Stable iron (58Fe) isotopic measurements in Kenyan toddlers during 3 months of iron supplementation demonstrate that half of the iron absorbed is lost.

Increased iron loss may reduce the effectiveness of iron supplementation. The objective of this study was to determine if daily oral iron supplementation increases iron loss, measured using a stable isotope of iron (58Fe). We enrolled and dewormed 24 iron-depleted Kenyan children, 24-27 months of age, whose body iron was enriched and equilibrated with 58Fe given at least 1 year earlier. Over 3 months of supplementation (6 mg iron/kg body weight [BW]/day), mean (±SD) iron absorption was 1.10 (±0.28) mg/day. During supplementation, 0.55 (±0.36) mg iron/day was lost, equal to half of the amount of absorbed iron. Supplementation did not increase faecal haem/porphyrin or biomarkers of enterocyte damage and gut or systemic inflammation. Using individual patient data, we examined iron dose, absorption and loss among all available long-term iron isotopic studies of supplementation. Expressed in terms of body weight, daily iron loss was correlated significantly with iron absorption (Pearson's r = 0.66 [95% confidence interval 0.48-0.78]) but not with iron dose (r = 0.16 [95% CI -0.10-0.40]). The results of this study indicate that iron loss is increased with daily oral iron supplementation and may blunt the efficacy of iron supplements in children. This study was registered at ClinicalTrials.gov as NCT04721964.

Oral iron therapy: Current concepts and future prospects for improving efficacy and outcomes.

Iron deficiency (ID) and iron-deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults. IDA is usually treated by oral iron supplementation, typically using iron salts (e.g. FeSO4 ); however, dosing at several-fold above the RDA may be required due to less efficient absorption. Excess enteral iron causes adverse gastrointestinal side effects, thus reducing compliance, and negatively impacts the gut microbiome. Recent research has sought to identify new iron formulations with better absorption so that lower effective dosing can be utilized. This article outlines emerging research on oral iron supplementation and focuses on molecular mechanisms by which different supplemental forms of iron are transported across the intestinal epithelium and whether these transport pathways are subject to regulation by the iron-regulatory hormone hepcidin.

Bioavailability of Australian pre-schooler iron intakes at specific eating occasions is low.

PURPOSE: Poor bioavailability may contribute to iron deficiency among children in high-resource countries, but iron bioavailability of Australian pre-schooler diets is unknown. This study aimed to estimate the bioavailability of Australian pre-schooler iron intakes across the day and by eating occasions to identify optimal timing for intervention, by using five previously developed algorithms, and to estimate the proportion of children with intakes of absorbable iron below the requirements. METHODS: Dietary data of children aged 2 to < 6 y (n = 812) from the 2011-12 National Nutrition and Physical Activity Survey were collected via two 24-h recalls. Usual food and nutrient intakes were estimated via Multiple Source Method. Phytate, polyphenol, and heme iron values were sourced from international databases or the literature. Five previously published algorithms were applied to observed dietary data to estimate iron bioavailability and calculate the prevalence of children with intakes of absorbable iron below requirements. RESULTS: Pre-schooler daily iron bioavailability was low (2.7-10.5%) and corresponded to intakes of 0.18-0.75 mg/d of absorbable iron. The proportion of children with inadequate intakes of absorbable iron ranged between 32 and 98%. For all eating occasions, dinner offered iron of the greatest bioavailability (4.2-16.4%), while iron consumed at breakfast was of the lowest bioavailability (1.2-5.6%). CONCLUSION: Future strategies are required to improve intakes of bioavailable iron for pre-schoolers to prevent the risk of deficiency. These strategies could include the encouragement of concomitant consumption of enhancers of iron absorption with iron-rich sources, particularly at breakfast.

Total Iron Absorbed from Iron-Biofortified Potatoes Is Higher than that from Nonbiofortified Potatoes: A Randomized Trial Using Stable Iron Isotopes in Women from the Peruvian Highlands.

