A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption

Abstract

Background: A large oral dose of iron will reduce the absorption of a subsequent smaller dose of iron in a phenomenon known as mucosal block. Molecular analysis of this process may provide insights into the regulation of intestinal iron absorption. Aims: To determine the effect of an oral bolus of iron on duodenal expression of molecules associated with intestinal iron transport in rats and to relate this to changes in iron absorption. Methods: Rats were given an oral dose of iron and duodenal expression of divalent metal transporter 1 (DMT1), Dcytb, Ireg1, and hephaestin (Hp) was determined using the ribonuclease protection assay, western blotting, and immunofluorescence. Iron absorption was measured using radioactive 59 Fe. Results: A decrease in intestinal iron absorption occurred following an oral dose of iron and this was associated with increased enterocyte iron levels, as assessed by iron regulatory protein activity and immunoblotting for ferritin. Reduced absorption was also accompanied by a rapid decrease in expression of the mRNAs encoding the brush border iron transport molecules Dcytb and the iron responsive element (IRE) containing the splice variant of DMT1. No such change was seen in expression of the non-IRE splice variant of DMT1 or the basolateral iron transport molecules Ireg1 and Hp. Similar changes were observed at the protein level. Conclusions: These data indicate that brush border, but not basolateral, iron transport components are regulated locally by enterocyte iron levels and support the hypothesis that systemic stimuli exert their primary effect on basolateral transport molecules.

IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin

“…It is remarkable that in humans the stimulatory effect of dietary iron on hepcidin is largely lost after the first dose of iron. We surmise that the second and third iron doses present a weaker stimulus to hepcidin production because iron absorption is greatly diminished by the "mucosal block" phenomenon (29)(30)(31), and the rise in transferrin saturation is much smaller from the second and third dose than from the first one (32). It remains to be seen whether the mucosal block to iron absorption is due to the inhibitory effects of hepcidin on iron transport by enterocytes or whether the enterocytes limit further iron uptake in response to their own increased cellular iron content.…”

Diurnal Rhythm rather than Dietary Iron Mediates Daily Hepcidin Variations

“…This mucosal block describes the ability of an initial dose of ingested iron to block iron absorption of a second dose given 2-4 h later. The exact mechanism of this mucosal block is unknown, but in vitro and animal studies suggest the involvement of inhibition of enterocyte import of ingested iron by the ferrous iron transporter divalent metal transporter 1 at the brush border secondary to an increase in intracellular iron (22 ) or a reduction in function of divalent metal transporter 1 and/or the function of the basolateral iron exporter ferroportin secondary to an increase in circulating hepcidin (23)(24)(25)(26). Importantly, the latter mechanism is supported by recent human studies showing an inverse relation between intestinal iron uptake and circulating hepcidin concentrations (9,16 ).…”

Assessment of iron absorption in mice by ICP-MS measurements of 57Fe levels

“…A weak point of this methodology is the impossibility to detect the amount of absorbed iron in the entire carcass, which the use of radioactive compound allows [24,25,26]. Of course, separated analyses on different organs of interest can be performed in order to reach a global assessment of iron distribution in the entire organism.…”