Research Article: Comparison of iron-reduced and iron-supplemented semisynthetic diets in T cell transfer colitis

Date Published: July 5, 2019

Publisher: Public Library of Science

Author(s): Anamarija Markota, Rebecca Metzger, Alexander F. Heiseke, Lisa Jandl, Ezgi Dursun, Katharina Eisenächer, Wolfgang Reindl, Dirk Haller, Anne B. Krug, Jörn Karhausen.


Clinical observations in inflammatory bowel disease patients and experimental studies in rodents suggest that iron in the intestinal lumen derived from iron-rich food or oral iron supplementation could exacerbate inflammation and that iron depletion from the diet could be protective. To test the hypothesis that dietary iron reduction is protective against colitis development, the impact of iron reduction in the diet below 10 mg/kg on the course of CD4+ CD62L+ T cell transfer colitis was investigated in adult C57BL/6 mice. Weight loss as well as clinical and histological signs of inflammation were comparable between mice pretreated with semisynthetic diets with either < 10mg/kg iron content or supplemented with 180 mg/kg iron in the form of ferrous sulfate or hemin. Accumulation and activation of Ly6Chigh monocytes, changes in dendritic cell subset composition and induction of proinflammatory Th1/Th17 cells in the inflamed colon were not affected by the iron content of the diets. Thus, dietary iron reduction did not protect adult mice against severe intestinal inflammation in T cell transfer induced colitis.

Partial Text

Inflammatory bowel diseases (IBD)—ulcerative colitis and Crohn’s disease—are chronic inflammatory disorders of the gastrointestinal tract resulting from a dysregulated immune response to the intestinal microbiota which is influenced by the genetic susceptibility of the host and environmental factors [1]. In addition to dietary intake of macronutrients (fat, carbohydrates and proteins), micronutrients including iron influence the epithelial barrier function, the mucosal immune response and directly or indirectly the microbiota [2]. The consumption of red meat containing heme iron has been associated with a higher risk for IBD and colorectal cancer [3, 4]. Oral iron supplementation is often avoided during phases of active IBD, because it is poorly tolerated by some IBD patients and may promote IBD symptoms [5]. Results of recent clinical studies however do not provide clear evidence for exacerbation of IBD as a consequence of oral iron supplementation [6]. Animal studies performed in rodents using chemically induced erosive colitis models demonstrated a proinflammatory effect of iron in the intestinal lumen by showing that high dose oral iron supplementation causes an increase in disease activity, inflammatory score and oxidative stress [7–12]. Luminal iron, especially in the form of heme iron was shown to induce oxidative stress and cytotoxicity in the intestinal epithelium [13]. However, it was shown recently that exposure of intestinal macrophages to hemin inhibited their expression of LPS-induced proinflammatory cytokines and this effect was reversed by dietary iron reduction [14]. The effect of dietary iron reduction for the development of intestinal inflammation has been explored in the spontaneous Crohn’s disease-like ileitis model in tumor necrosis factor (TNF)ΔARE mice, which developed less severe intestinal inflammation when treated with an iron-reduced diet [15]. In this study, mice fed with an iron-free (< 10 mg/kg) semisynthetic diet for 11 weeks depleted hepatic iron stores without developing anemia and the protective effect of the iron-reduced diet was still observed when systemic iron stores were repleted by parenteral iron administration demonstrating that luminal iron depletion was responsible for the observed effect [15]. However, iron reduction has not been tested as dietary intervention in the T cell transfer induced colitis model, which causes T cell driven microbiota-dependent colonic inflammation resembling human IBD. Clinical observations in IBD patients and experimental studies suggested that iron in the intestinal lumen derived from iron-rich food or iron supplementation exacerbates inflammation in IBD patients [4, 5, 7–12]. This led to the assumption that oral iron replacement therapy for iron-deficiency anemia should be avoided during active IBD and that iron reduction in the diet may be protective. Indeed, evidence for a protective effect of luminal iron depletion was found in a murine model of ileitis [15]. In this model the beneficial effect of luminal iron depletion correlated with reduced ER-stress in the epithelium and changes in the microbiota composition. In contrast, we found that colitis activity in the T cell transfer induced mouse model of colitis was not affected by alterations in the iron content of the experimental diet in recipient mice. Examination of the frequency and activation of relevant innate and adaptive immune cell populations in the colon during colitis revealed that the iron-reduced diet had no significant effect on these parameters of intestinal inflammation.   Source: