The Rare Immune Cells Feeding Iron to Gut Bacteria in IBD

If you have inflammatory bowel disease, ulcerative colitis or Crohn's disease, one of the hardest problems is not just calming inflammation but actually convincing the gut lining to heal, and getting it to stop feeding the bacteria that keep the wound open. A new study in Cell Reports has found a surprisingly specific culprit behind that stalled healing: a rare population of immune cells in the colon that pump iron out into the surrounding tissue, effectively feeding the microbes that keep recovery from happening. Blocking that iron handoff sped up healing in mice, without starving the rest of the body of iron. The mechanism, tested in mice and confirmed in tissue from human IBD patients, points to an unusually precise new way to think about treating gut disease.

Key takeaways:

• A rare, tissue-resident colon macrophage population expresses high levels of ferroportin, a protein that exports iron out of cells, and that iron appears to feed the dysbiotic bacteria that stall mucosal healing in colitis.
• The same iron-exporting macrophages turned up in human ulcerative colitis and Crohn's disease tissue, but the human evidence is correlational, not causal.
• Locally blocking ferroportin in the colon, using hepcidin (the body's own iron-regulating hormone), shifted the gut microbiome, reduced inflammation, and sped healing in mice, without lowering iron levels elsewhere in the body.
• Nothing here has been tested in people; this is a mechanistic finding in mice and human tissue samples, not an available treatment.

Rare Colon Macrophages Export Iron Through Ferroportin

A specific, rare subset of tissue-resident macrophages (a type of immune cell that clears debris and helps regulate tissue repair) in the colon expresses unusually high levels of ferroportin, the only known protein that moves iron out of a cell, the study found. Researchers led by Bhupendra Singh Rawat and senior author Nicholas J. Bessman at Rutgers used single-cell RNA sequencing (a technique that reads which genes are switched on in thousands of individual cells at once) on macrophages sorted directly from the colon lining of mice. Pooling cells from twelve mice produced 1,395 individual cell profiles across ten distinct clusters; five of those clusters, accounting for 60% of the cells, were confirmed as macrophages, and two of those subsets stood out for actively running an iron-handling gene program built around ferroportin (encoded by the gene Slc40a1). These same macrophages also expressed high levels of selenoprotein P and complement genes, markers associated with tissue-repair, anti-inflammatory macrophages, and lineage-tracing experiments confirmed they are tissue-resident, meaning they develop locally rather than arriving fresh from the bloodstream as monocytes.

Why This Matters for People With IBD and Anemia

Inflammatory bowel disease, the umbrella term for ulcerative colitis and Crohn's disease, is marked by two problems that look separate but may be linked: an imbalanced gut microbiome (dysbiosis) and iron-deficiency anemia. Doctors already know that oral iron supplements, a common anemia treatment, can worsen gut inflammation and dysbiosis in some IBD patients, because unabsorbed iron in the gut is a resource many bacteria can use to grow. This study helps explain why the immune system itself may be part of that problem: the researchers report that dysbiotic bacteria in the inflamed colon are dependent on macrophage-derived iron, not just dietary iron, to keep mucosal healing from happening. In other words, the same immune cells meant to help control infection may be inadvertently feeding the bacterial imbalance that keeps IBD active.

Mouse Genetics and Human Biopsies Point to the Same Cells

The strongest evidence came from a genetic experiment rather than a drug alone. The researchers engineered mice whose macrophages carried a mutant ferroportin (called Slc40a1 C326Y) that cannot be shut off by hepcidin, then gave those mice colitis using dextran sodium sulfate (DSS, a chemical that damages the gut lining to model IBD in mice). This let the team isolate the effect of macrophage ferroportin specifically, apart from ferroportin in other cell types like neutrophils. Alongside the mouse work, the researchers analyzed two independently published single-cell datasets from human ulcerative colitis and Crohn's disease patients and confirmed, with direct antibody staining of intestinal biopsy tissue, that the same iron-export gene is active in human colon macrophages, correlating with the same selenoprotein and complement genes seen in mice. The team also raised germ-free mice (born and kept with no gut microbes) and then exposed some to normal gut bacteria for three weeks, showing that ferroportin expression on colon macrophages rises specifically in response to the microbiome, rather than being a fixed trait of the cells.

