Nanoparticulate iron(III) oxo-hydroxide delivers safe iron that is well absorbed and utilised in humans

Dora I A Pereira, Sylvaine F A Bruggraber, Nuno Faria, Lynsey K Poots, Mani A Tagmount, Mohamad F Aslam, David M Frazer, Chris D Vulpe, Gregory J Anderson, Jonathan J Powell, Dora I A Pereira, Sylvaine F A Bruggraber, Nuno Faria, Lynsey K Poots, Mani A Tagmount, Mohamad F Aslam, David M Frazer, Chris D Vulpe, Gregory J Anderson, Jonathan J Powell

Abstract

Iron deficiency is the most common nutritional disorder worldwide with substantial impact on health and economy. Current treatments predominantly rely on soluble iron which adversely affects the gastrointestinal tract. We have developed organic acid-modified Fe(III) oxo-hydroxide nanomaterials, here termed nano Fe(III), as alternative safe iron delivery agents. Nano Fe(III) absorption in humans correlated with serum iron increase (P < 0.0001) and direct in vitro cellular uptake (P = 0.001), but not with gastric solubility. The most promising preparation (iron hydroxide adipate tartrate: IHAT) showed ~80% relative bioavailability to Fe(II) sulfate in humans and, in a rodent model, IHAT was equivalent to Fe(II) sulfate at repleting haemoglobin. Furthermore, IHAT did not accumulate in the intestinal mucosa and, unlike Fe(II) sulfate, promoted a beneficial microbiota. In cellular models, IHAT was 14-fold less toxic than Fe(II) sulfate/ascorbate. Nano Fe(III) manifests minimal acute intestinal toxicity in cellular and murine models and shows efficacy at treating iron deficiency anaemia.

From the clinical editor: This paper reports the development of novel nano-Fe(III) formulations, with the goal of achieving a magnitude less intestinal toxicity and excellent bioavailability in the treatment of iron deficiency anemia. Out of the tested preparations, iron hydroxide adipate tartrate met the above criteria, and may become an important tool in addressing this common condition.

Keywords: Bioavailability; Iron supplementation; Ligand-modified Fe(III) poly oxo-hydroxide; Microbiota; Redox damage.

Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Solubility and cellular uptake of nano Fe(III). (A) Acid dissolution at pH 3.0 in 9 g/L NaCl. Data are for different formulations of ligand-modified Fe(III) oxo-hydroxides: nano Fe(III) (a)- ligands are tartaric (T) and adipic (A) acids at a ratio 1:1:2 (T:A:Fe) and the material was dried prior to re-suspension; nano Fe(III) (b)—ligands are tartaric (T) and succinic (S) acids at a ratio 1:1:2 (T:S:Fe) and the material was dried prior to re-suspension; nano Fe(III) (c)- ligands are tartaric (T) and succinic (S) acids at a ratio 1:6:2 (T:S:Fe) and the material was dried prior to re-suspension; nano Fe(III) (d)- ligands are gluconic (G) and adipic (A) acids at a ratio 1:1:2 (G:A:Fe) and the material was dried prior to re-suspension; nano Fe(III) (e)- ligands are tartaric (T) and adipic (A) acids at a ratio 1:1:2 (T:A:Fe) and the material was used as a colloidal suspension (i.e. as synthesised) without drying (more details in Table 1). Negative and positive controls are, respectively, unmodified Fe(III) oxo-hydroxide (Fe(III)(OH)3) and Fe(III) maltolate (Fe(III) maltol). Data are shown for the two independent replicates. Dotted black lines show 0 and 100% solubility. All data were obtained by measuring the iron concentration in the supernatant following ultrafiltration (Mr 3000 cut-off). (B) Dispersion of the different iron materials in the BSS uptake medium, used for the Caco-2 cell experiments, as assessed by the fractional percentage of microparticulate (black), nanoparticulate (red) and soluble (white) Fe for each Fe material. Values are mean ± SD of three independent replicates. (C) Cellular iron (open bars) and ferritin (closed bars) levels in Caco-2 cells 23 hours following a one hour exposure to 0.5 mM Fe as unmodified Fe(III) oxo-hydroxide (Fe(III)(OH)3), ligand-modified Fe(III) oxo-hydroxides (nano Fe(III) (a-e)), or soluble Fe(III) maltolate (Fe(III)maltol). Results are mean ± SD of three independent experiments (each condition tested in triplicate wells within each experiment). Statistical comparisons in relation to the soluble control, Fe(III) maltol: ***, P = 0.0008; ****, P < 0.0001 for cellular iron; ##, P = 0.003; ###, P = 0.0002 and ####, P < 0.0001 for ferritin. (D) Pearson's correlation between the solubility of nano Fe(III) at pH3.0 after 15 minutes and cellular iron levels of Caco-2 cells following exposure to nano Fe(III). (E) Pearson's correlation between cellular ferritin levels and cellular iron levels in Caco-2 cell monolayers following exposure to nano Fe(III). For panels (D) and (E), values are mean ± SD, in both the X and Y directions. Where not apparent, the error bars are smaller than the symbol size. Data points are labelled with the nano Fe(III) preparation codes (a–e).