BACKGROUND: Yellow-fleshed potatoes biofortified with iron have been developed through conventional breeding, but the bioavailability of iron is unknown. OBJECTIVES: Our objective was to measure iron absorption from an iron-biofortified yellow-fleshed potato clone in comparison with a nonbiofortified yellow-fleshed potato variety. METHODS: We conducted a single-blinded, randomized, crossover, multiple-meal intervention study. Women (n = 28; mean ± SD plasma ferritin 21.3 ± 3.3 µg/L) consumed 10 meals (460 g) of both potatoes, each meal extrinsically labeled with either 58Fe sulfate (biofortified) or 57Fe sulfate (nonfortified), on consecutive days. Iron absorption was estimated from iron isotopic composition in erythrocytes 14 d after administration of the final meal. RESULTS: Mean ± SD iron, phytic acid, and ascorbic acid concentrations in iron-biofortified and the nonfortified potato meals (mg/per 100 mg) were 0.63 ± 0.01 and 0.31 ± 0.01, 39.34 ± 3.04 and 3.10 ± 1.72, and 7.65 ± 0.34 and 3.74 ± 0.39, respectively (P < 0.01), whereas chlorogenic acid concentrations were 15.14 ± 1.72 and 22.52 ± 3.98, respectively (P < 0.05). Geometric mean (95% CI) fractional iron absorption from the iron-biofortified clone and the nonbiofortified variety were 12.1% (10.3%-14.2%) and 16.6% (14.0%-19.6%), respectively (P < 0.001). Total iron absorption from the iron-biofortified clone and the nonbiofortified variety were 0.35 mg (0.30-0.41 mg) and 0.24 mg (0.20-0.28 mg) per 460 g meal, respectively (P < 0.001). CONCLUSIONS: TIA from iron-biofortified potato meals was 45.8% higher than that from nonbiofortified potato meals, suggesting that iron biofortification of potatoes through conventional breeding is a promising approach to improve iron intake in iron-deficient women. The study was registered at www. CLINICALTRIALS: gov as Identifier number NCT05154500.

Ferric Pyrophosphate Forms Soluble Iron Coordination Complexes with Zinc Compounds and Solubilizing Agents in Extruded Rice and Predicts Increased Iron Solubility and Bioavailability in Young Women.

BACKGROUND: Co-extrusion of ferric pyrophosphate (FePP) with solubilizers, citric acid/trisodium citrate (CA/TSC), or ethylenediaminetetraacetic acid (EDTA) sharply increases iron absorption. Whether this can protect against the inhibition of iron absorption by phytic acid (PA) is unclear. Sodium pyrophosphate (NaPP) may be a new enhancer of iron absorption from FePP. OBJECTIVES: Our objectives were to 1) investigate the ligand coordination of iron, zinc, and solubilizers in extruded rice and test associations with iron solubility and absorption, 2) assess whether co-extrusion of FePP + CA/TSC rice can protect against inhibition of iron absorption by PA; 3) determine the effect of zinc oxide (ZnO) compared with zinc sulfate (ZnSO4), and 4) quantify iron absorption from FePP + NaPP rice. METHODS: We produced labeled 57FePP rice cofortified with ZnSO4 and EDTA, CA/TSC or NaPP, and FePP + EDTA rice with ZnO. We used electron paramagnetic resonance (EPR) to characterize iron-ligand complexes. We measured in vitro iron solubility and fractional iron absorption (FIA) in young women (n = 21, age: 22 ± 2 y, BMI: 21.3 ± 1.5 kg/m2 geometric mean plasma ferritin, 28.5 µg/L) compared with ferrous sulfate (58FeSO4). FIA was compared by linear mixed-effect model analysis. RESULTS: The addition of zinc and solubilizers created new iron coordination complexes of Fe(III) species with a weak ligand field at a high-spin state that correlated with solubility (r2 = 0.50, P = 0.02) and absorption (r2 = 0.72, P = 0.02). Phytic acid reduced FIA from FePP + CA/TSC rice by 50% (P < 0.001), to the same extent as FeSO4. FIA from FePP + EDTA + ZnO and FePP + EDTA + ZnSO4 rice did not significantly differ. Mean FIAs from FePP + EDTA + ZnSO4, FePP + CA/TSC + ZnSO4, and FePP + NaPP + ZnSO4 rice were 9% to 11% and did not significantly differ from each other or from FeSO4. CONCLUSION: Rice extrusion of FePP with solubilizers resulted in bioavailable iron coordination complexes. In the case of FePP + CA/TSC, PA exerted similar inhibition of FIA as with FeSO4. FePP + NaPP could be a further viable solubilizing agent for rice fortification. This study was registered at clinicaltrials.gov as NCT03703739.

