Chronic intestinal inflammation increases the risk of colorectal cancer. Anaemia of inflammation is a common complication in inflammatory bowel disease (IBD) and is frequently treated by oral iron supplementation. The aim of this study was to investigate the effect of oral iron on inflammation, iron homeostasis and carcinogenesis in a mouse model of colitis-associated cancer (CAC).
Colonic inflammation and tumours were induced by the administration of azoxymethane (AOM) and dextran sodium sulphate (DSS) to mice fed either an iron supplemented or control diet (1% vs. 0.01% iron). Inflammation and tumourigenesis were scored via mini-endoscopy. Plasma transferrin saturation and liver iron were measured biochemically, colonic ferritin levels were assessed by immunohistochemistry and iron levels by histology. Cytokine expression was measured by real-time PCR and STAT3 phosphorylation by immunoblotting.
Oral iron increased iron stores in the colonic epithelium, mucosal macrophages and liver. In iron-treated mice, colonic macrophages secreted IL-6 and colonic STAT3 phosphorylation was elevated in the absence of inflammation (p<0.01) indicating an effect of dietary iron on signalling by the IL-6 cytokine family. After 7 days of AOM/DSS treatment, endoscopic inflammation scores were higher in iron-loaded mice (p<0.05). AOM/DSS treatment reduced haemoglobin and transferrin saturation, and increased hepatic iron levels (p<0.01), changes that are consistent with anaemia of inflammation. Oral iron further enhanced IL-6, IL-11 and IL-17a gene expression and STAT3 phosphorylation in AOM/DSS-treated mice (p<0.05). At 5 weeks, endoscopic colonic tumour numbers increased in AOM/DSS treated mice with more and larger colonic tumours developing in iron-loaded mice (p<0.05). Oral iron also increased intratumoural IL-6 and IL-11 gene expression (p<0.05).
Dietary iron supplementation promotes colitis and tumour formation and anaemia of inflammation in mice and this may be linked through IL-6/11-STAT3 signalling pathways. This suggests oral iron supplementation may exacerbate inflammation, anaemia and tumourigenesis in IBD patients and needs to be evaluated further.