Category Archives: Hot Off The Press

A commentary by Elizabeta Nemeth 

Bessman et al. Dendritic cell-derived hepcidin promotes intestinal repair. Science. April 10, 2020. https://www.ncbi.nlm.nih.gov/pubmed/32273468

The liver-derived hormone hepcidin regulates systemic iron homeostasis by occluding and causing the degradation of ferroportin on duodenal enterocytes that absorb dietary iron and on macrophages that recycle iron from old red blood cells. In recent years, however, generation of floxed-hepcidin mice has enabled conditional deletion of hepcidin in different cell types, and has revealed tissue-specific roles of the locally-produced hepcidin. Ablation of cardiomyocyte hepcidin led to cardiomyocyte iron deficiency, and contractile and metabolic dysfunction of the heart1. Ablation of hepcidin in macrophages, on the other hand, improved cardiac repair and regeneration in a model of acute myocardial infarction2. Ablation of hepcidin in keratinocytes worsened necrotizing fasciitis by impairing the recruitment of neutrophils3.

In a recent study published in Science by Bessman et al4 (also see the accompanying commentary5), the spectrum of local hepcidin roles was expanded to mucosal healing in a mouse model of inflammatory bowel disease (IBD). Surprisingly, it was the dendritic cells in the intestinal lamina propria of inflamed mice and human IBD patients that had elevated hepcidin expression. Ablation of hepcidin in these antigen-presenting cells in mice worsened the recovery from DSS-induced intestinal damage. Mice lost more weight, had disordered colon tissue architecture and shorter colon length compared to the control animals. Similarly impaired mucosal healing was observed in mice expressing hepcidin-resistant ferroportin in macrophages and neutrophils, suggesting that these cells are the targets of dendritic cell-derived hepcidin.

As to the mechanism by which hepcidin promotes mucosal healing, Bessman et al. show that hepcidin ablation in dendritic cells resulted in altered microbiota composition. This occurred in naïve mice (in the absence of the DSS insult), and in the absence of detectable iron changes in the gut. How the low levels of hepcidin production by dendritic cells in the absence of inflammation affect microbiota remains to be determined. However, fecal microbiota transplantation from the knockouts to germ-free wild-type mice recapitulated the impaired mucosal healing after DSS administration. This was partially attributed to the decreased abundance in the knockouts of the iron-sensitive Bifidobacterium species, which are known to protect the intestinal barrier. The authors hypothesized that in the absence of local hepcidin production during the DSS insult in KO mice, macrophage iron export increases, potentiated by enhanced recycling of RBCs due to local bleeding. This would result in higher extracellular iron concentration, and affect the growth of luminal and tissue-infiltrating bacteria. In support of this hypothesis, systemic administration of the iron chelator DFO improved mucosal healing in dendritic cell hepcidin KOs.

The article raises a number of important questions and therapeutic implications. Can hepcidin mimetics be used to improve mucosal healing in IBD? How does locally derived hepcidin in the absence of inflammation alter microbiota? Does hepcidin derived from dendritic cells play a role in other inflammatory conditions and in other tissues?

  1. Lakhal-Littleton S, Wolna M, Chung YJ, et al. An essential cell-autonomous role for hepcidin in cardiac iron homeostasis. Elife. 2016;5.
  2. Zlatanova I, Pinto C, Bonnin P, et al. Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury. Circulation. 2019;139(12):1530-1547.
  3. Malerba M, Louis S, Cuvellier S, et al. Epidermal hepcidin is required for neutrophil response to bacterial infection. J Clin Invest. 2020;130(1):329-334.
  4. Bessman NJ, Mathieu JRR, Renassia C, et al. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science. 2020;368(6487):186-189.
  5. Rescigno M. The “iron will” of the gut. Science. 2020;368(6487):129-130.

Ancestral Iron Metabolism

Finoshin, A.D. et al (Iron in the processes of sponge plasticity PLoS ONE · Feb 2020 DOI: 10.1371/journal.pone.0228722)

Although iron has been proposed to have played a pivotal role in life since its inception, few studies have dealt with iron metabolism in ancestral invertebrates.  In a recent publication Finoshin et al (2020) investigated ironmetabolic pathways in White Sea cold water sponges, the oldest animal phylum that have unique structural plasticity and capacity to re-aggregate after complete dissociation. The sea-water sponges undergo severe tissue reorganizations during their life-cycle, and degenerative and regenerative phenomena are associated with sexual and asexual reproduction. The reaggregation process which begins in the sponge cell suspension immediately after the body dissociation depends on iron availability, a feature that is also reflected in dramatic changes in the expression of genes encoding proteins of iron metabolic pathways.