Figure 2
Figure 2
Absorption of iron from nano Fe(III) in iron-deficient women. (A) Relative bioavailability values (RBV) in relation to Fe(II) sulfate (100%). Percentage RBV for the nano Fe(III) preparations was calculated from the incorporation of labelled 58Fe into red blood cells, as measured by ICP-MS 14 days after ingestion of a single-dose of labelled compound (60 mg elemental Fe). Absorption from Fe(II) sulfate was estimated from the serum Fe curve with validated algorithms., Nano Fe(III) (a)—ligands are tartaric (T) and adipic (A) acids at a ratio 1:1:2 (T:A:Fe) and the material was dried prior to re-suspension; nano Fe(III) (b)—ligands are tartaric (T) and succinic (S) acids at a ratio 1:1:2 (T:S:Fe) and the material was dried prior to re-suspension; nano Fe(III) (c)—ligands are tartaric (T) and succinic (S) acids at a ratio 1:6:2 (T:S:Fe) and the material was dried prior to re-suspension; nano Fe(III) (d)— ligands are gluconic (G) and adipic (A) acids at a ratio 1:1:2 (G:A:Fe) and the material was dried prior to re-suspension; nano Fe(III) (e)—ligands are tartaric (T) and adipic (A) acids at a ratio 1:1:2 (T:A:Fe) and the material was used as a colloidal suspension (i.e. as synthesised) without drying (more details in Table 1). Controls are unmodified Fe(III) oxo-hydroxide (Fe(III)(OH)3) and an ‘unformulated’ mixture of Fe(III) chloride, tartaric acid and adipic acid in the same ratios as those used in nano Fe(III) (a). Box and whisker plots show median, minimum and maximum for n = 2 (Fe(III) (OH)3) or n = 4 (all other iron materials). **, P = 0.004. (B) Pearson's correlation between cellular iron levels in Caco-2 cells exposed to nano Fe(III) (preparations a-e) and relative bioavailability values (%RBV) of the same materials, as shown in Figures 1, C and 2, A. Nano Fe(III) (c) (shown in red triangle) was excluded from the correlation parameters presented in the panel (see Results and Discussion). Values are shown as mean ± SD in both the X and Y directions. Data points are labelled with the nano Fe(III) preparation codes (a-e).
Figure 3
Figure 3
Serum iron absorption following ingestion of a single-dose of the different Fe materials in iron-deficient women. Serum iron increase (A) and transferrin saturation increase (B) following a single dose of nano Fe(III) preparation (a) (closed circles) and Fe(II) sulfate (open triangles). Values are shown as mean and error bars represent SEM (n = 4). Transferrin saturation was defined as serum iron divided by total iron binding capacity and expressed as a percentage. (C-D) Pearson's correlation between percentage of iron absorption (calculated from the red cell incorporation of 58Fe) and maximum serum Fe increase (C) or rate of serum iron increase (D) for the five nano Fe(III) materials. Data points correspond to each individual study participant and are colour coded to reflect the different nano Fe(III) preparations: closed diamonds, nano Fe(III) (a); open triangles, nano Fe(III) (b); open circles, nano Fe(III) (c); closed triangles, nano Fe(III) (d); closed circles, nano Fe(III) (e). Nano Fe(III) (a)—ligands are tartaric (T) and adipic (A) acids at a ratio 1:1:2 (T:A:Fe) and the material was dried prior to re-suspension; nano Fe(III) (b)—ligands are tartaric (T) and succinic (S) acids at a ratio 1:1:2 (T:S:Fe) and the material was dried prior to re-suspension; nano Fe(III) (c)—ligands are tartaric (T) and succinic (S) acids at a ratio 1:6:2 (T:S:Fe) and the material was dried prior to re-suspension; nano Fe(III) (d)—ligands are gluconic (G) and adipic (A) acids at a ratio 1:1:2 (G:A:Fe) and the material was dried prior to re-suspension; nano Fe(III) (e)— ligands are tartaric (T) and adipic (A) acids at a ratio 1:1:2 (T:A:Fe) and the material was used as a colloidal suspension (i.e. as synthesised) without drying (more details in Table 1).
