{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T03:17:37Z","timestamp":1782789457080,"version":"3.54.5"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T00:00:00Z","timestamp":1654646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Background and Aims:<\/jats: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-1\u03b1 (HIF1\u03b1), a transcription factor regulating iron homeostasis. We hypothesized that iron deficiency affects mucosal HIF1\u03b1 activity in IBD.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> IBD patients (<jats:italic>n<\/jats: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 HIF1\u03b1 pathway-associated genes and related to iron and inflammation status. <jats:italic>In vitro<\/jats:italic> expression of selected HIF1\u03b1 pathway genes were analyzed in wild-type and <jats:italic>HIF1A-<\/jats:italic>null Caco-2 cells.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Gene expression of the mucosal HIF1\u03b1 pathway was most affected by intestinal location and inflammatory status. Especially, ileal mucosal <jats:italic>TFRC<\/jats:italic> expression, encoding the transferrin receptor TFR1, was increased in inflamed tissue (<jats:italic>p<\/jats:italic> &amp;lt; 0.001), and further enhanced in ID. Accordingly, <jats:italic>TFRC<\/jats:italic> expression in inflamed tissue associated negatively with serum iron levels, which was not observed in the non-inflamed mucosa. The HIF1\u03b1 pathway agonist DMOG increased <jats:italic>TFRC<\/jats:italic> expression in Caco-2 cells, which was blunted in <jats:italic>HIF1A<\/jats:italic>-null cells.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> We demonstrate that inflammation and anatomical location primarily determine HIF1\u03b1 pathway activation and downstream <jats:italic>TFRC<\/jats:italic> expression in the intestinal mucosa. IBD patients with ID may benefit from treatment with HIF1\u03b1-agonists by 1) increasing <jats:italic>TFRC<\/jats:italic>-mediated iron absorption in non-inflamed tissue and 2) decreasing mucosal inflammation, thereby improving their responsiveness to oral iron supplementation.<\/jats:p>","DOI":"10.3389\/fphys.2022.889091","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T07:47:40Z","timestamp":1654674460000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["HIF1\u03b1-Dependent Induction of TFRC by a Combination of Intestinal Inflammation and Systemic Iron Deficiency in Inflammatory Bowel Disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Raphael R.","family":"Fagundes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arno R.","family":"Bourgonje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixian","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruggero","family":"Barbieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadien H.","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nienke","family":"Sinnema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjasso","family":"Blokzijl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cormac T.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinse K.","family":"Weersma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaas Nico","family":"Faber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Dijkstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1016\/j.bbamcr.2012.05.010","article-title":"Mammalian Iron Metabolism and its Control by Iron Regulatory Proteins","volume":"1823","author":"Anderson","year":"2012","journal-title":"Biochim. 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