellular matrix remodeling, and inflammatory responses.</p> Conclusions <p>These findings demonstrate that intestinal bacteria with distinct <i>pks</i> activities differentially modulate DNA methylation thereby influencing gene expression and tumor development. This highlights bacterial modulation of epigenetic responses as a potential mechanism underlying CRC progression.</p>