HIF1α-Dependent Induction of TFRC by a Combination of Intestinal Inflammation and Systemic Iron Deficiency in Inflammatory Bowel Disease

Abstract

<b>Background and Aims:</b> Iron deficiency (ID) is a frequent extra-intestinal manifestation in patients with Inflammatory Bowel Disease (IBD), who often do not respond to iron supplementation. Iron is a cofactor for hydroxylases that suppress the hypoxia-inducible factor-1α (HIF1α), a transcription factor regulating iron homeostasis. We hypothesized that iron deficiency affects mucosal HIF1α activity in IBD. <b>Methods:</b> IBD patients (<i>n</i> = 101) were subdivided based on iron status (ferritin levels or transferrin saturation) and systemic inflammation (C-reactive protein levels). 154 corresponding ileal and colonic biopsies were analyzed for differential expression of 20 HIF1α pathway-associated genes and related to iron and inflammation status. <i>In vitro</i> expression of selected HIF1α pathway genes were analyzed in wild-type and <i>HIF1A-</i>null Caco-2 cells. <b>Results:</b> Gene expression of the mucosal HIF1α pathway was most affected by intestinal location and inflammatory status. Especially, ileal mucosal <i>TFRC</i> expression, encoding the transferrin receptor TFR1, was increased in inflamed tissue (<i>p</i> < 0.001), and further enhanced in ID. Accordingly, <i>TFRC</i> expression in inflamed tissue associated negatively with serum iron levels, which was not observed in the non-inflamed mucosa. The HIF1α pathway agonist DMOG increased <i>TFRC</i> expression in Caco-2 cells, which was blunted in <i>HIF1A</i>-null cells. <b>Conclusion:</b> We demonstrate that inflammation and anatomical location primarily determine HIF1α pathway activation and downstream <i>TFRC</i> expression in the intestinal mucosa. IBD patients with ID may benefit from treatment with HIF1α-agonists by 1) increasing <i>TFRC</i>-mediated iron absorption in non-inflamed tissue and 2) decreasing mucosal inflammation, thereby improving their responsiveness to oral iron supplementation.