Iron (III)-Sodium-EDTA, as used for food fortification, aggravates intestinal inflammation and drives tumorigenesis in mouse models of colitis-associated cancer

Abstract

Western lifestyle is associated with increasing prevalence of IBD, processed food and food fortification being a likely cause. Iron supplementation may increase gut inflammation and colitis-associated cancer (CAC). Novel Fe products which are chemically not Fe(II) salts and presumably better tolerated have become available. Here we compared various Fe compounds at 450 mg elemental Fe/kg chow [Na-EDTA-Fe(III) (as used for food fortification), Fe(III)maltol (Iron Therapeutics), plant Fe (Biogena), and Fe(II)SO4)], in their potential to promote colitis and CAC in animal models (AOM/DSS and IL-10-/-). In addition, in vitro experiments evaluated ROS production (DCFD assay), DNA damage (yH2AX) and oncogenic pathways in HT29, HCT116, Caco-2, RKO, and 1CT cells. Unexpectedly, Na-EDTA-Fe(III)-treated mice developed the severest form of colitis and only the 1st and last DSS cycles were administered. Similarly, in IL-10-/- mice, the Na-EDTA-Fe(III) group was euthanized 4 months before all other groups due to severe weight loss and disease activity (DAI). The mean DAI in the Na-EDTA-Fe(III) AOM/DSS mice was higher (1.82 vs. 0.94 (control), 0.76 (Fe(II)SO4), 0.67 (Fe(III)maltol), 0.54 (plant Fe), 0.80 (iron deficient); p < 0.001 by ANOVA). The total tumor area was higher with Na-EDTA-Fe(III) (5.96 mm2 vs. 1.38 mm2 (control), 1.88 mm2 (FeSO4), 1.97 mm2 (Fe(III)maltol), 0.98 mm2 (plant Fe), 1.51 mm2 (iron deficient); p = 0.001 by ANOVA) and there were more invasive tumors. ROS production was not elevated but there was an increase in yH2AX with Na-EDTA-Fe(III) and phosphorylation of Akt and Erk. Na-EDTA-Fe(III), as used for fortification in flour and cereals, exacerbates intestinal inflammation and drives tumorigenesis in mouse models of IBD. It is unclear whether this effect is caused by EDTA itself (which also is added to food as Na-EDTA or Na-EDTA-Ca(II)) or only in conjunction with Fe. Nevertheless, our data point to the hazard of food processing and fortification regarding IBD and to the necessity of food safety testing in animal models thereof.