Hemochromatosis, an inherited iron-overload disease, causes tissue damage due to deposition of iron in toxic levels in most tissues including the liver, heart, kidney, pancreas and colon. Free iron, both in the inorganic form (i.e, non-transferrin-bound and non-ferritin-bound) and organic form (i.e. heme), facilitates Fenton reaction to generate hydroxyl radicals and to induce cellular oxidative damage that is observed in carcinogenesis. The primary site of iron deposition in hemochromatosis patients is liver, and therefore, liver cancer formation in these patients has been studied extensively. However, little is known about the iron-elicited colonic pathologies, mainly colonic inflammation and colon cancer. Here we postulate that iron overload as observed in hemochromatosis disrupts healthy colonic homeostasis and exacerbates the development of colon inflammation and colon cancer. To test our hypothesis, we examined the progression and severity of colitis and colon cancer in Hfe-/- mouse and the wild type control. Hfe-/- mouse is a model for classical hemochromatosis. Besides serum and liver, high concentrations of iron and heme deposits are found in the colon of Hfe-/- mouse. Experimental colitis was induced by administration of Dextran Sodium Sulfate (DSS) in drinking water. Colitis-associated colon cancer was initiated by the intraperitoneal injection of carcinogen, azoxymethane (AOM) and the carcinogenesis was driven by DSS administration. Colonic inflammation was more severe in the Hfe-/- mouse than in control. In addition, hemochromatosis mouse developed more and larger colonic polyps than the control group. We observed that this high susceptibility to colitis and colon cancer in Hfe-/- but not wild type mouse, lies in the differences in strains regarding the bacterial composition and colonic defense machinery. 16S ribosomal RNA sequencing of fecal bacteria revealed that the microbiota composition of Hfe-/- mouse altered to favor the pathogenic bacteria that belong to phyla Proteobacteria and TM7. In addition, the Hfe-/- proinflammatory bacteria adhered to colon and thus increased the colonic bacterial load. This phenomenon, addressed as bacterial dysbiosis, is considered a hallmark of colon inflammation and colon cancer. Furthermore, we observed that the colonic epithelial cells of Hfe-/- mouse had a lower expression of antimicrobial peptides and thus a defective first line defense against the pathogens. Finally, hemochromatosis mouse colon under inflammation released higher concentration of the pro-inflammatory cytokines that contributed to the creation of the hostile colonic environment. In summary, iron overload as seen in hemochromatosis, impairs the colonic defense machinery and it causes bacterial dysbiosis, thus providing the ideal environment for the colitis and colon cancer development.
Citation Format: Bojana Ristic, Sathish Sivaprakasam, Rao Kottapalli, Abdul Hamood, Vadivel Ganapathy. Bacterial dysbiosis in the mouse model of hemochromatosis: Increased risk of colitis and colitis-associated colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1479.