In this work the authors examined molecular features that accompany dissociation and reaggregation using de novo transcriptomes that were assembled using RNA-Seq data, and analyzed evolutionary trends with bioinformatic tools. They observed that:

1. The classical proteins of iron metabolism that are present in more distant classes of invertebrates and mammals are not detected in sponges:  e.g. ferritin light chain, the ferrous iron transporter Zip14, the metal reductase transporters Dcytb and STEAP2 / 3 , Ceruloplasmin, Hephaestin (Intestinal and ferroxidase) IRP2 mitochondrial transporter ABCB10, Hepcidin , Hemojuvelin,  Tf and Tfr1 / 2 (although the Tfr1/2 family is represented in sponges by an ancient homolog, NAALAD2

2. in the course of body dissociation,  oxygenation of sponge cells evokes a decrease in the expression of ferritin FTH1 and most of the genes connected to the heme biosynthesis and hypoxic response, whereas

3. in the course of reaggregation, they found: a.  differential expression patterns of enzymes of the heme biosynthetic pathway and transport globins; b. increased expression of IRP1, the antiapoptotic factor BCL2, the inflammation factor NFκB (p65), FTH1 (ferritin heavy chain) and NGB (neuroglobin), and c. an increase in mitochondrial density. The authors suggest that the induction of globin NGB expression in aggregating cells and the marked increase in mitochondrial density reflect a high demand for energy in the reaggregation process. The increased expression of IRP1 was implicated in terms of coordinated regulation of translation of the key mRNAs of ferritin (FTH1) and a putative transferrin receptor analog NAALAD2.  In fact, they detected 25 IREs in the mRNAs of sponge proteins involved in iron metabolism: 9 IREs located in the 5´ UTRs of mRNAs, 10 in IREs located in the 3´ untranslated regions and 8 IREs in the coding regions of mRNAs.

As the expression of IRP1 markedly increases under the aggregation of dissociated cells, it might implicate IRP1 in the regulation of sponge morphogenesis and the IRP-IRE regulatory system in early evolutionary development of metazoans. However, how does the parallel increase of IRP1 and FTH1 expression during re-aggregation fit with the proposed role of FT in protecting cells from potential toxic effects of labile iron remains unclear. The same functional uncertainty pertains to the expression patterns of three HIFa homologs during dissociation/reaggregation processes.

It is hoped that with proteomic analysis, the dramatic changes in the expression of genes encoding proteins of iron metabolic pathways found during dissociation-reaggregation of sponges, the role of iron metabolism in animal differentiation will be firmly established.

Ioav Cabantchik

 Feb 2020

Ironing the Gut

It is well known that iron is not only an essential nutrient for mammals but also serves as a growth factor for most bacteria, including those residing in the intestine, known as the microbiome. Accordingly, intestinal bacteria compete for iron within the gut by different mechanisms. That  provides a growth advantage to those microbes which have more sophisticated strategies to acquire the metal needed for their proliferation and pathogenicity1. In addition, increased iron availability in the intestine severely changes the composition of the gut microbiome with the expansion of more virulent, potentially pathogenic bacteria2. The struggle for iron is now well appreciated as a central mechanism in host pathogen interaction and the outcome of infections3.  In a recent paper published in Cell Metabolism, Das and co-workers (2020) add a new facet to this picture as they provide novel evidence that the gut microbiome affects host iron homeostasis by modulating iron absorption4.  They noted that germ free (GF) but not specific pathogen free C57BL6 mice developed anemia when fed an iron poor diet, which already implied that bacteria in the gut may compete with host iron uptake. Mechanistically, this could be attributed to inhibition of hypoxia inducible factor 2 alpha (HIF2alpha) expression in the intestine by Lactobacilli with subsequent alterations of HIF2alpha mediated effects on transmembrane iron transfer from the intestinal lumen to the circulation.  Das and co-workers found that intestinal microbes sense iron deficiency and produce metabolites, namely, 1,3-diaminopropane (DAP) and reuterin, which block HIF2 heterodimerisation and thus its biological activity resulting in dietary iron accumulation within enterocyte ferritin. These data first suggest, that mice kept under SPF conditions may not be an ideal model to study host iron homeostasis as effects of intestinal microbes and their secreted products will be missed. Secondly, modulation of intestinal bacterial composition may open a new therapeutic avenue, as specific compositions of probiotics  could affect dietary iron absorption in either direction, for treatment of iron overload conditions (more Lactobacilli) or to ameliorate iron absorption (bacteria outcompeting Lactobacilli, antibiotics) in subjects with iron deficiency.    