Iron delivery systems for controlled release of iron and enhancement of iron absorption and bioavailability.

Iron deficiency is a global nutritional problem, and adding iron salts directly to food will have certain side effects on the human body. Therefore, there is growing interest in food-grade iron delivery systems. This review provides an overview of iron delivery systems, with emphasis on the controlled release of iron during gastrointestinal digestion, as well as the enhancement of iron absorption and bioavailability. Iron-bearing proteins are easily degraded by digestive enzymes and absorbed through receptor-mediated endocytosis. Instead, protein aggregates are slowly degraded in the stomach, which delays iron release and serves as a potential iron supplement. Amino acids, peptides and polysaccharides can bind iron through iron binding sites, but the formed compounds are prone to dissociation in the stomach. Moreover, peptides and polysaccharides can deliver iron by mediating the formation of ferric oxyhydroxide which is absorbed through endocytosis or bivalent transporter 1. In addition, liposomes are unstable during gastric digestion and iron is released in large quantities. Complexes formed by polysaccharides and proteins, and microcapsules formed by polysaccharides can delay the release of iron in the gastric environment and prolong iron release in the intestinal environment. This review is conducive to the development of iron functional ingredients and dietary supplements.

A short-term intervention of ingesting iron along with methionine and threonine leads to a higher hemoglobin level than that with iron alone in young healthy women: a randomized, double-blind, parallel-group, comparative study.

PURPOSE: Enhancing iron absorption and utilization is important for amelioration iron status faster and thereby, for improving quality of life. Dietary protein and amino acids, including methionine and threonine, have been reported to facilitate the absorption and utilization of dietary iron. Here, we investigated the effect of combined ingestion of methionine, threonine, and iron on the improvement of iron status during a short-term intervention, by comparing that with iron ingestion alone in healthy young women. METHODS: This was a randomized, double-blind, parallel-group, comparative study with 45 participants (aged 20-39) randomly assigned to three groups (n = 15 each): one group was administered 200 mg methionine, 400 mg threonine, and 6 mg iron once daily (FEMT); another ingested 6 mg iron alone (FE); and the third group ingested a placebo (PCG). Blood samples and dietary nutrient data were collected before the intervention (week 0) and after 2, 4, and 6 weeks. Serum iron, hemoglobin, transferrin, and ferritin levels were measured. RESULTS: Blood hemoglobin levels were significantly higher in the FEMT than in the FE group (P < 0.05) at week 4. Serum iron, transferrin, and ferritin levels were not changed across groups. In addition, our analyses showed that the observed increase in hemoglobin levels was affected by the intervention rather than changes in dietary nutrient intake. CONCLUSIONS: Ingestion of methionine and threonine with low doses of iron leads to a higher hemoglobin levels than that with iron alone in a short period of 4 weeks. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN000046621).

Oral Iron Absorption of Ferric Citrate Hydrate and Hepcidin-25 in Hemodialysis Patients: A Prospective, Multicenter, Observational Riona-Oral Iron Absorption Trial.

Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body's iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (-0.459, -0.643 to -0.276, p = 0.000; -0.648, -1.099 to -0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (-1.392, -1.749 to -1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake.

Absorption of iron from Tegillarca granosa using an in vitro simulated digestion and Caco-2/HepG2 co-culture system.