Figure 4
Figure 4
Effects of nano Fe(III) on cell viability and the intestinal microbiome of rats. (A) Viability of Caco-2 (red lines) and HT-29 (bold blue lines) cells exposed to increasing concentrations of Fe as nano Fe(III) (a) (ligands are tartaric (T) and adipic (A) acids at a ratio 1:1:2 (T:A:Fe) and the material was dried prior to re-suspension) for 24 (solid line) or 48 (dashed line) hours. Fe(II)-ascorbate (molar ratio 1:10) data in Caco-2 cells are shown in black. Results shown are mean ± SD of three independent experiments (each condition tested in triplicate wells per experiment). **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 in relation to control cells incubated in the absence of the iron materials (100% viability). (B) Haemoglobin levels of anaemic Sprague–Dawley male rats following 14 days dietary supplementation with nano Fe(III) (a) or Fe(II) sulfate (FeSO4). Data are shown for each animal at baseline (d0) and after 14 days (d14) iron supplementation. Data for the reference iron-replete group (i.e. rats fed the standard iron-sufficient diet throughout) are also shown. *, P = 0.04; **, P = 0.01 corresponding to the paired t test between day 0 and day 14 for FeSO4 and nano Fe(III) (a), respectively. (C) Characterisation of the faecal microbiota at the genus level of rats receiving either Fe(II) sulfate or nano Fe(III) (a) at baseline (d0) and after 14 days supplementation (d14). Proportions (mean ± SEM) of the three predominant genera Lactobacillus(D), Bacteroides(E) and Escherichia(F)) are shown at baseline and at day 14. *, P = 0.03. The differences between Fe(II) sulfate and nano Fe(III) (a) did not reach significance for Lactobacillus (P = 0.1) or Bacteroides (P = 0.2). (G) Paraffin-embedded sections of the small intestine of animals supplemented with (i) nano Fe(III) (a) or (ii) Fe(II) sulfate without detectable iron staining (Perls' Prussian Blue). Scale bar represents 100 μm.

References

    1. WHO . WHO; Geneva: 2008. The global burden of disease: 2004 update.
    1. De Benoist B., McLean E., Egli I., Cogswell M. WHO; Geneva: 2008. Worldwide prevalence of anaemia 1993-2005.
    1. McLean E., Cogswell M., Egli I., Wojdyla D., de Benoist B. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutr. 2008;23:1–11.
    1. WHO . 2002. The World Health Report. Reducing risks, promoting healthy life. [Geneva]
    1. Ezzati M., Lopez A.D., Rodgers A., Vander Hoorn S., Murray C.J. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360(9343):1347–1360.
    1. Stoltzfus R.J. Iron deficiency: global prevalence and consequences. Food Nutr Bull. 2003;24(4 Suppl.):S99–S103.
    1. Zimmermann M.B., Chassard C., Rohner F., N'Goran E.K., Nindjin C., Dostal A. The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am J Clin Nutr. 2010;92(6):1406–1415.
    1. Sazawal S., Black R.E., Ramsan M., Chwaya H.M., Stoltzfus R.J., Dutta A. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006;367(9505):133–143.
    1. McDermid J.M., Jaye A., Schim van der Loeff M.F., Todd J., Bates C., Austin S. Elevated iron status strongly predicts mortality in West African adults with HIV infection. J Acquir Immune Defic Syndr. 2007;46(4):498–507.
    1. Seril D.N., Liao J., Ho K.L., Warsi A., Yang C.S., Yang G.Y. Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig Dis Sci. 2002;47(6):1266–1278.
    1. Radulescu S., Brookes M.J., Salgueiro P., Ridgway R.A., McGhee E., Anderson K. Luminal iron levels govern intestinal tumorigenesis after apc loss in vivo. Cell Rep. 2012;2(2):270–282.
    1. Carrier J., Aghdassi E., Cullen J., Allard J.P. Iron supplementation increases disease activity and vitamin E ameliorates the effect in rats with dextran sulfate sodium-induced colitis. J Nutr. 2002;132(10):3146–3150.
