Publications by authors named "Michael B Zimmermann"

264 Publications

Isotopic measurement of iron requirements in sub-Saharan African children.

Am J Clin Nutr 2021 Jun 10. Epub 2021 Jun 10.

Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zürich, Zurich, Switzerland.

Background: Prevention of iron deficiency in African children is a public health priority. Current WHO/FAO estimations of iron requirements are derived from factorial estimates based on healthy, iron-sufficient "model" children using data derived mainly from adults.

Objectives: In this study, we aimed to quantify iron absorption, loss, and balance in apparently healthy 5- to 7-y-old children living in rural Africa.

Methods: We directly measured long-term iron absorption and iron loss in a 2-y observational study in Malawian children (n = 48) using a novel stable iron isotope method.

Results: Of the 36 children with height-for-age and weight-for-age z scores ≥-2, 13 (36%) were iron deficient (soluble transferrin receptor >8.3 mg/L) and 23 were iron sufficient. Iron-deficient children weighed more than iron-sufficient children [mean difference (95% CI): +2.1 (1.4, 2.7) kg; P = 0.01]. Mean iron losses did not differ significantly between iron-deficient and iron-sufficient children and were comparable to WHO/FAO median estimates of 19 µg/(d × kg). In iron-sufficient children, median (95% CI) dietary iron absorption was 32 (28, 34) µg/(d × kg), comparable to WHO/FAO-estimated median requirements of 32 µg/(d × kg). In iron-deficient children, absorption of 28 (25, 30) µg/(d × kg) was not increased to correct their iron deficit, likely because of a lack of bioavailable dietary iron. Twelve children (25%) were undernourished (underweight, stunted, or both).

Conclusions: Our results suggest that WHO/FAO iron requirements are adequate for healthy iron-sufficient children in this rural area of Malawi, but iron-deficient children require additional bioavailable iron to correct their iron deficit.
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http://dx.doi.org/10.1093/ajcn/nqab161DOI Listing
June 2021

Tea Consumption Reduces Iron Bioavailability from NaFeEDTA in Nonanemic Women and Women with Iron Deficiency Anemia: Stable Iron Isotope Studies in Morocco.

J Nutr 2021 May 26. Epub 2021 May 26.

Ibn Tofail University- National Center for Energy, Nuclear Sciences and Techniques,Joint Research Unit in Nutrition and Food, RDC-Nutrition "Regional Designated Center of Nutrition Associated to AFRA/IAEA", Rabat-Kénitra, Morocco.

Background: Available data suggest that polyphenols from tea can inhibit iron absorption from ferric sodium EDTA (NaFeEDTA), but previous studies were done in small groups of mostly nonanemic adults. Morocco recently introduced national wheat flour fortification with NaFeEDTA, but tea is the national beverage and is consumed with most meals.

Objectives: Our objective was to quantify bioavailability of iron from NaFeEDTA when added to a wheat flour-based meal in both nonanemic women and women with iron deficiency anemia (IDA), when consumed with and without traditional Moroccan green tea.

Methods: We recruited 2 groups of healthy Moroccan women (n = 46): women with IDA (n = 25; hemoglobin <12 g/dL,  serum ferritin <15 μg/L) and nonanemic women (n = 21). Each group received in random order 2 standardized test meals containing 6 mg Fe as isotopically labeled NaFeEDTA and either 300 mL of tea or water. Fractional iron absorption (FIA) was measured by the erythrocyte incorporation of stable iron isotopes after 14 d. We performed linear mixed-model analysis and post hoc sample t tests to assess the effects of group and tea on FIA.

Results: The polyphenol content of the tea serving was 492 mg. Tea consumption reduced iron absorption from NaFeEDTA by >85% in both IDA and nonanemic women. There were group (P < 0.001) and tea (P < 0.001) effects on FIA, but no group by tea interaction (P = 0.312). Median (IQR) FIA (%) in women with IDA from test meals consumed without and with tea was 36.7 (24.2-39.8) and 4.1 (2.8-6.1), respectively (P < 0.001). Median (IQR) FIA (%) in nonanemic women from test meals consumed without and with tea was 16.7 (9.2-24.2) and 1.4 (0.8-2.9), respectively (P < 0.001).

