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The aim of this study was to establish the effect of a prebiotic mix on heme and non-heme iron (Fe) bioavailability in humans. To this purpose, twenty-four healthy women were randomized into one of two study groups. One group ate one yogurt per day for 12 days with a prebiotic mix (prebiotic group) and the other group received the same yogurt but without the prebiotic mix (control group). Before and after the intake period, the subjects participated in Fe absorption studies. These studies used 55 Fe and 59 Fe radioactive isotopes as markers of heme Fe and non-heme Fe, respectively, and Fe absorption was measured by the incorporation of radioactive Fe into erythrocytes. The results showed that there were no significant differences in heme and non-heme Fe bioavailability in the control group. Heme Fe bioavailability of the prebiotic group increased significantly by 56% post-prebiotic intake. There were no significant differences in non-heme Fe bioavailability in this group. We concluded that daily consumption of a prebiotic mix increases heme Fe bioavailability and does not affect non-heme iron bioavailability.

Background: Epidemiologic studies of heme iron and non-heme iron intake in relation to risk of acute myocardial infarction (AMI) are lacking. Therefore, we examine the associations between heme iron and non-heme iron intake and fatal and nonfatal AMI in men. Moreover, we investigated whether the associations were modified by intake of minerals (calcium, magnesium, and zinc) that decreases iron absorption., Methods: The population-based prospective cohort of Swedish Men (COSM) included 36882 men, aged 45-79 years, who completed a self-administered questionnaire on diet and had no history of coronary heart disease, stroke, diabetes, or cancer at baseline., Results: During an 11.7 year follow-up, 678 fatal and 2593 nonfatal AMI events were registered. The hazard ratio (HR) of fatal AMI among men in the highest compared with the lowest quintile of heme iron intake was 1.51 (95%CI: 1.07-2.13, P-trend=0.02). The association was confined to men with a low intake of minerals that can decrease iron absorption. Among men with combined intakes of calcium, magnesium, and zinc below the medians, the HR of fatal AMI was 2.89 (95%CI: 1.43-5.82) for the highest vs. the lowest quintile of heme iron intake. There was no association between heme iron intake and nonfatal AMI, or between non-heme iron intake and fatal or nonfatal AMI., Conclusions: Findings from this prospective study indicate that a high heme iron intake, particularly with simultaneous low intake of minerals that can decrease iron absorption, may increase the risk of fatal AMI., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Conventional iron deficiency treatment with pharmacologic iron doses often causes side effects. Heme iron has high bioavailability and a low capacity to cause gastrointestinal side effects. This study investigated the possibility of using heme iron in the form of blood-based crisp bread as a diet-based treatment program to improve the iron status of women of reproductive age., Methods: In a 12-wk intervention study, 77 women (mean age 24 y) were assigned to one of four groups: blood-based crisp bread (35 mg of iron [Fe], 27 mg of which was heme Fe), iron supplementation consisting of 35 mg of non-heme iron/day (Fe35), iron supplementation consisting of 60 mg of non-heme iron/day (Fe60), and controls (iron-free tablets)., Results: Body iron increased significantly in the crisp bread group by a median of 2.7 mg/kg (interquartile range 3.1, n = 18), in the Fe35 group by 2.7 mg/kg (interquartile range 2.8, n = 11), and in the Fe60 group by 4.1 mg/kg (interquartile range 3.6, n = 13), whereas no change was observed in the control group. No statistically significant difference in iron status increase was observed between the crisp bread group compared with the two iron-supplemented groups., Conclusion: Dietary-based treatment containing heme iron has few side effects and can be used efficiently to improve the iron status of women of reproductive age., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Calcium is the only known component in the diet that may affect absorption of both nonheme and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses ≥1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme (as sulfate) and heme (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium.

Background: Heme iron is found in the diet mainly in the form of hemoglobin and myoglobin. It is known that heme iron (heme-Fe) and inorganic iron are absorbed differently. Intracellularly, heme oxygenase-1 (HO1) participates in the cleavage of the heme ring producing biliverdin, CO and ferrous iron. Iron released from heme becomes part of labile iron pool, and it can be stored in ferritin or released through the basolateral membrane. The mechanism by which heme-Fe is metabolized within cells is not completely understood., Objective: This study focused on the uptake and transport of heme iron and on the role of heme oxygenase-1 on heme iron metabolism., Design: Caco-2 cells were incubated with different concentrations of heme-Fe. A full-length heme oxygenase-1 cDNA was expressed in Caco-2 cells and intracellular iron and heme-Fe content, heme uptake, heme and iron transport and heme oxygenase-1 immunolocalization were assessed in these cells., Results: Heme-Fe was bioavailable and induced an intracellular increase in iron, ferritin and HO1 levels and a decrease in DMT1 expression. In cells overexpressing HO1, heme-Fe uptake and transepithelial Fe transport was higher than in controls. Most heme-Fe was metabolized to free iron, most of which was found mainly in the basolateral chamber. However, there is a fraction of heme that is delivered intact to the basolateral side. In a high heme-Fe condition, HO1 is found near the plasma membrane., Conclusions: These results suggest that heme oxygenase-1 catabolizes most of the heme-Fe and favors iron influx and efflux in intestinal cells.

