Iron Homeostasis and Gut Microbiota Interactions

Iron is a vital micronutrient for both the human host and the diverse community of microorganisms inhabiting the gastrointestinal tract. The host regulates systemic iron levels through coordinated processes of dietary absorption, intracellular storage and controlled export, while gut microbes deploy specialised acquisition systems to scavenge luminal iron. This dynamic gives rise to a finely balanced interplay in which both cooperation and competition shape immune function, epithelial barrier integrity and microbial ecosystem structure. Under iron-replete conditions, commensal bacteria can assist the host by converting diet-derived compounds into metabolites that enhance iron uptake and promote regulatory immune responses. Conversely, iron limitation triggers microbial adaptations that may suppress host transporters or alter bacterial community composition, potentially undermining mucosal defence. Fluctuations in iron availability thus reverberate through host signalling pathways—such as those governed by hepcidin, hypoxia-inducible factors and cytokines—and drive changes in microbial diversity, metabolic output and pathogenic potential. Understanding these reciprocal interactions is crucial for optimising clinical interventions, including oral iron therapy, probiotic supplementation and dietary strategies aimed at restoring both host iron balance and microbial homeostasis.

Research from Nature Portfolio

Recent studies have revealed that specific microbiota-derived metabolites directly enhance intestinal iron uptake to support immune tolerance. In one investigation, a short-chain fatty acid produced by commensal bacteria was shown to stimulate expression of the transferrin receptor on regulatory T cells, boosting cellular iron levels. Elevated iron promoted translation of hypoxia-inducible factor-2α (HIF-2α) mRNA, which in turn induced transcriptional programmes essential for differentiation of anti-inflammatory Treg populations in the gut. Restoration of microbial production of this metabolite in models of colitis not only corrected iron deficiency in Treg cells but also ameliorated tissue inflammation and maintained epithelial barrier integrity. These findings uncover a mechanistic link between microbial metabolism, iron uptake and mucosal immune regulation.

Iron Homeostasis and Gut Microbiota Interactions publication trend

The graph below shows the total number of articles in iron homeostasis and gut microbiota interactions across all publications each year (not limited to Nature Index journals).

Technical terms

Transferrin receptor 1: A cell-surface protein that mediates uptake of transferrin-bound iron into host cells.
Short-chain fatty acid: A microbial metabolite (e.g. pentanoate) produced by fermentation of dietary fibres, influencing host metabolism and immunity.
Hypoxia-inducible factor-2α (HIF-2α): A transcription factor stabilised under low oxygen or high iron conditions, regulating genes involved in iron transport and immune function.
Divalent metal transporter 1 (DMT1): An intestinal epithelial transporter responsible for uptake of ferrous iron from the lumen.
Regulatory T cell (Treg): A subset of T lymphocytes that suppress inflammatory responses and maintain immune tolerance in the gut.

References

1. Microbiota-assisted iron uptake promotes immune tolerance in the intestine. Nature Communications (2023).
2. The microbiota and the host organism switch between cooperation and competition based on dietary iron levels. Gut Microbes (2024).
3. The Role of Iron in Intestinal Mucus: Perspectives from Both the Host and Gut Microbiota. Advances in Nutrition (2024).