    1. Erichsen K., Ulvik R.J., Grimstad T., Berstad A., Berge R.K., Hausken T. Effects of ferrous sulphate and non-ionic iron–polymaltose complex on markers of oxidative tissue damage in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2005;22(9):831–838.
    1. Lund E.K., Wharf S.G., Fairweather-Tait S.J., Johnson I.T. Oral ferrous sulfate supplements increase the free radical-generating capacity of feces from healthy volunteers. Am J Clin Nutr. 1999;69(2):250–255.
    1. Orozco M.N., Solomons N.W., Schumann K., Friel J.K., de Montenegro A.L. Antioxidant-rich oral supplements attenuate the effects of oral iron on in situ oxidation susceptibility of human feces. J Nutr. 2010;140(6):1105–1110.
    1. Werner T., Wagner S.J., Martinez I., Walter J., Chang J.S., Clavel T. Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis. Gut. 2011;60(3):325–333.
    1. Dostal A., Chassard C., Hilty F.M., Zimmermann M.B., Jaeggi T., Rossi S. Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats. J Nutr. 2012;142(2):271–277.
    1. Hutchinson C., Al-Ashgar W., Liu D.Y., Hider R.C., Powell J.J., Geissler C.A. Oral ferrous sulphate leads to a marked increase in pro-oxidant nontransferrin-bound iron. Eur J Clin Invest. 2004;34(11):782–784.
    1. Barton Pai A., Pai M.P., Depczynski J., McQuade C.R., Mercier R.C. Non-transferrin-bound iron is associated with enhanced Staphylococcus aureus growth in hemodialysis patients receiving intravenous iron sucrose. Am J Nephrol. 2006;26(3):304–309.
    1. van der A D.L., Marx J.J., Grobbee D.E., Kamphuis M.H., Georgiou N.A., van Kats-Renaud J.H. Non-transferrin-bound iron and risk of coronary heart disease in postmenopausal women. Circulation. 2006;113(16):1942–1949.
    1. van Tits L.J., Jacobs E.M., Swinkels D.W., Lemmers H.L., van der Vleuten G.M., de Graaf J. Non-transferrin-bound iron is associated with plasma level of soluble intercellular adhesion molecule-1 but not with in vivo low-density lipoprotein oxidation. Atherosclerosis. 2007;194(1):272–278.
    1. Tripathi A.K., Sullivan D.J., Stins M.F. Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB. Infect Immun. 2006;74(6):3262–3270.
    1. Powell J.J., Bruggraber S.F., Faria N., Poots L.K., Hondow N., Pennycook T.J. A nano-disperse ferritin-core mimetic that efficiently corrects anaemia without luminal iron redox activity. Nanomedicine. 2014 doi: 10.1016/j.nano.2013.12.011.
    1. Aslam M.F., Frazer D.M., Faria N., Bruggraber S.F., Wilkins S.J., Mirciov C. Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice. FASEB J. 2014 [Epub ahead of print]
    1. Pereira D.I., Mergler B.I., Faria N., Bruggraber S.F., Aslam M.F., Poots L.K. Caco-2 cell acquisition of dietary iron(III) invokes a nanoparticulate endocytic pathway. PLoS ONE. 2013;8(11):e81250. doi: 10.1371/journal.pone.0081250.
    1. Bejjani S., Pullakhandam R., Punjal R., Nair K.M. Gastric digestion of pea ferritin and modulation of its iron bioavailability by ascorbic and phytic acids in caco-2 cells. World J Gastroenterol. 2007;13(14):2083–2088.
    1. San Martin C.D., Garri C., Pizarro F., Walter T., Theil E.C., Nunez M.T. Caco-2 intestinal epithelial cells absorb soybean ferritin by mu2 (AP2)-dependent endocytosis. J Nutr. 2008;138(4):659–666.
    1. Davila-Hicks P., Theil E.C., Lonnerdal B. Iron in ferritin or in salts (ferrous sulfate) is equally bioavailable in nonanemic women. Am J Clin Nutr. 2004;80(4):936–940.
    1. Hoppler M., Schonbachler A., Meile L., Hurrell R.F., Walczyk T. Ferritin–iron is released during boiling and in vitro gastric digestion. J Nutr. 2008;138(5):878–884.
    1. Theil E.C., Chen H., Miranda C., Janser H., Elsenhans B., Nunez M.T. Absorption of iron from ferritin is independent of heme iron and ferrous salts in women and rat intestinal segments. J Nutr. 2012;142(3):478–483.