Conclusions: FIA from wheat flour-based meals without and with tea was ∼2-fold higher in women with IDA than in nonanemic women. Providing fortificant iron as NaFeEDTA cannot overcome the inhibition of tea polyphenols on iron absorption, even in IDA, where iron absorption is strongly upregulated. This trial was registered at www.clinicaltrials.gov as NCT02175888.
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http://dx.doi.org/10.1093/jn/nxab159DOI Listing
May 2021

Strengthening the immunity of the Swiss population with micronutrients: A narrative review and call for action.

Clin Nutr ESPEN 2021 06 24;43:39-48. Epub 2021 Mar 24.

Department of Internal Medicine, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Background: The enormous health impact of the COVID-19 pandemic has refocused attention on measures to optimize immune function and vaccine response. Dietary deficiencies of micronutrients can weaken adaptive immunity. The aim of this review was to examine links between micronutrients, immune function and COVID-19 infection, with a focus on nutritional risks in subgroups of the Swiss population.

Methods: Scoping review on the associations between selected micronutrients (vitamins D and C, iron, selenium, zinc, and n-3 PUFAs) and immunity, with particular reference to the Swiss population. These nutrients were chosen because previous EFSA reviews have concluded they play a key role in immunity.

Results: The review discusses the available knowledge on links between sufficient nutrient status, optimal immune function, and prevention of respiratory tract infections. Because of the rapid spread of the COVID-19 pandemic, controlled intervention studies of micronutrients in the context of COVID-19 infection are now underway, but evidence is not yet available to draw conclusions. The anti-inflammatory properties of n-3 PUFAs are well established. In Switzerland, several subgroups of the population are at clear risk of nutrient deficiencies; e.g., older adults, multiple comorbidities, obesity, pregnancy, and institutionalized. Low intakes of n-3 PUFA are present in a large proportion of the population.

Conclusion: There are clear and strong relationships between micronutrient and n-3 PUFA status and immune function, and subgroups of the Swiss population are at risk for deficient intakes. Therefore, during the COVID-19 pandemic, as a complement to a healthy and balanced diet, it may be prudent to consider supplementation with a combination of moderate doses of Vitamins C and D, as well as of Se, Zn and n-3 PUFA, in risk groups.
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http://dx.doi.org/10.1016/j.clnesp.2021.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987506PMC
June 2021

GLOBAL ENDOCRINOLOGY: Global perspectives in endocrinology: coverage of iodized salt programs and iodine status in 2020.

Eur J Endocrinol 2021 Jun 10;185(1):R13-R21. Epub 2021 Jun 10.

Iodine Global Network, Ottawa, Ontario, Canada.

Iodine deficiency has multiple adverse effects on growth and development. Diets in many countries cannot provide adequate iodine without iodine fortification of salt. In 2020, 124 countries have legislation for mandatory salt iodization and 21 have legislation allowing voluntary iodization. As a result, 88% of the global population uses iodized salt. For population surveys, the urinary iodine concentration (UIC) should be measured and expressed as the median, in μg/L. The quality of available survey data is high: UIC surveys have been done in 152 out of 194 countries in the past 15 years; in 132 countries, the studies were nationally representative. The number of countries with adequate iodine intake has nearly doubled from 67 in 2003 to 118 in 2020. However, 21 countries remain deficient, while 13 countries have excessive intakes, either due to excess groundwater iodine, or over-iodized salt. Iodine programs are reaching the poorest of the poor: of the 15 poorest countries in the world, 10 are iodine sufficient and only 3 (Burundi, Mozambique and Madagascar) remain mild-to-moderately deficient. Nigeria and India have unstable food systems and millions of malnourished children, but both are iodine-sufficient and population coverage with iodized salt is a remarkable 93% in both. Once entrenched, iodine programs are often surprisingly durable even during national crises, for example, war-torn Afghanistan and Yemen are iodine-sufficient. However, the equity of iodized salt programs within countries remains an important issue. In summary, continued support of iodine programs is needed to sustain these remarkable global achievements, and to reach the remaining iodine-deficient countries.
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http://dx.doi.org/10.1530/EJE-21-0171DOI Listing
June 2021

Elucidating the effect of specific surface area on the gastrointestinal absorption of nanostructured calcium through Calcium-45 in vivo radiotracing.