1.            Skaar EP, Raffatellu M. Metals in infectious diseases and nutritional immunity. Metallomics. 2015;7(6):926-928.

2.            Jaeggi T, Kortman GA, Moretti D, et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut. 2015;64(5):731-742.

3.            Nairz M, Schroll A, Sonnweber T, Weiss G. The struggle for iron – a metal at the host-pathogen interface. Cell Microbiol. 2010;12(12):1691-1702.

4.            Das NK, Schwartz AJ, Barthel G, et al. Microbial Metabolite Signaling Is Required for Systemic Iron Homeostasis. Cell Metab. 2020;31(1):115-130 e116.

Günter Weiss, Medical University of Innsbruck, Austria  (guenter.weiss@i-med.ac.at)

Iron transport and regulation in pregnancy: the fourth musketeer of iron homeostasis

The past two decades have witnessed increasing understanding of the molecular pathways and regulation of the three large iron flows in the body: intestinal iron absorption, macrophage-mediated recycling of iron from senescent erythrocytes, and the uptake of iron and its retrieval from storage in hepatocytes.  Often forgotten is another large iron flow, the transfer of iron during pregnancy from the mother through the placenta to the fetus. Understanding how the placenta transports iron and how the placental-fetal unit responds to maternal iron stresses is of more than academic interest, as iron deficiency during pregnancy is a major global problem, too often compounded by maternal infection and inflammation. In this context, the recent contributions of Sangkhae et al. JCI 2020 (and the associated commentary by Parrow et al. JCI 2020) and Fisher et al. JCI Insight 2020 are particularly noteworthy.

New Method for quantitation of food iron content- another tool in the fight against malnutrition?

THE BIGGER PICTURE

Waller and colleagues, at the University of Illinois have developed an affordable, reliable paper-based method to detect iron levels in food products (4).  The research, published in the journal of Nutrients, describes a colorimetric paper-based method, which when combined with specialized phone app (also developed at the University of Illinois), can give accurate estimates of iron levels in the various foods tested. 

Food-fortification programs in low-income countries have been at the forefront of fighting malnutrition, with iron deficiency a primary target in this battle. Affordable quality control tools to assess the nutritional value of fortified foods, such as the one developed by the Illinois team, could help advance this cause. 

Contributed by Prof Samira Lakhal-Littleton, Department of Physiology, Anatomy & Genetics

University of Oxford

COMMENT by Ioav Cabantchik

A comment on “New Method for quantitation of food iron content- another tool in the fight against malnutrition? THE BIGGER PICTURE”.

The advent of new smartphone applications in Analytica (industrial, clinical and scientific research) is rapidly increasing and important to follow by both professionals (clinical nutritionists, researchers, etc) and the general public. The new application for analyzing iron content in food sources and supplements is equally welcome, although iron in animal and plant sources has been one of the most studied and publicized (in professional and public media) for many years in terms of content and RDA values. The  story of spinach as an “ironic” nutritional source has recently been addressed in Bioiron Forum (section “Interesting”) and more is upcoming. 

While “Affordable quality control tools to assess the nutritional value of fortified foods, such as the one developed by the Illinois team, could help advance this cause” (as posted in Bioiron Forum), we must also caution that the real problem of edible iron sources is not merely “content” (that in most countries is mandatory to indicate in food labels) but “limited nutritional bioavailability”. That problem pertains not only to green vegetables like spinach (due to oxalates), legumes and nuts (due to phytic acid and other polyphosphates) but to iron salts (inorganic and organic)  given as supplements, alone or in combination with vitamins and polyphenols (some potent iron chelators).

On the positive side, the new application could help labs and field studies to create and/or  improve crops enriched in iron or identifying new edible iron-rich sources in plants. However,  the ultimate (if not sole) nutritional test remains how to assess nutritional efficacy in terms of bioavailability, and it is here where we still need reliable analytical applications (hopefully non-invasive, as for blood glucose GlucoWise™).