Hepcidin

Hepcidin: the iron “gatekeeper” peptide hormone

Hepcidin is a liver-derived peptide hormone that controls how much iron enters the bloodstream and where iron is stored in tissues. It was first identified as a cysteine-rich antimicrobial peptide in human plasma ultrafiltrate (as LEAP-1) and in urine (named “hepcidin” for hepatic origin and antimicrobial activity).^[1][2] In clinical medicine, hepcidin is now recognized as the central regulator of systemic iron availability, integrating signals from iron stores, inflammation, and erythropoietic demand.^[3]

How hepcidin controls iron flow through ferroportin

Hepcidin acts by binding to ferroportin, the only known cellular iron exporter, located on intestinal absorptive cells (enterocytes), macrophages that recycle iron from aged red blood cells, and hepatocytes that store iron.^[4] When hepcidin binds ferroportin, ferroportin is internalized and degraded, reducing iron release from these cells into plasma and lowering circulating iron.^[5] This mechanism explains why high hepcidin causes reduced dietary iron absorption and iron sequestration in tissues, whereas low hepcidin promotes iron loading.^[6][7]

Inflammation, microbiome signals, and hepcidin upregulation

Hepcidin is an acute-phase mediator of inflammation. Interleukin-6 (IL-6), a key inflammatory cytokine, increases hepatic hepcidin transcription through STAT3 signaling, linking immune activation to hypoferremia.^[8] This pathway underlies anemia of inflammation, in which iron becomes unavailable for red blood cell production despite adequate body iron stores.^[9] Microbial products can also stimulate hepcidin: pathogen-associated molecules and innate immune signaling increase hepcidin expression, reinforcing iron restriction as a host-defense strategy.^[10]

From a microbiome medicine perspective, iron and gut microbes form a bidirectional system: intestinal iron availability can reshape microbial ecology, while microbiota-driven inflammation and gut–liver immune signaling can influence hepatic hepcidin output.^[11] This relationship is clinically relevant because dysbiosis-associated inflammation may sustain hepcidin elevation and contribute to iron-restricted states.^[12]

Clinical relevance in microbiome-focused care

Hepcidin measurement is increasingly used to distinguish iron deficiency (typically low hepcidin) from inflammation-driven iron restriction (often high hepcidin), guiding iron therapy decisions and avoiding unnecessary supplementation that may worsen gut microbial imbalance by increasing luminal iron.^[13][14][15] In microbiome-informed practice, hepcidin can be viewed as a liver-integrated readout of iron status and immune–microbial signaling, with therapeutic implications across chronic inflammatory, infectious, and metabolic disorders.^[16][17][18]

Research Feed

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