BACKGROUND: Iron-deficiency anemia is one severe micronutrient malnutrition and has captured worldwide attention. This study evaluated the in vitro iron absorption of two iron-binding proteins (hemoglobin and ferritin) from Tegillarca granosa. In addition, the protein structure-iron absorption relationship and the regulatory effect of hepcidin on cellular iron absorption were explored. RESULTS: Our findings revealed that both hemoglobin and ferritin extracted from T. granosa contained abundant iron-binding sites, as evidenced by stronger peaks in amide I and II regions compared with the two proteins from humans. Less ß-sheet (27.67%) structures were found in hemoglobin compared with ferritin (36.40%), probably contributing to its greater digestibility and more release of available iron. This was confirmed by the results of Caco-2/HepG2 cell culture system that showed iron absorption of hemoglobin was 26.10-39.31% higher than that of ferritin with an iron content of 50-150 µmol L-1 . This high iron absorption of hemoglobin (117.86-174.10 ng mg-1 ) could also be due to more hepcidin produced by HepG2 cells, thereby preventing ferroportin-mediated iron efflux from Caco-2 cells. In addition, the possible risk of oxidative stress was evaluated in cells post-iron exposure. In comparison with ferrous sulfate, a common iron supplement, Caco-2 cells treated with the iron-binding proteins had a 9.50-25.73% lower level of intracellular reactive oxygen species, indicating the safety of hemoglobin and ferritin. CONCLUSION: Collectively, the data of this research would be helpful for understanding the key features and potential of developing hemoglobin and ferritin from T. granosa as novel iron supplements. © 2022 Society of Chemical Industry.

Expression profiles of iron transport molecules along the duodenum.

Duodenal biopsies are considered a suitable source of enterocytes for studies of dietary iron absorption. However, the expression level of molecules involved in iron absorption may vary along the length of duodenum. We aimed to determine whether the expression of molecules involved in the absorption of heme and non-heme iron differs depending on the location in the duodenum. Analysis was performed with samples of duodenal biopsies from 10 individuals with normal iron metabolism. Samples were collected at the following locations: (a) immediately post-bulbar, (b) 1-2 cm below the papilla of Vater and (c) in the distal duodenum. The gene expression was analyzed at the mRNA and protein level using real-time PCR and Western blot analysis. At the mRNA level, significantly different expression of HCP1, DMT1, ferroportin and Zip8 was found at individual positions of duodenum. Position-dependent expression of other molecules, especially of FLVCR1, HMOX1 and HMOX2 was also detected but with no statistical significances. At the protein level, we observed statistically significantly decreasing expression of transporters HCP1, FLVCR1, DMT1, ferroportin, Zip14 and Zip8 with advancing positions of duodenum. Our results are consistent with a gradient of diminishing iron absorption along the duodenum for both heme and non-heme iron.

Iron chelates hitch a ride on PAT1.

The nicotianamine-iron chelate [NA-Fe2+], which is found in many plant-based foods, has been recently described as a new form of bioavailable iron in mice and chickens. How NA-Fe2+ is assimilated from the diet, however, remains unclear. The current investigation by Murata et al. has identified the proton-coupled amino acid transporter 1 (PAT1) as the main mechanism by which NA-Fe2+ is absorbed in the mammalian intestine. Discovery of this new form of dietary iron and elucidation of its pathway of intestinal absorption may lead to the development of improved iron supplementation approaches.

Prebiotic Galacto-Oligosaccharides and Fructo-Oligosaccharides, but Not Acacia Gum, Increase Iron Absorption from a Single High-Dose Ferrous Fumarate Supplement in Iron-Depleted Women.