Appl Radiat Isot 2021 Jul 20;173:109702. Epub 2021 Apr 20.

Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Private Bag X169, Pretoria, 0001, South Africa; Department of Science and Technology, Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa; Radiochemistry, The South African Nuclear Energy Corporation (Necsa), Brits, 0240, South Africa. Electronic address:

Low dietary calcium intake and absorption may increase the risk of hypocalcaemia disease states. Reducing the particle size of calcium-containing powders and increasing the specific surface area (SSA), may have high oral calcium bioavailability. The absorption of a single dose of different sized calcium carbonate nanoparticles was traced in Sprague-Dawley rats with radioactive calcium-45 (half-life = 162.6 days, β endpoint = 258 keV; 100%). Four calcium carbonate formulations (calcium-45) were administered to Sprague-Dawley rodents (6 per treatment; n = 24). The groups were [Ca]CaCO SSA 3 m/g, [Ca]CaCO 36 m/g, [Ca]CaCO 64 m/g and a separate [Ca]CaCO 36 m/g formulation produced by flame assisted pyrolysis. Blood and urine were sampled periodically, and organs collected and analysed after euthanasia. No changes in SSA or crystallinity were observed when powders before or after irradiation were compared. The [Ca]CaCO 64 m/g formulation presented with higher levels in blood 2 h after administration and a higher liver and femur concentration. These findings suggest [Ca]CaCO 64 m/g could lead to increased oral bioavailability.
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http://dx.doi.org/10.1016/j.apradiso.2021.109702DOI Listing
July 2021

Examining Associations of HIV and Iron Status with Nutritional and Inflammatory Status, Anemia, and Dietary Intake in South African Schoolchildren.

Nutrients 2021 Mar 16;13(3). Epub 2021 Mar 16.

Division of Human Nutrition, Department of Global Health, Stellenbosch University, Cape Town 7505, South Africa.

The etiology of multifactorial morbidities such as undernutrition and anemia in children living with the human immunodeficiency virus (HIV) (HIV+) on antiretroviral therapy (ART) is poorly understood. Our objective was to examine associations of HIV and iron status with nutritional and inflammatory status, anemia, and dietary intake in school-aged South African children. Using a two-way factorial case-control design, we compared four groups of 8 to 13-year-old South African schoolchildren: (1) HIV+ and low iron stores (inflammation-unadjusted serum ferritin ≤ 40 µg/L), = 43; (2) HIV+ and iron sufficient non-anemic (inflammation-unadjusted serum ferritin > 40 µg/L, hemoglobin ≥ 115 g/L), = 41; (3) children without HIV (HIV-ve) and low iron stores, = 45; and (4) HIV-ve and iron sufficient non-anemic, = 45. We assessed height, weight, plasma ferritin (PF), soluble transferrin receptor (sTfR), plasma retinol-binding protein, plasma zinc, C-reactive protein (CRP), α-1-acid glycoprotein (AGP), hemoglobin, mean corpuscular volume, and selected nutrient intakes. Both HIV and low iron stores were associated with lower height-for-age -scores (HAZ, < 0.001 and = 0.02, respectively), while both HIV and sufficient iron stores were associated with significantly higher CRP and AGP concentrations. HIV+ children with low iron stores had significantly lower HAZ, significantly higher sTfR concentrations, and significantly higher prevalence of subclinical inflammation (CRP 0.05 to 4.99 mg/L) (54%) than both HIV-ve groups. HIV was associated with 2.5-fold higher odds of iron deficient erythropoiesis (sTfR > 8.3 mg/L) (95% CI: 1.03-5.8, = 0.04), 2.7-fold higher odds of subclinical inflammation (95% CI: 1.4-5.3, = 0.004), and 12-fold higher odds of macrocytosis (95% CI: 6-27, < 0.001). Compared to HIV-ve counterparts, HIV+ children reported significantly lower daily intake of animal protein, muscle protein, heme iron, calcium, riboflavin, and vitamin B, and significantly higher proportions of HIV+ children did not meet vitamin A and fiber requirements. Compared to iron sufficient non-anemic counterparts, children with low iron stores reported significantly higher daily intake of plant protein, lower daily intake of vitamin A, and lower proportions of inadequate fiber intake. Along with best treatment practices for HIV, optimizing dietary intake in HIV+ children could improve nutritional status and anemia in this vulnerable population. This study was registered at clinicaltrials.gov as NCT03572010.
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http://dx.doi.org/10.3390/nu13030962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002246PMC
March 2021