The iron-regulated surface proteins IsdA, IsdB, and IsdC and transporter IsdDEF of Staphylococcus aureus are involved in heme acquisition. To establish an experimental model of heme acquisition by this system, we have investigated hemin transfer between the various couples of human methemoglobin (metHb), IsdA, IsdB, IsdC, and IsdE by spectroscopic and kinetic analyses. The efficiencies of hemin transfer from hemin-containing donors (holo-protein) to different hemin-free acceptors (apo-protein) were examined, and the rates of the transfer reactions were compared with that of indirect loss of hemin from the relevant donor to H64Y/V68F apomyoglobin. The efficiencies, spectral changes, and kinetics of the transfer reactions demonstrate that: 1) metHb directly transfers hemin to apo-IsdB, but not to apo-IsdA, apo-IsdC, and apo-IsdE; 2) holo-IsdB directly transfers hemin to apo-IsdA and apo-IsdC, but not to apo-IsdE; 3) apo-IsdE directly acquires hemin from holo-IsdC, but not from holo-IsdB and holo-IsdA; and 4) IsdB and IsdC enhance hemin transfer from metHb to apo-IsdC and from holo-IsdB to apo-IsdE, respectively. Taken together with our recent finding that holo-IsdA directly transfers its hemin to apo-IsdC, these results provide direct experimental evidence for a model in which IsdB acquires hemin from metHb and transfers it directly or through IsdA to IsdC. Hemin is then relayed to IsdE, the lipoprotein component of the IsdDEF transporter.

The objective of this work was to evaluate the bioavailability of heme iron added to biscuit filling. It comprised two stages: first, the development of the heme iron enriched biscuit filling; second, the evaluation of the bioavailability of the mineral in fattening piglets. Two groups were selected randomly and fed: a) Low iron feed and biscuits with heme iron supplemented filling; b) Normal feed (with ferrous sulphate). Weight and blood parameters were measured every fifteen days. Averages were compared after duplicate analyses. The filling had a creamy appearance, chocolate taste and smell, appropriate spreadability, heme iron content of 2.6 mg per gram and a shelf-life of a month. The heme iron supplemented pigs registered a greater (P<0.05) weight gain (27.8% more than the control group). Mortality in the heme iron group was 10%, compared to 50% in the control group. The amount of iron measured in the different compartment was greater in the heme group (3315 mg) than in the control group (2792 mg). However, the amount of iron consumed in the latter was greater. We show that an acceptable product with high heme iron content can be formulated, suitable for use as biscuit filling. The heme iron supplement produced better weight increase and lesser mortality in fattening pigs. The bioavailability of heme iron was 23% greater (P<0.05) compared to ferrous sulphate.

Fe absorption is affected by many dietary factors. The objective of the present study was to measure the effects of high v. low content of vitamin C, meat and phytic acid in whole diets with Fe-fortified bread on the efficacy of Fe absorption. Thirty-two healthy women with low Fe stores were randomised to three groups, each of which was given two of six test diets containing either low/high amounts of vitamin C, meat or phytic acid, respectively, in a cross-over design. Each diet was served throughout a 5 d period. Fe-fortified rye bread, extrinsically labelled with (59)Fe, was given with all main meals. Fe absorption was determined from whole-body counter measurements of (59)Fe retention. The fractional non-haem Fe absorption (corrected to a 40 % standard absorption by measurements from the reference dose) was 1.9 % v. 3.4 % (P=0.04) for the low/high vitamin C diets, 3.0 % v. 3.5 % (P=0.58) on the low/high meat diets and 4.9 % v. 3.8 % (P=0.24) on the low/high phytic acid diet, respectively. The total Fe absorbed (geometric mean with standard error) varied from 0.43 (se 0.11) mg from the diet with lowest bioavailability to 1.09 (se 0.18) mg from the diet with highest bioavailability (P<0.001). The present whole-diet study indicates that diet composition is a strong predictor of Fe absorption. In the diet with a low content of enhancers and a high content of inhibitors, vitamin C improved non-haem Fe absorption. The total Fe absorption varied 2.5-fold after small alterations of the content of enhancers and inhibitors in the diet.

