• Colitis and colon cancer progressed more strongly in Hfe-/- mice than in wild-type mice.• Sequencing of fecal 16S RNA showed considerable changes in the colonic microbiome in Hfe-/- mice: pathogenic bacteria like phyla Proteobacteria and TM7 were more dominant.• Expression of innate antimicrobial peptides declined• The level of pro-inflammatory cytokines increased significantly in Hfe-/- mouse colon. Here, HFE is linked to colitis.