    1. Pan Y.H., Sader K., Powell J.J., Bleloch A., Gass M., Trinick J. 3D morphology of the human hepatic ferritin mineral core: new evidence for a subunit structure revealed by single particle analysis of HAADF-STEM images. J Struct Biol. 2009;166(1):22–31.
    1. Simonian H.P., Vo L., Doma S., Fisher R.S., Parkman H.P. Regional postprandial differences in pH within the stomach and gastroesophageal junction. Dig Dis Sci. 2005;50(12):2276–2285.
    1. Beiseigel J.M., Hunt J.R., Glahn R.P., Welch R.M., Menkir A., Maziya-Dixon B.B. Iron bioavailability from maize and beans: a comparison of human measurements with Caco-2 cell and algorithm predictions. Am J Clin Nutr. 2007;86(2):388–396.
    1. Bengtsson A., Scheers N., Andlid T., Alminger M.L., Sandberg A.S., Svanberg U. Impaired uptake of beta-carotene by Caco-2 human intestinal cells in the presence of iron. Int J Food Sci Nutr. 2009;60(Suppl. 5):125–135.
    1. Valberg L.S., Taylor K.B., Witts L.J., Richards W.C. The effect of iron deficiency on the stomach of the rat. Br J Nutr. 1961;15:473–480.
    1. Faria N., Winship P.D., Weiss D.J., Coles B.J., Schoenberg R., Hutchison C. Development of DRC-ICP-MS methodology for the rapid determination of Fe-58 erythrocyte incorporation in human iron absorption studies. J Anal At Spectrom. 2011;26(8):1648–1652.
    1. Ruiz-Arguelles G.J., Diaz-Hernandez A., Manzano C., Ruiz-Delgado G.J. Ineffectiveness of oral iron hydroxide polymaltose in iron-deficiency anemia. Hematology. 2007;12(3):255–256.
    1. Derman D.P., Bothwell T.H., Torrance J.D., Macphail A.P., Bezwoda W.R., Charlton R.W. Iron absorption from ferritin and ferric hydroxide. Scand J Haematol. 1982;29(1):18–24.
    1. Conway R.E., Geissler C.A., Hider R.C., Thompson R.P., Powell J.J. Serum iron curves can be used to estimate dietary iron bioavailability in humans. J Nutr. 2006;136(7):1910–1914.
    1. Mergler B.I., Roth E., Bruggraber S.F.A., Powell J.J., Pereira D.I.A. Development of the Caco-2 model for assessment of iron absorption and utilisation at supplemental levels. J Pharm Nutr Sci. 2012;2(1):27–34.
    1. Rudzki Z., Baker R.J., Deller D.J. The iron-binding glycoprotein of human gastric juice. II. Nature of the interaction of the glycoprotein with iron. Digestion. 1973;8(1):53–67.
    1. Wang Z., Li C., Ellenburg M., Soistman E., Ruble J., Wright B. Structure of human ferritin L chain. Acta Crystallogr. 2006;62(Pt 7):800–806.
    1. Masuda H., Ishimaru Y., Aung M.S., Kobayashi T., Kakei Y., Takahashi M. Iron biofortification in rice by the introduction of multiple genes involved in iron nutrition. Sci Rep. 2012;2:543. doi: 10.1038/srep00543.
    1. Murgia I., Arosio P., Tarantino D., Soave C. Biofortification for combating ‘hidden hunger’ for iron. Trends Plant Sci. 2012;17(1):47–55.
    1. Sperotto R.A., Ricachenevsky F.K., Waldow Vde A., Fett J.P. Iron biofortification in rice: it's a long way to the top. Plant Sci. 2012;190:24–39.
    1. Stein A.J., Meenakshi J.V., Qaim M., Nestel P., Sachdev H.P., Bhutta Z.A. Potential impacts of iron biofortification in India. Soc Sci Med. 2008;66(8):1797–1808.
    1. Lopez-Castro J.D., Delgado J.J., Perez-Omil J.A., Galvez N., Cuesta R., Watt R.K. A new approach to the ferritin iron core growth: influence of the H/L ratio on the core shape. Dalton Trans. 2012;41(4):1320–1324.
    1. Swain J.H., Newman S.M., Hunt J.R. Bioavailability of elemental iron powders to rats is less than bakery-grade ferrous sulfate and predicted by iron solubility and particle surface area. J Nutr. 2003;133(11):3546–3552.