BACKGROUND: Prebiotic galacto-oligosaccharides (GOS) increase iron absorption from fortification-level iron doses given as ferrous fumarate (FeFum) in women and children. Whether GOS or other fibers, such as prebiotic fructo-oligosaccharides (FOS) and acacia gum, increase iron absorption from higher supplemental doses of FeFum is unclear. OBJECTIVES: In iron-depleted [serum ferritin (SF) <25 µg/L] women, we tested if oral coadministration of 15 g GOS, FOS, or acacia gum increased iron absorption from a 100 mg Fe supplement given as FeFum. METHODS: In a randomized, single-blind, crossover study, 30 women (median age: 26.2 y; median SF: 12.9 µg/L) consumed a 100 mg Fe tablet labeled with 4 mg 57Fe or 58Fe, given with either 1) 15 g GOS; 2) 15 g FOS; 3) 15 g acacia gum; or 4) 6.1 g lactose and 1.5 g sucrose (control; matching the amounts of sucrose and lactose present in the GOS powder providing 15 g GOS), dissolved in water. The primary outcome, fractional iron absorption (FIA), was assessed by erythrocyte isotopic incorporation 14 d after administration. Data were analyzed using a linear mixed-effect model. We also tested, in vitro, iron solubility at different pH and dialyzability from the different supplement combinations administered in vivo. RESULTS: FIA from FeFum given with GOS and FOS was significantly higher (+45% and +51%, respectively; P < 0.001 for both) than control; median [IQR] total iron absorption was 34.6 mg [28.4-49.1 mg], 36.1 mg [29.0-46.2 mg], and 23.9 mg [20.5-34.0 mg], respectively. Acacia gum did not significantly affect FIA from FeFum (P = 0.688). In vitro, iron dialyzability of FeFum + GOS was 46% higher than that of FeFum alone (P = 0.003). CONCLUSIONS: In iron-depleted women, both GOS and FOS coadministration with FeFum increased iron absorption by ∼50% from a 100 mg oral iron dose, resulting in an additional 10-12 mg of absorbed iron. Thus, GOS and FOS may be promising new enhancers of supplemental iron absorption. This trial was registered at clinicaltrials.gov as NCT04194255.

Prebiotic Galacto-Oligosaccharides and Fructo-Oligosaccharides, but Not Acacia Gum, Increase Iron Absorption from a Single High-Dose Ferrous Fumarate Supplement in Iron-Depleted Women.

BACKGROUND: Prebiotic galacto-oligosaccharides (GOS) increase iron absorption from fortification-level iron doses given as ferrous fumarate (FeFum) in women and children. Whether GOS or other fibers, such as prebiotic fructo-oligosaccharides (FOS) and acacia gum, increase iron absorption from higher supplemental doses of FeFum is unclear. OBJECTIVES: In iron-depleted [serum ferritin (SF) <25 µg/L] women, we tested if oral coadministration of 15 g GOS, FOS, or acacia gum increased iron absorption from a 100 mg Fe supplement given as FeFum. METHODS: In a randomized, single-blind, crossover study, 30 women (median age: 26.2 y; median SF: 12.9 µg/L) consumed a 100 mg Fe tablet labeled with 4 mg 57Fe or 58Fe, given with either 1) 15 g GOS; 2) 15 g FOS; 3) 15 g acacia gum; or 4) 6.1 g lactose and 1.5 g sucrose (control; matching the amounts of sucrose and lactose present in the GOS powder providing 15 g GOS), dissolved in water. The primary outcome, fractional iron absorption (FIA), was assessed by erythrocyte isotopic incorporation 14 d after administration. Data were analyzed using a linear mixed-effect model. We also tested, in vitro, iron solubility at different pH and dialyzability from the different supplement combinations administered in vivo. RESULTS: FIA from FeFum given with GOS and FOS was significantly higher (+45% and +51%, respectively; P < 0.001 for both) than control; median [IQR] total iron absorption was 34.6 mg [28.4-49.1 mg], 36.1 mg [29.0-46.2 mg], and 23.9 mg [20.5-34.0 mg], respectively. Acacia gum did not significantly affect FIA from FeFum (P = 0.688). In vitro, iron dialyzability of FeFum + GOS was 46% higher than that of FeFum alone (P = 0.003). CONCLUSIONS: In iron-depleted women, both GOS and FOS coadministration with FeFum increased iron absorption by ∼50% from a 100 mg oral iron dose, resulting in an additional 10-12 mg of absorbed iron. Thus, GOS and FOS may be promising new enhancers of supplemental iron absorption.This trial was registered at clinicaltrials.gov as NCT04194255.

