Intestinal Iron Absorption in Inflammatory Bowel Diseases

There are two forms of dietary iron: heme iron (found in meat products) and non-heme iron (found in vegetable products). Heme iron is found mainly in the stable porphyrin complex unaffected by other food compounds. Heme iron is particularly well absorbed; despite making up only 10–15% of the total dietary iron intake, heme iron makes up 40% of iron absorbed by the body. The bioavailability of heme iron from food is around 20–30%.

Non-heme iron can be found in vegetable products as “free” or in weak Fe³⁺ or Fe²⁺ ion complexes or encased as a multi-ion form in a protein such as ferritin (FTN), the storage form of iron in plants, particularly legumes (i.e. soybeans). Non-heme iron Fe²⁺ is taken up into mucosal cells via the divalent metal (cation) transporter 1 (DMT1), which is mainly located in the duodenum. Apical import of Fe²⁺ by DMT1 is driven along a proton gradient, which is also able to mediate the import of additional divalent cations [10].

FTN iron is a large mineral containing thousands of iron molecules inside a protein nanocage, that is very stable to temperature, heat, and protein denaturants and survives in vitro digestion [12]. The mechanisms involved in the intestinal absorption of FTN iron are not yet understood. However, because ferritin has been shown to be a very stable protein and ferritin iron can be absorbed from soybean ferritin even in the presence of iron-binding inhibitors such as phytate, it is speculated that FTN enters intestinal epithelial cells by receptor-mediated endocytosis, an absorption mechanism distinct from transport of non-heme iron salts (ferrous sulfate), iron chelators (ferric-EDTA), or heme [3,4,6]. Endocytosis of iron-FTN is a much more efficient transport event than transport of individual iron atoms across the cell membrane as ferrous iron via DMT1 or heme via heme carrier protein 1 (HCP1), e.g., as the FTN protein cages contain thousands of mineralized iron atoms [13].

Alike FTN iron, the mechanism of heme iron absorption remain less well understood. The apical heme transporter, HCP1, first reported in 2005 was later described to be more efficient as a folate transporter. It seems likely that when heme iron is absorbed into the enterocyte it is then liberated from its porphyrin framework by heme oxygenase to enter a common pathway with non-heme iron before leaving the absorptive epithelium.

Once inside the intestinal epithelial cell, iron either binds to ferritin, the cellular iron storage protein (whose synthesis is closely correlated to the iron content of the mucosa cell, and is excreted in faeces when the senescent enterocyte is sloughed) or iron is directly released by means of ferroportin 1 via the basolateral membrane (Fig. 3.1).

Impaired iron absorption in chronic inflammatory bowel disease

Anemia is the most prevalent systemic complication of inflammatory bowel diseases (IBD) such as Crohn's disease, ulcerative colitis and celiac disease and can substantially affect the quality of life of these patients. The cause of anemia in these patients is multifactorial and may be caused by lack of intake, chronic blood loss, micronutrient deficiency (iron, folate, and vitamin B12), hemolysis, and medication-induced myelosuppression [2,10]. However, the two most common causes of anemia in chronic intestinal disease are iron deficiency and anemia of inflammation (ACI; also referred to as the anemia of chronic disease). Although the underlying pathogenesis of ACI is unknown, one hypothesis suggests that ACI arises at least in part as a result of an impaired duodenal iron absorption and the inability to release iron from macrophages and monocytes, both induced by increased systemic hepicidin levels. Hepcidin, an antimicrobial, acute phase protein, has a central role in controlling the regulation of iron homeostasis; (for review see [10]).

