Tissue-resident colon macrophages shape the microbiome and regulate mucosal healing via ferroportin.

Inflammatory bowel diseases (IBDs) are complex disorders marked by microbial dysbiosis and dysregulated iron. Iron homeostasis is controlled by endogenous hepcidin, which inhibits iron export through ferroportin, to promote mucosal healing via nutritional immunity. However, the relevant site of ferroportin activity and the clinical potential of this pathway in IBD remain unknown. Using unbiased profiling, we demonstrate that functional ferroportin is expressed by discrete colon macrophage subsets in both mice and humans. In mice, ferroportin is highly expressed in a rare, colon-resident macrophage population. We further identified that colon-specific hepcidin delivery can target ferroportin on colon macrophages without disrupting iron homeostasis, modulate microbiome composition, and accelerate recovery after intestinal inflammation. Altogether, these findings outline a model where dysbiotic bacteria critically depend on macrophage-derived iron to inhibit mucosal healing in IBD. Identification of a site-specific therapeutic window for ferroportin inhibition reveals a strategy to promote mucosal healing in IBD.