Consumption of a Single Dose of Prebiotic Galacto-Oligosaccharides Does Not Enhance Iron Absorption from Micronutrient Powders in Kenyan Infants: A Stable Iron Isotope Study.

J Nutr 2021 May;151(5):1205-1212

Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.

Background: Long-term feeding of prebiotic galacto-oligosaccharides (GOS) increases iron absorption in African infants, but the underlying mechanism and how long GOS need to be fed to infants to achieve an increase in absorption is uncertain.

Objectives: In Kenyan infants, we tested whether the addition of GOS to a single test meal would affect iron absorption from a micronutrient powder (MNP) containing ferrous sulfate (FeSO4) and another MNP containing ferrous fumarate (FeFum) and sodium iron ethylenediaminetetraacetate (NaFeEDTA).

Methods: In a randomized-entry, prospective crossover study, iron deficient (87%) and anemic (70%) Kenyan infants (n  = 23; mean ± SD age, 9.9 ± 2.1 months) consumed 4 stable iron isotope-labeled maize porridge meals fortified with MNPs containing 5 mg iron as FeFum + NaFeEDTA, or FeSO4, either without or with 7.5 g GOS. The primary outcome, fractional iron absorption (FIA), was assessed by erythrocyte incorporation of isotopic labels. Data were analyzed using a 2-way repeated-measures ANOVA.

Results: There was no significant interaction between GOS and the iron compounds on FIA, and the addition of GOS did not have a significant effect on FIA. There was a statistically significant difference in FIA between the meals fortified with FeSO4 and with FeFum + NaFeEDTA (P  < 0.001).Given with GOS, FIA from FeSO4 was 40% higher than from FeFum + NaFeEDTA (P  < 0.001); given without GOS, it was 51% higher (P  < 0.01).

Conclusions: The addition of GOS to a single iron-fortified maize porridge test meal in Kenyan infants did not significantly increase iron absorption, suggesting long-term feeding of GOS may be needed to enhance iron absorption at this age. This study was registered at clinicaltrials.gov as NCT02666417.
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http://dx.doi.org/10.1093/jn/nxab007DOI Listing
May 2021

Direct assessment of body iron balance in women with and without iron supplementation using a long-term isotope dilution method in Benin and Switzerland.

Am J Clin Nutr 2021 06;113(6):1657-1669

Laboratory of Human Nutrition, Institute of Food, Nutrition, and Health, ETH Zürich, Zurich, Switzerland.

Background: Long-term isotopic dilution measurements of body iron may allow quantification of basal body iron balance and iron gains during an iron intervention with higher precision and accuracy than conventional iron indices.

Objectives: We compared body iron balance before, during, and after oral iron supplementation in women in Benin and in Switzerland.

Methods: In prospective studies, Beninese (n = 11) and Swiss (n = 10) women previously labeled with stable iron isotopes were followed preintervention for 90-120 d, then received 50-mg iron daily for 90-120 d and were followed postintervention for 90-120 d. We used changes in blood isotopic composition to calculate iron absorption (Feabs), iron loss (Feloss), and net iron balance (Fegain).

