AUTHOR=Fagundes Raphael R. , Bourgonje Arno R. , Hu Shixian , Barbieri Ruggero , Jansen Bernadien H. , Sinnema Nienke , Blokzijl Tjasso , Taylor Cormac T. , Weersma Rinse K. , Faber Klaas Nico , Dijkstra Gerard 

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

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.889091

DOI=10.3389/fphys.2022.889091

ISSN=1664-042X

ABSTRACT=<p><bold>Background and Aims:</bold> 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.</p><p><bold>Methods:</bold> IBD patients (<italic>n</italic> = 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. <italic>In vitro</italic> expression of selected HIF1α pathway genes were analyzed in wild-type and <italic>HIF1A-</italic>null Caco-2 cells.</p><p><bold>Results:</bold> Gene expression of the mucosal HIF1α pathway was most affected by intestinal location and inflammatory status. Especially, ileal mucosal <italic>TFRC</italic> expression, encoding the transferrin receptor TFR1, was increased in inflamed tissue (<italic>p</italic> &lt; 0.001), and further enhanced in ID. Accordingly, <italic>TFRC</italic> 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 <italic>TFRC</italic> expression in Caco-2 cells, which was blunted in <italic>HIF1A</italic>-null cells.</p><p><bold>Conclusion:</bold> We demonstrate that inflammation and anatomical location primarily determine HIF1α pathway activation and downstream <italic>TFRC</italic> expression in the intestinal mucosa. IBD patients with ID may benefit from treatment with HIF1α-agonists by 1) increasing <italic>TFRC</italic>-mediated iron absorption in non-inflamed tissue and 2) decreasing mucosal inflammation, thereby improving their responsiveness to oral iron supplementation.</p>