Iron, an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense, is absorbed from the diet in the duodenum and loaded onto transferrin, the main iron transport protein.[1]

Iron is an important component of the blood pigment hemoglobin, which is responsible for transporting oxygen in the red blood cells. A lack of this trace element can lead to anemia. However, equally fatal is an excess of iron or iron overload, which can be triggered by certain genetic diseases such as hemochromatosis. Healthy humans absorb the precise amount of iron needed. Nonetheless, the most common causes of iron deficiency and anaemia include not only iron-deficient nutrition, but also impaired iron absorption despite sufficient availability of iron in the diet.

Inefficient dietary (nutritional) iron uptake may result in iron deficiency.  This deficiency, which may be caused by an insufficient intake of dietary iron to cover physiological iron requirements, is one of the five main causes of impaired health. It affects approximately 30 percent of the world’s population, particularly women. However, the mechanisms regulating iron absorption, even if Iron is supplied through the diet, remain poorly understood.

Why iron deficiency can occur, even if enough iron is supplied through the diet, has not yet been sufficiently clarified in scientific research. Now, for the first time, a research team from MedUni Vienna has discovered that certain immune cells in the intestine play an important role in iron absorption in the body.

The study results, which provide a new approach for possible therapeutic approach, were recently published in the journal “Blood.” [1]

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Daily intake
For healthy people, one to two milligrams of iron must be supplied as part of daily diet and absorbed in the duodenum for a balanced iron metabolism.

For the first time, the research team led by Nyamdelger Sukhbaatar and Thomas Weichhart from MedUni Vienna’s Centre for Pathobiochemistry and Genetics has demonstrated that macrophages in the intestine control iron absorption.

The researchers found that the activation of macrophages directly in the duodenum leads to a halt in iron availability in the body.

“We were able to determine that the macrophages in the duodenum ‘eat away’ the iron transport molecule transferrin. This means that the iron remains in the intestinal cells and can no longer enter the bloodstream,” Sukhbaatar, who is the study’s first author,  explained.

Paradigm shift
In addition, the study found that macrophages are also activated during fasting, food intake or during an intestinal infection, thereby changing the amount of transferrin in the intestine.

“Our findings thus represent a real paradigm shift, as it was previously assumed that transferrin is always present in equal amounts everywhere in the body and does not actually play any role in iron regulation,” noted study leader Thomas Weichhart.

New therapeutic options
Against the background of their study results, the research team is currently investigating whether the macrophages in the intestine and their regulation of transferrin could also be disturbed in inflammatory bowel diseases, intestinal infections or gastritis.

In animal models, clinically approved mTOR inhibitors with everolimus (Afinitor®; Novartis) or serine protease blockers with nafamostat (Torii Pharmaceuticals) were able to increase the amounts of transferrin and restore iron availability. Whether or not these treatment options can also be used in humans is to be researched in further studies as well.

Highlights of prescribing information
Everolimus (Afinitor®; Novartis) [Prescribing Information]

[1] Sukhbaatar N, Schöller M, Fritsch SD, Linke M, Horer S, Träger M, Mazic M, Forisch S, Gonzales K, Kahler JP, Binder C, Lassnig C, Strobl B, Mueller M, Scheiber-Mojdehkar B, Gundacker C, Dabsch S, Kain R, Hengstschläger M, Verhelst S, Weiss G, Theurl I, Weichhart T. Duodenal macrophages control dietary iron absorption via local degradation of transferrin. Blood. 2023 Apr 5:blood.2022016632. doi: 10.1182/blood.2022016632. Epub ahead of print. PMID: 37018657. [Article]

Featured image: Blood.  Photo courtesy: © 2016 – 2023 Fotolia/Adobe. Used with permission.

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