Ferroportin inhibition in colon macrophages shapes the microbiome and promotes mucosal healing

Iron homeostasis is controlled by endogenous hepcidin, which inhibits iron export through ferroportin (Fpn) to promote mucosal healing via nutritional immunity against tissue-infiltrating bacteria. However, the relevant site of Fpn activity is unknown, and the clinical potential of this pathway in IBD remains unexplored.

Using unbiased profiling approaches, we demonstrate that functional Fpn is specifically expressed by discrete intestinal macrophage subsets in both mice and humans. While systemic Fpn inhibition and intestinal inflammation both cause iron deficiency, we identified that colon-specific hepcidin delivery can target Fpn on colon macrophages without disrupting iron homeostasis. Further, colon macrophage Fpn inhibition significantly accelerated recovery in a pre-clinical model of intestinal inflammation and modulated microbiome composition.