    1. Forbes A.L., Arnaud M.J., Chichester C.O., Cook J.D., Harrison B.N., Hurrell R.F. Comparison of in vitro, animal, and clinical determinations of iron bioavailability: International Nutritional Anemia Consultative Group Task Force report on iron bioavailability. Am J Clin Nutr. 1989;49(2):225–238.
    1. Hilty F.M., Teleki A., Krumeich F., Buchel R., Hurrell R.F., Pratsinis S.E. Development and optimization of iron- and zinc-containing nanostructured powders for nutritional applications. Nanotechnology. 2009;20(47):475101.
    1. Kapsokefalou M., Alexandropoulou I., Komaitis M., Politis I. In vitro evaluation of iron solubility and dialyzability of various iron fortificants and of iron-fortified milk products targeted for infants and toddlers. Int J Food Sci Nutr. 2005;56(4):293–302.
    1. Hilty F.M., Arnold M., Hilbe M., Teleki A., Knijnenburg J.T., Ehrensperger F. Iron from nanocompounds containing iron and zinc is highly bioavailable in rats without tissue accumulation. Nat Nanotechnol. 2010;5(5):374–380.
    1. Glahn R.P., Rassier M., Goldman M.I., Lee O.A., Cha J. A comparison of iron availability from commercial iron preparations using an in vitro digestion/Caco-2 cell culture model. J Nutr Biochem. 2000;11(2):62–68.
    1. Glahn R.P., Wortley G.M., South P.K., Miller D.D. Inhibition of iron uptake by phytic acid, tannic acid, and ZnCl2: studies using an in vitro digestion/Caco-2 cell model. J Agric Food Chem. 2002;50(2):390–395.
    1. Glahn R.P., Lee O.A., Yeung A., Goldman M.I., Miller D.D. Caco-2 cell ferritin formation predicts nonradiolabeled food iron availability in an in vitro digestion/Caco-2 cell culture model. J Nutr. 1998;128(9):1555–1561.
    1. Kalgaonkar S., Lonnerdal B. Receptor-mediated uptake of ferritin-bound iron by human intestinal Caco-2 cells. J Nutr Biochem. 2009;20(4):304–311.
    1. Schumann K., Solomons N.W., Romero-Abal M.E., Orozco M., Weiss G., Marx J. Oral administration of ferrous sulfate, but not of iron polymaltose or sodium iron ethylenediaminetetraacetic acid (NaFeEDTA), results in a substantial increase of non-transferrin-bound iron in healthy iron-adequate men. Food Nutr Bull. 2012;33(2):128–136.
    1. Dresow B., Petersen D., Fischer R., Nielsen P. Non-transferrin-bound iron in plasma following administration of oral iron drugs. Biometals. 2008;21(3):273–276.
    1. Hurrell R.F. Safety and efficacy of iron supplements in malaria-endemic areas. Ann Nutr Metab. 2011;59(1):64–66.
    1. Lomer M.C., Cook W.B., Jan-Mohamed H.J., Hutchinson C., Liu D.Y., Hider R.C. Iron requirements based upon iron absorption tests are poorly predicted by haematological indices in patients with inactive inflammatory bowel disease. Br J Nutr. 2012;107(12):1806–1811.
    1. Glover J., Jacobs A. Observations on iron in the jejunal lumen after a standard meal. Gut. 1971;12(5):369–371.
    1. Simpson R.J., Peters T.J. Forms of soluble iron in mouse stomach and duodenal lumen: significance for mucosal uptake. Br J Nutr. 1990;63(1):79–89.
    1. Powell J.J., Faria N., Thomas-McKay E., Pele L.C. Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract. J Autoimmun. 2010;34(3):J226–J233.
    1. Powell J.J., Ainley C.C., Harvey R.S., Mason I.M., Kendall M.D., Sankey E.A. Characterisation of inorganic microparticles in pigment cells of human gut associated lymphoid tissue. Gut. 1996;38(3):390–395.
    1. Chaudhury A., Nath G., Tikoo A., Sanyal S.C. Enteropathogenicity and antimicrobial susceptibility of new Escherichia spp. J Diarrhoeal Dis Res. 1999;17(2):85–87.
    1. Hoppe M., Hulthen L., Hallberg L. The validation of using serum iron increase to measure iron absorption in human subjects. Br J Nutr. 2004;92(3):485–488.

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