Higher Extrusion Temperature Induces Greater Formation of Less Digestible Type V and Retrograded Starch in Iron-Fortified Rice Grains But Does Not Affect Iron Bioavailability: Stable Isotope Studies in Young Women.

BACKGROUND: Hot extrusion is widely used to produce iron-fortified rice, but heating may increase resistant starch and thereby decrease iron bioavailability. Cold-extruded iron-fortified rice may have higher bioavailability but has higher iron losses during cooking. Thus, warm extrusion could have nutritional benefits, but this has not been tested. Whether the addition of citric acid (CA) and trisodium citrate (TSC) counteracts any detrimental effect of high-extrusion temperature on iron bioavailability is unclear. OBJECTIVES: Our aim was to assess the effects of varying processing temperatures on the starch microstructure of extruded iron-fortified rice and resulting iron solubility and iron bioavailability. METHODS: We produced extruded iron-fortified rice grains at cold, warm, and hot temperatures (40°C, 70°C, and 90°C), with and without CA/TSC at a molar ratio of iron to CA/TSC of 1:0.3:5.5. We characterized starch microstructure using small- and wide-angle X-ray scattering and differential scanning calorimetry, assessed color over 6 mo, and measured in vitro iron solubility. In standardized rice and vegetable test meals consumed by young women (n = 22; mean age: 23 y; geometric mean plasma ferritin: 29.3 µg/L), we measured iron absorption from the fortified rice grains intrinsically labeled with 57ferric pyrophosphate (57FePP), compared with ferrous sulfate (58FeSO4) solution added extrinsically to the meals. RESULTS: Warm and hot extrusion altered starch morphology from native type A to type V and increased retrograded starch. However, extrusion temperature did not significantly affect iron solubility or iron bioavailability. The geometric mean fractional iron absorption of iron from fortified rice extruded with CA/TSC (8.2%; 95% CI: 7.9%, 11.0%) was more than twice that from extruded rice without CA/TSC (3.0%; 95% CI: 2.7%, 3.4%; P < 0.001). CONCLUSIONS: Higher extrusion temperatures did not affect iron bioavailability from extruded rice in young women, but co-extrusion of CA/TSC with FePP sharply increased iron absorption independently from extrusion temperature. This trial is registered at www.clinicaltrials.gov as NCT03703726.

A Prolonged Bout of Running Increases Hepcidin and Decreases Dietary Iron Absorption in Trained Female and Male Runners.

BACKGROUND: Declines in iron status are frequently reported in those who regularly engage in strenuous physical activity. A possible reason is increases in the iron regulatory hormone hepcidin, which functions to inhibit dietary iron absorption and can be induced by the inflammatory cytokine interleukin-6 (IL-6). OBJECTIVES: The current study aimed to determine the impact of a prolonged bout of running on hepcidin and dietary iron absorption in trained female and male runners. METHODS: Trained female and male collegiate cross country runners (n = 28, age: 19.7 ± 1.2 y, maximal oxygen uptake: 66.1 ± 6.1 mL $\cdot$ kg -1$\cdot$ min-2, serum ferritin: 21.9 ± 13.3 ng/mL) performed a prolonged run (98.8 ± 14.7 min, 21.2 ± 3.8 km, 4.7 ± 0.3 min/km) during a team practice. Participants consumed a stable iron isotope with a standardized meal 2 h postrun and blood was collected 1 h later. The protocol was repeated 2 wk later except participants abstained from exercise (rest). RBCs were collected 15 d after exercise and rest to determine isotope enrichment. Differences between exercise and rest were assessed by paired t tests and Wilcoxon matched-pairs signed rank tests. Data are means ± SDs. RESULTS: Plasma hepcidin increased 51% after exercise (45.8 ± 34.4 ng/mL) compared with rest (30.3 ± 27.2 ng/mL, P = 0.0010). Fractional iron absorption was reduced by 36% after exercise (11.8 ± 14.6 %) compared with rest (18.5 ± 14.4 %, P = 0.025). Plasma IL-6 was greater after exercise (0.660 ± 0.354 pg/mL) than after rest (0.457 ± 0.212 pg/mL, P < 0.0001). Exploratory analyses revealed that the increase in hepcidin with exercise may be driven by a response in males but not females. CONCLUSIONS: A prolonged bout of running increases hepcidin and decreases dietary iron absorption compared with rest in trained runners with low iron stores. The current study supports that IL-6 contributes to the increase in hepcidin with prolonged physical activity, although future studies should explore potential sex differences in the hepcidin response.This trial was registered at Clinicaltrials.gov as NCT04079322.