Results: Compliance with supplementation was >90%. In Benin, during the preintervention, intervention, and postintervention periods, Fe means ± SDs were as follows: 1) Feabs: 0.92 ± 1.05, 3.75 ± 2.07, and 0.90 ± 0.93 mg/d; 2) Feloss: 1.46 ± 1.95, 1.58 ± 1.57, and 1.84 ± 1.61 mg/d; and 3) Fegain: -0.55 ± 1.56 mg/d, 2.17 ± 1.81 mg/d, and -0.94 ± 1.13 mg/d. In Switzerland, the corresponding values were: 1) 1.51 ± 0.37, 4.09 ± 1.52, and 0.97 ± 0.41 mg/d; 2) 0.76 ± 1.37, 2.54 ± 1.43, and 2.08 ± 1.05 mg/d; and 3) 0.75 ± 1.37, 1.55 ± 1.75, and -1.11 ± 1.06 mg/d. Inflammation was low in both settings, and isotopically calculated iron balance was comparable to that calculated from changes in conventional iron indices.

Conclusion: Without iron supplementation, Beninese women had lower long-term dietary iron absorption and higher iron losses in the preintervention period than Swiss women. During iron supplementation, both groups had high iron absorption and similar iron gains. However, there was a 3-fold increase in iron losses in the Swiss women during the supplementation and postintervention period compared with the preintervention period. Body iron isotope dilution is a promising new method for quantifying long-term body iron balance and for assessing the impact of iron interventions. The studies were registered at clinicaltrials.gov as NCT02979080 and NCT02979132, respectively.
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http://dx.doi.org/10.1093/ajcn/nqaa433DOI Listing
June 2021

Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection.

Med (N Y) 2021 Feb;2(2):164-179.e12

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Background: How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant burden of global disease; however, its effects on immunity remain unclear.

Methods: We used a hepcidin mimetic and several genetic models to examine the effect of low iron availability on T cells and on immune responses to vaccines and viral infection in mice. We examined humoral immunity in human patients with raised hepcidin and low serum iron caused by mutant . We tested the effect of iron supplementation on vaccination-induced humoral immunity in piglets, a natural model of iron deficiency.

Findings: We show that low serum iron (hypoferremia), caused by increased hepcidin, severely impairs effector and memory responses to immunizations. The intensified metabolism of activated lymphocytes requires the support of enhanced iron acquisition, which is facilitated by IRP1/2 and TFRC. Accordingly, providing extra iron improved the response to vaccination in hypoferremic mice and piglets, while conversely, hypoferremic humans with chronically increased hepcidin have reduced concentrations of antibodies specific for certain pathogens. Imposing hypoferremia blunted the T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist and exacerbating lung inflammation and morbidity.

Conclusions: Hypoferremia, a well-conserved physiological innate response to infection, can counteract the development of adaptive immunity. This nutrient trade-off is relevant for understanding and improving immune responses to infections and vaccines in the globally common contexts of iron deficiency and inflammatory disorders.

Funding: Medical Research Council, UK.
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http://dx.doi.org/10.1016/j.medj.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895906PMC
February 2021

Key Considerations for Policymakers-Iodized Salt as a Vehicle for Iron Fortification: Current Evidence, Challenges, and Knowledge Gaps.

J Nutr 2021 Feb;151(Supplement_1):64S-73S

Department of Health Science and Technology, Laboratory of Human Nutrition, Institute of Food Nutrition and Health, ETH Zurich, Zurich, Switzerland.