What This Could Mean If You're Managing IBD Today

For now, this is a mechanism, not a medicine. Nothing here is an approved or recommended treatment, and the local hepcidin delivery used in the study exists only as a mouse experiment, delivered as oral beads targeted to the colon over several days. That said, the finding gives a concrete biological reason iron management matters for gut health beyond correcting a number on a blood panel. If you have IBD and take oral iron, this research reinforces why gastroenterologists sometimes weigh intravenous iron or careful dosing against oral supplements, since unabsorbed oral iron passing through an inflamed gut can reach the same bacteria this study implicates. It's reasonable to ask a doctor how your iron therapy is chosen and monitored, but this study does not establish that any specific iron regimen changes disease outcomes in people.

The Open Question: This Hasn't Been Tested in People

The clearest limitation is translation. Every causal experiment in this study, the genetically engineered macrophage mutant, the local hepcidin delivery, and the resulting microbiome shifts, was done in mice with chemically induced colitis, which only approximates human IBD. The human evidence, while striking, is correlational: the researchers found the same iron-exporting macrophages and gene correlations in tissue from ulcerative colitis and Crohn's patients, but they did not test whether blocking ferroportin changes disease course in a person. Scaling a local, site-specific hepcidin therapy to humans, one that inhibits ferroportin in the colon without lowering iron levels body-wide, is also a nontrivial delivery problem that this paper does not attempt to solve.

What Comes Next

The authors frame their result as identifying a therapeutic window: a way to inhibit ferroportin specifically where it matters, in the colon, without triggering the anemia that would come from blocking it throughout the body. That distinction matters because ferroportin inhibitors are already being tested clinically for other conditions, meaning the pharmacological tools to target this pathway already exist in some form. Follow-up work would need to test whether a similarly local approach can be delivered safely in human patients with active IBD, and whether screening patients for how much ferroportin their colon macrophages express, which the researchers found varied notably between individual UC patients, could help identify who is most likely to benefit from this kind of strategy.

Common Questions

What is ferroportin? Ferroportin is the only known protein that exports iron out of a cell. It sits on the surface of certain immune cells and intestinal cells and controls how much iron reaches the surrounding tissue and the gut microbes living there.

What is hepcidin and how does it relate to this study? Hepcidin is a hormone the body makes naturally to shut down ferroportin. The researchers used a locally delivered form of hepcidin in mice to block iron export from colon macrophages specifically, without lowering iron levels in the blood, spleen, or liver.

Does this mean iron supplements cause IBD? No. The study did not test dietary or supplemental iron directly. It shows that immune cells in the colon actively export iron into the gut environment, and that blocking that cellular export, not blocking dietary iron, helped mice recover from colitis.

Is there a treatment based on this available now? No. This is an early-stage mechanistic study in mice and human tissue samples. No ferroportin-targeting treatment for IBD has been tested in a human clinical trial.

References

1. Bhupendra Singh Rawat, Jaehyeon Kim, Waleed Mujib, et al. (2026). Tissue-resident colon macrophages shape the microbiome and regulate mucosal healing via ferroportin. Cell Reports. https://doi.org/10.1016/j.celrep.2026.117724
2. Awad Mahalhal, Jonathan M. Williams, Sophie Johnson, et al. (2018). Oral iron exacerbates colitis and influences the intestinal microbiome. PLOS ONE. https://doi.org/10.1371/journal.pone.0202460
3. The Dark Side of Iron: The Relationship between Iron, Inflammation and Gut Microbiota (Nutrients, PMC review). NIH. https://pmc.ncbi.nlm.nih.gov/articles/PMC9458173/
4. Association between hepcidin levels and inflammatory bowel disease: a systematic review and meta-analysis (Food Science & Nutrition). NIH. https://pmc.ncbi.nlm.nih.gov/articles/PMC11266881/