The effect of a natural polyphenol supplement on iron absorption in adults with hereditary hemochromatosis.

OBJECTIVES: We developed a natural polyphenol supplement that strongly chelates iron in vitro and assessed its effect on non-heme iron absorption in patients with hereditary hemochromatosis (HH). METHODS: We performed in vitro iron digestion experiments to determine iron precipitation by 12 polyphenol-rich dietary sources, and formulated a polyphenol supplement (PPS) containing black tea powder, cocoa powder and grape juice extract. In a multi-center, single-blind, placebo-controlled cross-over study, we assessed the effect of the PPS on iron absorption from an extrinsically labelled test meal and test drink in patients (n = 14) with HH homozygous for the p.C282Y variant in the HFE gene. We measured fractional iron absorption (FIA) as stable iron isotope incorporation into erythrocytes. RESULTS: Black tea powder, cocoa powder and grape juice extract most effectively precipitated iron in vitro. A PPS mixture of these three extracts precipitated ~ 80% of iron when 2 g was added to a 500 g iron solution containing 20 µg Fe/g. In the iron absorption study, the PPS reduced FIA by ~ 40%: FIA from the meal consumed with the PPS was lower (3.01% (1.60, 5.64)) than with placebo (5.21% (3.92, 6.92)) (p = 0.026)), and FIA from the test drink with the PPS was lower (10.3% (7.29 14.6)) than with placebo (16.9% (12.8 22.2)) (p = 0.002). CONCLUSION: Our results indicate that when taken with meals, this natural PPS can decrease dietary iron absorption, and might thereby reduce body iron accumulation and the frequency of phlebotomy in patients with HH. TRIAL REGISTRY: clinicaltrials.gov (registration date: 9.6.2019, NCT03990181).

Absorption of nonheme iron during gastric acid suppression in patients with hereditary hemochromatosis and healthy controls.

Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton-pump inhibitors (PPIs) can reduce the number of phlebotomies in patients with HH. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. In 10 p.cysteine282tyrosine (p.C282Y) homozygous HH patients with normalized iron stores and 10 healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron [ferric iron (Fe3+)] polymaltose and hourly for 4 h afterward. This was repeated after 7 days of treatment with pantoprazole 40 mg once daily. Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the patients with HH, whereas no changes were observed in the HCs. Hepcidin concentrations were lower in the patients with HH compared with the HCs both before and during PPI use. In both groups, hepcidin levels did not significantly decrease during the treatment. Seven-day PPI use significantly reduces iron absorption in patients with HH but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size.NEW & NOTEWORTHY This study confirms that lowering gastric acidity by proton pump inhibitors results in a reduction in iron absorption in patients with hemochromatosis and not in healthy control subjects. The presupposition that a decrease in hepcidin concentration in healthy control subjects in response to lowering gastric acidity can explain the difference in iron absorption between these groups could not be confirmed probably because of a small sample size.

Measurement of long-term iron absorption and loss during iron supplementation using a stable isotope of iron (57 Fe).