Could DFS help prevent iron deficiency and anemia? Studies in controlled settings (efficacy) demonstrate that double-fortified salt (DFS; iron added to iodized salt) reduces the prevalence of anemia and iron deficiency anemia. Studies in program settings (effectiveness) are limited and reported differing levels of DFS coverage, resulting in mixed evidence of impact on anemia. What iron formulations are available and how do they affect iodized salt? Ferrous sulfate and encapsulated ferrous fumarate (both with various enhancers and/or coating materials) are the main iron formulations currently in use for DFS. Adding iron to iodized salt may lead to adverse changes in the product, specifically discoloration and losses in iodine content. These changes are greatest when the iodized salt used in DFS production is of low quality (e.g., contain impurities, has high moisture, and is of large crystal size). DFS requires iodized salt of the highest quality and a high-quality iron formulation in order to minimize adverse sensory changes and iodine losses. Appropriate packaging of iodized salt is also important to prevent losses. What is known about the minimum requirements to manufacture DFS? DFS producers must use high-quality refined iodized salt meeting the minimum standards for DFS production (which is higher than standards for salt intended for iodization alone), and an iron formulation for which there are rigid quality-assurance measures to ensure consistent quality and blending techniques. The actual proportion of iodized salt meeting the stringent requirements necessary for DFS production is unclear, but likely to be low in many countries, especially those with fragmented salt industries and a low proportion of industrially produced salt. What are the financial implications of adding iron to iodized salt? As a result of higher input costs both for input salt and the iron compound, DFS is more expensive to produce than iodized salt and thus has a higher production cost. Various grades of iodized salt are produced and consumed in different sectors of the market. Experience in India indicates that, on average, producing DFS costs 31-40 US dollars/metric ton or 0.03-0.04 US dollars/kg more than high-quality refined iodized salt. The exact impact of this production-level cost difference on profit margins and consumer price is specific to the conditions of different salt markets. Factors such as transport costs, customary wholesale and retail mark-ups, and taxes all vary greatly and need to be assessed on a case by case basis. Is DFS in alignment with salt-reduction efforts? The WHO has long recognized that salt iodization is an important public health intervention to achieve optimal iodine nutrition and is compatible with salt-reduction goals. Fortification of salt (with any nutrient) should not be used to justify or encourage an increase in salt intake to the public. Any effort to expand salt fortification to other nutrients should be done in close consultation with WHO and those working on salt reduction. What has been the experience with DFS delivery under different platforms? To date, DFS has been introduced into the retail market and in social safety net (primarily in India) programs, but sensory changes in DFS have been raised as concerns. The higher price for DFS has limited expansion in the retail market. In social safety net programs where the cost of DFS is subsidized for beneficiaries, programs must consider long-term resourcing for sustainability. Overall: The optimal production and delivery of DFS are still under development, as many challenges need to be overcome. There is a beneficial impact on hemoglobin in efficacy trials. Thus, if those conditions can be replicated in programs or the technology can be adapted to better fit current production and delivery realities, DFS may provide an effective contribution in countries that need additional food-fortification vehicles to improve iron intake.
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http://dx.doi.org/10.1093/jn/nxaa377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882367PMC
February 2021

Global look at nutritional and functional iron deficiency in infancy.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):471-477

Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.

Iron-deficiency anemia (IDA) affects many infants in low- and middle-income countries (LMICs) and may impair cognitive development and adaptive immunity. Effective interventions to improve iron intakes for infants in LMICs are urgently needed. However, absorption of oral iron fortificants and supplements is low, usually <10%, and most of the iron passes into the colon unabsorbed. In randomized controlled trials, provision of iron to infants in LMICs adversely affects their gut microbiome and increases pathogenic Escherichia coli, gut inflammation, and diarrhea. To minimize these detrimental effects of iron, it is important to provide the lowest effective dosage and maximize fractional iron absorption. Prebiotic galacto-oligosaccharides and apo-lactoferrin may prove useful in iron formulations in LMICs because they increase absorption of fortificant iron and at the same time may mitigate the adverse effects of unabsorbed iron on the infant gut. Providing well-absorbed iron early in infancy may improve immune function. Recent data from a Kenyan birth cohort suggest IDA at the time of infant vaccination impairs the response to diphtheria, pertussis, and pneumococcus vaccines. A randomized trial follow-up study reported that providing iron to Kenyan infants at the time of measles vaccination increased antimeasles immunoglobulin G (IgG), seroconversion, and IgG avidity. Because IDA is so common among infants in LMICs and because the vaccine-preventable disease burden is so high, even if IDA only modestly reduces immunogenicity of vaccines, its prevention could have major benefits.
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http://dx.doi.org/10.1182/hematology.2020000131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727574PMC
December 2020

The effects of reducing chronic inflammation in overweight women on serum hepcidin and iron absorption with and without supplemental ascorbic acid.

Br J Nutr 2020 Nov 27:1-8. Epub 2020 Nov 27.

Department of Health Science and Technology, ETH Zurich, Laboratory of Human Nutrition, Institute of Food Nutrition and Health, Schmelzbergstrasse 7, 8092Zurich, Switzerland.