Our current state of knowledge of the mechanism and regulation of intestinal iron absorption has been critically dependent on the analysis of inherited disorders of iron homeostasis in both humans and other animal species. Mutations in DMT1 and Ireg1 have revealed that these molecules are major mediators of iron transport across the brush border and basolateral membranes of the enterocyte, respectively. Similarly, the iron oxidase hephaestin has been shown to play an important role in basolateral iron efflux. The analysis of a range of human iron loading disorders has provided very strong evidence that the products of the HFE, TfR2, hepcidin and hemojuvelin genes comprise integral components of the machinery that regulates iron absorption and iron traffic around the body. Engineered mouse strains have already proved very effective in helping to dissect pathways of iron homeostasis, and in the future they will continue to provide important insights into the absorption of both inorganic and haem iron by the gut.

Iron is an essential trace element in human nutrition and its deficiency is a world nutritional problem. Due to the high prevalence of anaemia in developing and industrialized countries, it is necessary to maintain a suitable iron intake through diet in order to achieve an appropriate status of this element in the body. For this reason, accurate knowledge of iron availability of foods is essential in order to plan intervention strategies that improve deficient situations of this nutrient. Regarding to the two forms of iron present in foods, heme iron has greater availability than non-heme iron. Beside this, non-heme iron availability is conditioned by several dietary factors, such as classic factors (meat, ascorbic acid, fibre, phytic acid, polyphenols) and new factors (caseinophosphopeptides and fructo-oligosaccharides with prebiotic characteristics). For that reason, the aim of this paper is to accurately review all investigations reported in the past decade related to dietetic factors that influence the bioavailability of different iron forms.

Heme-Fe is an important source of dietary iron in humans. Caco-2 cells have been used extensively to study human iron absorption with an emphasis on factors affecting nonheme iron absorption. Therefore, we examined several factors known to affect heme iron absorption. Cells grown in bicameral chambers were incubated with high specific activity [59Fe]heme alone or with 1% globin, BSA, or fatty acid-free BSA (BSA-FA) to examine the effect of protein source on absorption. Heme iron absorption was enhanced by globin and inhibited by BSA and BSA-FA. Absorption of heme iron in cells pretreated for 7 days with serum-free medium containing 1, 25, 50, or 100 microM Fe was higher in the 1-microM-Fe pretreatment group than in all other groups (P < 0.05), showing an effect of iron status. Increased heme concentrations resulted in decreased percent absorbed but increased total heme iron absorption and increased transport rate across the basolateral membrane. Finally, cells treated with 10 microM CdCl2, which induces heme oxygenase, demonstrated higher absorption of [59Fe]heme than control cells (P < 0.05). Our results from Caco-2 cells are in agreement with human studies and make this a promising model for examining intestinal heme iron absorption.

Heme iron is absorbed from meat more efficiently than dietary inorganic iron and in a different manner. Thus, iron deficiency is less frequent in countries where meat constitutes a significant part of the diet. Proteolytic digestion of myoglobin and hemoglobin results in the release of heme, which is maintained in a soluble form by globin degradation products so that it remains available for absorption. Chelators that either diminish or enhance the absorption of inorganic iron have little effect on the absorption of heme iron. Heme enters the small intestinal absorptive cell as an intact metalloporphyrin. This may be facilitated by a vesicular transport system. In the absorptive cell the porphyrin ring is split by heme oxygenase. The released inorganic iron becomes associated with mobilferrin and paraferritin, which acts as a ferrireductase to make iron available for production of iron-containing end products such as heme proteins. Mucosal transfer of iron into the body occurs competitively with dietary iron that entered the absorptive cell as inorganic iron because they both share a common pathway within the intestinal cell.

Dietary iron is present in food both in inorganic forms as ferrous and ferric compounds, and in organic forms, the most important of these being heme iron. The purpose of this review is to evaluate the contributions of both heme and nonheme iron in establishing and maintaining a healthful iron status. The human requirement for iron, bioavailability of heme and nonheme iron, and amounts of heme and nonheme iron in the diet are individually estimated after reviewing the relevant literature in Sections II, III, and IV, respectively. In Section V, the contribution of heme and nonheme iron to human nutrition, as compared to the human requirement for iron (Section II), is estimated after attenuating the amounts of heme and nonheme iron found in the diet (Section IV) by their bioavailabilities (Section III).