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Iron is essential for virtually all cells and higher eukaryotes due to its central role for oxygen transport, mitochondrial respiration, DNA synthesis and metabolic processes. Moreover, iron catalyses the formation of hydroxyl radicals, which can cause cellular damage but which also modulate the binding affinity of several transcription factors.1 Therefore, iron overload and iron deficiency exert subtle effects on essential metabolic pathways and on the growth, proliferation and differentiation of cells. Accordingly, iron is centrally involved in the regulation of cellular immune function. On the one hand iron promotes the proliferation and differentiation of immune cells, including lymphocytes; however, lymphocyte subsets differ in their dependence on a sufficient supply of iron. The induction of experimental iron overload in rats resulted in a shift in the ratio between T-helper (CD4+) and T-suppressor/cytotoxic T cells (CD8+) with a relative expansion of the latter.2 Moreover, T-helper (Th) subsets respond differently to iron perturbations with Th-1 cells being more sensitive to iron restriction than Th-2 cells. In addition, Th-1-mediated immune effector pathways are much more sensitive to changes in iron homeostasis in vivo.2 As with eukaryotes, microorganisms have evoked multiple strategies to capture and ingest iron, which they need for proliferation and pathogenicity while immune cells on the other hand try to restrict this essential nutrient from microbes which is a central component of host defence, called ‘nutritional immunity’.3
In their paper published in this issue of Gut, Werner and co-workers4 (see page 325) present novel evidence that the luminal iron status affects disease activity in a mouse model of experimental colitis. For their experiments they used TNFΔARE/WT mice which have an impaired control of tumour necrosis factor α (TNFα) formation and which develop a severe CD8+ T cell driven ileitis. The development of this type of ileitis has been associated with increased endoplasmatic reticulum (ER) stress which is also of central importance for the development of colitis both in Crohn's disease and ulcerative colitis.5 In an attempt to evaluate potential mechanisms underlying disease activity in this model the authors found that dietary iron supplementation drastically aggravated disease activity whereas iron injections had no disease promoting effect. While one might admit that the oral iron dosages given to the mice were extremely high (28 μg of iron/g mouse per day) which corresponds to an oral iron intake of approximately 2 g iron for an adult the authors could demonstrate that luminal iron depletion exerted protective effects on disease activity. This was parallelled by a reduction of CD8+ cell mediated apoptosis of primary ileal epithelial cells and absence of ER stress. In addition, modulation of luminal iron concentrations strikingly affected the composition of the gut microflora. Over the past years it has become clear that commensal intestinal bacteria interact with intestinal epithelial cells, thereby influencing the balance between inflammatory and regulatory immune responses and thus disease activity.6
These novel findings may impact on the treatment of patients suffering from inflammatory bowel disease (IBD). Many of these patients develop anaemia, which negatively affects their quality of life. Anaemia in association with IBD is caused by two major pathological features.7 First, IBD-driven inflammation results in impaired proliferation and differentiation of erythroid progenitor cells, a reduced biological activity of erythropoietin and in iron retention within monocytes and macrophages. The latter causes iron limitation for erythropoiesis and is due to the effects of cytokines and the acute phase peptide hepcidin on iron redistribution from monocytes/macrophages. Thereby, hepcidin binds to the only known iron export protein, ferroportin, leading to internalisation and degradation of the latter and blockade of iron egress from monocytes/macrophages but also from enterocytes,1 thus blocking duodenal iron absorption under inflammatory conditions.8
Second, IBD patients frequently develop true iron deficiency as a consequence of chronic intestinal bleeding. Thus, iron supplementation is vital to treat anaemia in IBD patients. According to the data presented in this paper,4 oral iron supplementation may harbour the potential of aggravating the disease.
This leads to the question by which mechanisms orally administrated may negatively impact on disease activity. Only a minimum percentage of dietary iron is taken up in the duodenum and the relative quantity of absorbed iron is further reduced under inflammatory conditions thanks to the action of cytokines and hepcidin on enterocyte iron transfer to the circulation.1 8 Thus, the vast majority of dietary iron remains in the gut where it reaches the sites of inflammation in subjects suffering from colitis. There, iron can promote inflammation by catalysing the formation of toxic oxygen radicals leading to cellular apoptosis, tissue damage and ER stress. This is of interest not only in respect to disease progression but also due to the fact that ER stress induces hepcidin formation9 which will further block iron absorption and increase luminal iron concentrations via a vicious cycle. Radicals formed by the catalytic action of iron lead to the activation of transcription factors such as NF-κB which then promotes the expression of inflammatory cytokines. Moreover, iron differently affects the proliferation of lymphocytes leading to an expansion of cytotoxic CD8 cells,2 which was also observed herein.4 Finally, as nicely demonstrated in this study iron affects the proliferation and differentiation of intestinal bacteria thus modulating the composition of the gut microbiota. In addition, the ingestion of iron by bacteria is frequently linked to their pathogenicity.3 Such bacteria will become invasive leading to emerge of pro-inflammatory immune response signals in the gut and propagation of inflammation. This is in agreement with the results of a randomised controlled trial in anaemic African children demonstrating that iron fortification of the diet led to an expansion of potentially pathogenic enterobacteria while the percentage of lactobacilli in the gut was reduced.10
Importantly, Werner et al4 have shown that in contrast to dietary iron intravenous iron had no effect on disease activity, indicating that the local appearance of iron in the intestinal lumen and not systemic iron overload contributes to the exacerbation of colitis in this murine model.
Clinical data from patients which favours the hypothesis that iron is a pro-inflammatory hit in IBD are scarce. While one very small study indicated that oral but not intravenous iron was associated with increased clinical disease activity in patients with IBD11 another investigation in such patients with mild anaemia did not provide clinical evidence for disease aggravation upon oral iron supplementation.12
While intravenous iron therapy is effective in correcting moderate anaemia of patients with IBD,7 it is not available everywhere. Thus, prospective clinical studies will have to clarify whether oral iron supplementation in patients with IBD and anaemia will impact on disease activity.
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