Intestinal Inflammation Differentially Influences Iron Homeostasis in WT versus Hepcidin KO Rats
Authors: Flores Shireen , Wang Xiaoyu , Nelson Savannah , Woloshun Regina , Ha Jungheun , Collins James 
Published: June 2021

IntroductionThe chronic anemia associated with IBD in humans may result from trans‐activation of the the iron‐regulatory hormone (Hamp) by pro‐inflammatory cytokines in hepatocytes. High hepcidin decreases serum iron by blunting intestinal iron absorption and impairing release of storage iron, thus decreasing iron delivery to the erythroid marrow and causing anemia. Pharmacological targeting of hepcidin offers an attractive therapeutic approach to mitigate IBD‐associated anemia. Testing of such interventions has mainly utilized mouse models of hereditary hemochromatosis (HH). Collectively, these mice have inappropriately low (or absent) hepcidin expression, and concomitant increases in intestinal iron absorption leading to iron overload. However, since iron metabolism in mice and humans varies notably, development of complementary experimental models is imperative.ObjectiveWe created a novel model of HH, the Hamp KO rat, and utilized the DSS model of colitis for this investigation. We hypothesized that Hamp levels would increase in rats with colitis (due to pro‐inflammatory cytokine signaling), which would then blunt intestinal iron absorption and cause anemia (thus modeling human IBD). We further postulated that iron absorption would be unaffected by inflammation in Hamp KO rats, thus preventing the development of anemia.MethodsIntestinal inflammation was induced by providing DSS (4% w/v) in drinking water for 7 days. Standard bioassays were utilized to track iron loading. Iron absorption was assessed by oral‐intragastric gavage of an 59Fe transport solution.ResultsHamp−/− rats displayed multi‐visceral iron overload, and intestinal iron absorption was increased (≈2.5 fold). DSS treatment caused similar pathological changes in the duodenum and colon of Hamp KO rats and WT littermates. Systemic inflammation was not observed in any experimental animals. DSS exposure decreased TSAT, and serum and splenic nonheme iron in both genotypes. In WT animals, DSS exposure: 1) decreased blood hemoglobin levels by ≈15%; 2) reduced liver hepcidin expression by ≈60%; 3) and increased intestinal iron absorption by >2‐fold. Conversely, in Hamp−/− rats, DSS treatment increased blood hemoglobin levels and decreased iron absorption by ≈2.5‐fold. Moreover, the distribution of absorbed 59Fe in blood and many tissues was different between genotypes after DSS txt.ConclusionsDespite the lack of systemic inflammation, iron homeostasis was perturbed in WT rats by DSS‐induced enteritis. Reduced hepcidin expression likely resulted from anemia and/or iron depletion of serum and spleen. This may explain why iron absorption increased, since a relative state of iron deficiency may have existed after DSS exposure. In the KOs, intestinal inflammation altered iron homeostasis in distinct ways. This differential response to DSS may relate to the iron‐overload phenotype of the KO rats, or alternatively, it could reflect a role for hepcidin in mediating the pathophysiologic response to intestinal inflammation. Future studies in iron‐depleted Hamp KO rats may allow for a better understanding of the role of hepcidin in regulating iron homeostasis in IBD.Support or Funding InformationNIH Grant R01 DK074867 and R01 DK109717 (to JFC)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.