Semrin et al. demonstrated for the first time in a small group of children with active Crohn's disease the presence of impaired intestinal iron absorption, which correlates with clinical disease activity and markers of inflammation. The authors demonstrated a significant negative correlation between impaired intestinal iron absorption and serum IL-6 and CRP levels, which vice versa positively correlated with the urine hepcidin levels providing evidence for a link between hepcidin and reduced iron absorption in IBD. However, this study was limitated by the small sample size, no control group and provided no data either for ulcerative colitis or adult IBD patients. We therefore performed a prospective, multicenter trial in which we were able to demonstrate that – when compared to healthy controls – firstly intestinal iron absorption is reduced both in active Crohn's disease and ulcerative colitis and secondly correlates with disease activity and markers of inflammation, but is independent of disease location [5].

Based on the data of Vanoaica and colleagues, showing that intestinal iron absorption is also regulated within the intestinal epithelium through production of the iron-sequestering protein ferritin and data demonstrating the induction of intraepithelial ferritin by TNF-alpha [7], a second hypothesis explaining reduced intestinal iron absorption in chronic inflammatory bowel disease was generated by Sharma et al. [8]. The authors found that anaemic celiac disease patients had a high enterocyte ferritin expression despite systemic iron deficiency when compared with the non-celiac group. The increased ferritin expression was associated with much greater enterocyte iron loading (Fig. 3.1).

References

[1] Andrews NC. Ferrit(in)ing out new mechanisms in iron homeostasis. Cell Metab 2010; 12: 203–204

[2] Harper JW, Holleran SF, Ramakrishnan R, Bhagat G, Green PH. Anemia in celiac disease is multifactorial in etiology. Am J Hematol 2007; 82: 996–1000

[3] Lönnerdal B, Bryant A, Liu X, Theil EC. Iron absorption from soybean ferritin in nonanemic women. Am J Clin Nutr 2006; 83: 103–107

[4] Lönnerdal B. Soybean ferritin: implications for iron status of vegetarians. Am J Clin Nutr 2009; 89: 1680S-1685S

[5] Loitsch SM, Diehl D, Hartman F, Dignass A, Stein J. Impaired intestinal iron absorption in inflammatory bowel disease correlates with disease activity and markers of iInflammation but is independent of disease location. J Crohns Colitis. 2011

[6] San Martin CD, Garri C, Pizarro F, Walter T, Theil EC, Núñez MT. Caco-2 intestinal epithelial cells absorb soybean ferritin by mu² (AP2)-dependent endocytosis. J Nutr 2008; 138: 659–666

[7] Sharma N, Laftah AH, Brookes MJ, Cooper B, Iqbal T, Tselepis C. A role for tumour necrosis factor alpha in human small bowel iron transport. Biochem J 2005; 390: 437–446

[8] Sharma N,Begum J, Eksteen B, Elagib A, Brookes MJ,Cooper B, Tselepis C, Iqbal T. Differential ferritin expression is associated with iron deficiency in coeliac disease. Eur J Gastroenterol Hepatol 2009; 21: 794–804

[9] Semrin G, Fishman DS, Bousvaros A, Zholudev A, Saunders AC, Correia CE, Nemeth E, Grand RJ, Weinstein DA. Impaired intestinal iron absorption in Crohn's disease correlates with disease activity and markers of inflammation. Inflamm Bowel Dis 2006; 12: 1101–1106

[10] Stein J, Hartmann F, Dignass AU. Diagnosis and management of iron deficiency anemia in patients with IBD. Nat Rev Gastroenterol Hepatol 2010; 7(11): 599–610

[11] Stein J, Hartmann F, Cordes HJ, Dignass AU. Pathophysiological-based diagnosis and therapy of iron-deficient anaemia in inflammatory bowel disease. Z Gastroenterol. 2009; 47: 228–236

[12] Theil EC. Iron, ferritin, and nutrition. Annu Rev Nutr 2004. 24: 327–343

[13] Theil EC. Iron homeostasis and nutritional iron deficiency. J Nutr 2011; 141: 724S-728S

[14] Vanoaica L, Darshan D, Richman L, Schümann K, Kühn LC. Intestinal ferritin H is required for an accurate control of iron absorption. Cell Metab 2010; 12: 273–282