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

ABSTRACT: Inflammatory bowel diseases (IBD) are complex inflammatory disorders marked by microbial dysbiosis and dysregulated iron homeostasis. 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. Altogether, these findings outline a model where bacteria critically depend on macrophage-derived iron and impair mucosal healing in IBD. Our identification of a tissue-specific therapeutic window for Fpn inhibition reveals a novel therapeutic strategy to promote mucosal healing in IBD.

ORGANISM(S): Mus musculus

PROVIDER: GSE282866 | GEO | 2026/06/08

REPOSITORIES: GEO

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Project description:Hepcidin, a peptide hormone that decreases intestinal iron absorption and macrophage iron release, is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. Endogenous stimulants of Hepcidin transcription include bone morphogenic protein 6 (BMP) and interleukin-6 (IL-6) via effects on Smad4 or Stat3, respectively. We conducted a small-scale chemical screen in zebrafish embryos to identify small molecules that modulate hepcidin expression. We found that treatment with the isoflavone genistein from 28−52 hours post-fertilization in zebrafish embryos enhanced Hepcidin transcript levels as assessed by whole mount in situ hybridization and quantitative realtime RT-PCR. Genistein’s stimulatory effect was conserved in human hepatocytes: genistein treatment of HepG2 cells increased both Hepcidin transcript levels and Hepcidin promoter activity. We found that genistein’s effect on Hepcidin expression did not depend on estrogen receptor signaling or increased cellular iron uptake, but was impaired by mutation of either the BMP response elements or the Stat3 binding site in the Hepcidin promoter. RNA-sequencing of transcripts from genistein-treated hepatocytes indicated that genistein upregulated 68% of the transcripts that were upregulated by BMP6, however genistein raised the levels of several transcripts involved in Stat3 signaling that were not upregulated by BMP6. Chromatin-immunoprecipitation and ELISA experiments revealed that genistein enhanced Stat3 binding to the Hepcidin promoter and increased phosphorylation of Stat3 in HepG2 cells. CONCLUSION: Genistein is the first small molecule experimental drug that stimulates Hepcidin expression in vivo and in vitro. These experiments demonstrate the feasibility of identifying and characterizing small molecules that increase Hepcidin expression. Genistein and other candidate molecules may subsequently be developed into new therapies for iron overload syndromes. RNA-seq of HepG2 cells treated with DMSO 1%, BMP6 50 ng/ml, or genistein 10 micromolar. The numbers of biological replicates were 3, 2, and 3.

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

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