Intestine is the only organ which absorbs dietary iron and harbors microbiota. The iron absorption is tightly regulated by hepcidin, hypoxia inducible factor (HIF) and iron regulatory protein (IRP)-iron responsive element (IRE). When iron is excess, the increased hepcidin from hepatocytes inhibits iron excretion from enterocytes by forming a complex with ferrorportin. Hypoxia or iron deficient condition activates HIF and affects the transcriptional up-regulation of divalent metal transporter 1 (DMT1), which is responsible for intestinal inorganic iron uptake. Dietary iron is constituted of heme and non-heme iron, both of which are absorbed in intestine. In the intestinal lumen, inorganic iron is present as ferric form and is reduced to ferrous form by ferrireductase duodenal cytochrome B. The apical site of cryptic enterocyte is responsible for the uptake of inorganic iron via DMT1 and for heme iron via heme transporters. Dietary ferritin is absorbed independently from heme and inorganic iron. On the basolateral site of enterocyte, transferrin-bound iron is taken up from circulation via TfR1 and non-transferrin-bound iron (NTBI) via ZRT/IRT-like protein 14 (ZIP-14). Within cytosol, there are two poly (rC) binding proteins (PCBs) as iron chaperons. PCBP1 transfers iron from the cytosol to ferritin, while PCB2 from DMT1 to ferroportin. Ferritin has an important role for iron storage and regulatory cell deaths (RCD) in enterocyte. At the villous tip, enterocyte is shed after 4 to 5 days of maturation from stem cells by RCD, corresponding to the daily loss of iron from the body. Meta-analysis of epidemiological studies indicates an association between high dietary heme iron intake and colorectal cancer risk. Microbiota also have an important role for maintaining and modifying iron homeostasis by producing siderophores in colon. The dysregulated proliferation of microbiota may be responsible for the development of inflammatory bowel disease and colon cancer.
Akita et al. (Mon,) studied this question.