Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications Original paper

What was studied?

This original research study evaluated whether microbiome signatures related to host iron regulation could be inferred from the hepcidin–ferroportin axis in anemia of chronic disease (ACD) versus combined ACD with true iron deficiency anemia (ACD/IDA), and whether serum hepcidin can guide diagnosis and iron therapy. Using a chronic inflammation rat model (peptidoglycan–polysaccharide–induced arthritis) with and without superimposed blood loss, the authors quantified serum hepcidin, tissue iron-transport gene expression (ferroportin, DMT1, transferrin receptor), macrophage iron uptake/release, and in vivo duodenal iron absorption; they then compared these patterns with parallel measurements in human patients. Although the work is not a gut microbiome sequencing study, it is highly relevant to microbiome-linked clinical phenotypes because iron availability is a major ecological constraint on intestinal microbes and many pathogens, and hepcidin-mediated hypoferremia is a classic “nutritional immunity” mechanism.

Who was studied?

The human cohort included 67 adults categorized as ACD (n=15), ACD/IDA (n=14), iron deficiency anemia without inflammation (IDA; n=12), and non-anemic, non-inflamed controls (n=26). ACD was defined by anemia with low transferrin saturation and normal/high ferritin (or intermediate ferritin with low soluble transferrin receptor/log ferritin ratio), while ACD/IDA required anemia with low transferrin saturation, ferritin <100 ng ml, and a high soluble transferrin receptor log ferritin ratio. underlying acd conditions included bacterial pneumonia, recurrent urinary tract infection, autoimmune diseases (e.g., rheumatoid arthritis, sle), colitis, osteomyelitis, malignancy-related inflammation. the animal work used female lewis rats assigned to control, ida (phlebotomy), (pg-aps arthritis), or plus phlebotomy), enabling controlled separation of inflammation-driven versus iron-deficiency–driven regulation. < p>

Most important findings

Across rats and humans, circulating hepcidin robustly separated ACD from ACD/IDA: ACD showed elevated serum hepcidin with reduced ferroportin expression in duodenum and macrophage-rich spleen, impaired duodenal iron uptake, and reduced macrophage iron release—classic functional iron deficiency. In contrast, ACD/IDA patients and rats had markedly lower hepcidin (similar to IDA), higher duodenal ferroportin, better intestinal iron absorption, and improved mobilization of macrophage iron despite ongoing inflammation and similar IL-6 levels, implying that erythropoietic iron demand and true iron deficiency can override inflammatory hepcidin induction. For microbiome-oriented databases, the key “signature” is not a specific bacterium but a host-state pattern: high-hepcidin/low-ferroportin (iron-restricted lumen and plasma) versus low-hepcidin/high-ferroportin (greater iron flux to plasma and potentially higher luminal iron exposure during supplementation), which can meaningfully shape microbial competition and pathogen risk.

Key implications

Clinically, serum hepcidin emerges as a practical discriminator between ACD and ACD/IDA when ferritin is confounded by inflammation, supporting more precise iron prescribing: patients with high hepcidin are unlikely to benefit from oral iron (blocked absorption and iron trapping) and may be harmed by indiscriminate iron exposure, whereas patients with low hepcidin (ACD/IDA) should absorb oral iron and mobilize macrophage iron, making supplementation rational and monitorable. Conceptually for microbiome-aware care, the study reframes anemia phenotyping as an “iron-ecology” problem: therapies that shift hepcidin/ferroportin status also shift iron availability, which can influence gut microbial composition and pathogen expansion, so integrating hepcidin status into microbiome signatures databases can help annotate host iron states that are known to modulate microbial niches even without sequencing data.

Citation

Theurl I, Aigner E, Theurl M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113(21):5277-5286. doi:10.1182/blood-2008-12-195651