Although hepcidin synthesis is stimulated by inflammation and inhibited by Fe deficiency, the strength of their opposing effects on serum hepcidin (SHep) in humans remains unclear. It was recently shown that an inflammatory stimulus in anaemic women did not increase SHep or decrease Fe absorption. The enhancing effect of ascorbic acid on Fe absorption may not be effective during inflammation because of increased SHep. Our study aim was to test whether reducing inflammation in Fe-depleted overweight (OW) women with low-grade inflammation would lower SHep and improve Fe absorption with and without ascorbic acid, compared with normal-weight (NW) women without inflammation. Before and after 14 d of anti-inflammatory treatment (3 × 600 mg ibuprofen daily) in OW and NW women (n 36; 19-46 years of age), we measured SHep and fractional Fe absorption (FIA) (erythrocyte Fe incorporation) from 57Fe- and 58Fe-labelled test meals with and without ascorbic acid. There were significant group effects on IL-6, C-reactive protein, serum ferritin and SHep (for all, P < 0·05). There was a significant treatment effect on SHep (P < 0·05): in OW women, treatment decreased IL-6 by approximately 30 % and SHep by approximately 45 %. However, there were no significant treatment or group effects on FIA. Body Fe stores (BIS) were a significant positive predictor of SHep before and after treatment (P < 0·001), but IL-6 was not. Reducing chronic inflammation in OW women halved SHep but did not affect Fe absorption with or without ascorbic acid, and the main predictor of Fe absorption was BIS.
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http://dx.doi.org/10.1017/S0007114520004730DOI Listing
November 2020

Iron Absorption from Iron-Biofortified Sweetpotato Is Higher Than Regular Sweetpotato in Malawian Women while Iron Absorption from Regular and Iron-Biofortified Potatoes Is High in Peruvian Women.

J Nutr 2020 12;150(12):3094-3102

ETH Zürich, Laboratory of Human Nutrition, Institute of Food, Nutrition, and Health, Department of Health Sciences and Technology, Zurich, Switzerland.

Background: Sweetpotato and potato are fast-maturing staple crops and widely consumed in low- and middle-income countries. Conventional breeding to biofortify these crops with iron could improve iron intakes. To our knowledge, iron absorption from sweetpotato and potato has not been assessed.

Objective: The aim was to assess iron absorption from regular and iron-biofortified orange-fleshed sweetpotato in Malawi and yellow-fleshed potato and iron-biofortified purple-fleshed potato in Peru.

Methods: We conducted 2 randomized, multiple-meal studies in generally healthy, iron-depleted women of reproductive age. Malawian women (n = 24) received 400 g regular or biofortified sweetpotato test meals and Peruvian women (n = 35) received 500 g regular or biofortified potato test meals. Women consumed the meals at breakfast for 2 wk and were then crossed over to the other variety. We labeled the test meals with 57Fe or 58Fe and measured cumulative erythrocyte incorporation of the labels 14 d after completion of each test-meal sequence to calculate iron absorption. Iron absorption was compared by paired-sample t tests.

Results: The regular and biofortified orange-fleshed sweetpotato test meals contained 0.55 and 0.97 mg Fe/100 g. Geometric mean (95% CI) fractional iron absorption (FIA) was 5.82% (3.79%, 8.95%) and 6.02% (4.51%, 8.05%), respectively (P = 0.81), resulting in 1.9-fold higher total iron absorption (TIA) from biofortified sweetpotato (P < 0.001). The regular and biofortified potato test meals contained 0.33 and 0.69 mg Fe/100 g. FIA was 28.4% (23.5%, 34.2%) from the regular yellow-fleshed and 13.3% (10.6%, 16.6%) from the biofortified purple-fleshed potato meals, respectively (P < 0.001), resulting in no significant difference in TIA (P = 0.88).

Conclusions: FIA from regular yellow-fleshed potato was remarkably high, at 28%. Iron absorbed from both potato test meals covered 33% of the daily absorbed iron requirement for women of reproductive age, while the biofortified orange-fleshed sweetpotato test meal covered 18% of this requirement. High polyphenol concentrations were likely the major inhibitors of iron absorption. These trials were registered at www.clinicaltrials.gov as NCT03840031 (Malawi) and NCT04216030 (Peru).
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http://dx.doi.org/10.1093/jn/nxaa267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726126PMC
December 2020

Iodine Supplementation in Mildly Iodine-Deficient Pregnant Women Does Not Improve Maternal Thyroid Function or Child Development: A Secondary Analysis of a Randomized Controlled Trial.