We report the first measurements of long-term iron absorption and loss during iron supplementation in African children using a stable isotope of iron (57 Fe). After uniform labelling of body iron with 57 Fe, iron absorption is proportional to the rate of decrease in the 57 Fe tracer concentration, while iron loss is proportional to the rate of decrease in the 57 Fe tracer amount. Anaemic Gambian toddlers were given 2 mg 57 Fe orally to equilibrate with total body iron over 8-11 months. After assignment to the positive control arm of the HIGH study, 22 toddlers consumed a micronutrient powder containing 12 mg iron for 12 weeks followed by 12 weeks without iron supplementation. Their daily iron absorption increased 3·8-fold during the iron supplementation period compared to the control period [median (interquartile range, IQR): 1·00 (0·82; 1·28) mg/day vs. 0·26 (0·22; 0·35) mg/day; P = 0·001]. Unexpectedly, during the supplementation period, daily iron loss also increased by 3·4-fold [0·75 (0·55; 0·87) mg/day vs. 0·22 (0·19; 0·29) mg/day; P = 0·005]. Consequently, most (~72%) of the absorbed iron was lost during supplementation. Long-term studies of iron absorption and loss are a promising and accurate method for assessing and quantifying long-term iron balance and may provide a reference method for evaluating iron intervention programs in vulnerable population groups. This study was registered as ISRCTN 0720906.

Resveratrol improves the iron deficiency adaptation of Malus baccata seedlings by regulating iron absorption.

BACKGROUND: Resveratrol (Res), a phytoalexin, has been widely reported to participate in plant resistance to fungal infections. However, little information is available on its role in abiotic stress, especially in iron deficiency stress. Malus baccata is widely used as apple rootstock in China, but it is sensitive to iron deficiency. RESULTS: In this study, we investigated the role of exogenous Res in M. baccata seedings under iron deficiency stress. Results showed that applying 100 µM exogenous Res could alleviate iron deficiency stress. The seedlings treated with Res had a lower etiolation rate and higher chlorophyll content and photosynthetic rate compared with the apple seedlings without Res treatment. Exogenous Res increased the iron content in the roots and leaves by inducing the expression of MbAHA genes and improving the H+-ATPase activity. As a result, the rhizosphere pH decreased, iron solubility increased, the expression of MbFRO2 and MbIRT1 was induced, and the ferric-chelated reductase activity was enhanced to absorb large amounts of Fe2+ into the root cells under iron deficiency conditions. Moreover, exogenous Res application increased the contents of IAA, ABA, and GA3 and decreased the contents of DHZR and BL for responding to iron deficiency stress indirectly. In addition, Res functioned as an antioxidant that strengthened the activities of antioxidant enzymes and thus eliminated reactive oxygen species production induced by iron deficiency stress. CONCLUSION: Resveratrol improves the iron deficiency adaptation of M. baccata seedlings mainly by regulating iron absorption.

A Substantial Proportion of 6- to 12-Month-Old Infants Have Calculated Daily Absorbed Iron below Recommendations, Especially Those Who Are Breastfed.

OBJECTIVE: To calculate the amount of bioavailable iron consumed among 6- to 12- month-old infants considering differences in iron bioavailability among dietary iron sources and to compare this with current recommended intakes. STUDY DESIGN: We used the Feeding Infants and Toddlers Study database of dietary intakes from 2016 and the estimated bioavailability of dietary iron sources to evaluate the proportion of infants whose calculated total daily absorbed iron fell below physiologic requirements, that is, the recommended amount needed to fully support growth and erythropoiesis. RESULTS: The calculated daily iron absorption was below the recommended amount in 54.3% of infants evaluated ranging from 19.5% of 448 exclusively formula-fed infants, to 95.8% of 296 exclusively breastfed infants and 72.2% of 102 mixed fed infants. The calculated mean iron absorption of 6- to 9- month-old breastfed infants was 0.27 mg/day, far less than the estimated physiologic requirement of 0.69 mg/day. The most highly bioavailable iron, heme iron, was <12% of the contributor to total iron absorbed in breastfed infants. CONCLUSIONS: These data indicate a need for further education and public health policies to support increased iron intake in 6- to 12- month-old infants, emphasizing those receiving any breast milk. Exclusively formula-fed infants are at lower risk, but rates of low absorbed iron indicate that all infants may need monitoring for clinical evidence of low iron status. Consideration should be given to increasing the proportion of heme iron obtained from animal products in the diet where feasible.