Front Endocrinol (Lausanne) 2020 6;11:572984. Epub 2020 Oct 6.

Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.

Iodine deficiency during pregnancy may be associated with lower offspring IQ, but there are few data on the safety and efficacy of maternal iodine supplementation on child development. In a previously reported multi-center randomized trial conducted in Thailand and India, we assessed the effect of iodine supplementation in mildly iodine-deficient pregnant women on offspring development. In this secondary analysis of that trial, we report data only from the Thai pregnant women in the study, who were more iodine deficient at entry. Pregnant women in Bangkok, Thailand, were randomized to receive daily 200 μg oral iodine or placebo until delivery. We assessed thyroid size and thyroid function during pregnancy and cognitive and motor development at ages 1, 2, and 5.7 years. The trial was registered at www.clinicaltrials.gov/NCT00791466. Women ( = 514) entered the trial between November 2008 and March 2011 at a mean ± SD gestational age of 11 ± 2.8 weeks; their median (IQR) UIC was 112 (75, 170) μg/L. Mean compliance with supplementation was 88%. We assessed 397 mothers in the 3rd trimester, 231 infants at age 2 y, and 157 children at mean age 5.7 y. During pregnancy, there was a slightly greater decrease in free and total thyroxine concentrations in the iodine group ( < 0.05). At age 2 years, the iodine group had borderline lower scores for combined fine and gross motor function ( = 0.05), but there were no other significant differences in development. At 5.7 years, there were no significant group differences in child development. Daily iodine supplementation in mildly iodine deficient pregnant women was associated with small negative effects on maternal thyroxine concentrations, but did not affect child development. The safety and efficacy of iodine supplementation in mildly-iodine deficient pregnant women needs to be evaluated further in large randomized controlled trials.
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http://dx.doi.org/10.3389/fendo.2020.572984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573140PMC
May 2021

The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption - a stable iron isotope study in Taiwanese women.

Haematologica 2020 10 5;Online ahead of print. Epub 2020 Oct 5.

Laboratory of Human Nutrition, Institute of Food Nutrition and Health, Department of Health Science and Technology, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland; Current address: Swiss Distance University of Applied Sciences, Department of Health, Regensdorf/Zurich, Switzerland.

Genome wide studies have associated TMPRSS6 rs855791 (2321 C>T) with iron status and hepcidin. It is unclear whether this polymorphism affects iron absorption. In nonanemic Taiwanese women (n=79, 44 TT variant, 35 CC variant), we administered standardized rice-based test meals containing 4 mg of labeled 57Fe or 58Fe as FeSO4 on alternate days. Fractional iron absorption was measured by erythrocyte incorporation of the tracers 14 days after administration. Compared to the CC variant, in the TT variant serum iron and transferrin saturation were lower (P=0.001; P<0.001, respectively) and serum hepcidin/transferrin saturation and serum hepcidin/serum iron ratios were higher (P=0.042; P=0.088, respectively). Serum hepcidin did not differ between groups (P=0.862). Geometric mean (95% CI) fractional iron absorption, corrected to a serum ferritin of 15 μg/L, was 26.6% (24.0, 29.5) in the CC variant and 18.5% (16.2, 21.1) in the TT variant (P=0.002). Overall, predictors of iron absorption were: serum ferritin (P<0.001); genetic variant (P=0.032); and hepcidin (P<0.001). In the models by variant, in the CC variant the model explained 67-71% of variability in absorption and serum ferritin was the only significant predictor (P<0.001); in the TT variant, the model explained only 35-43% of variability, and hemoglobin (P=0.032), soluble transferrin receptor (P=0.004) and hepcidin (P<0.001) were significant predictors. Women with the TMPRSS6 rs855791 (2321 C>T) polymorphism show altered iron homeostasis which affects oral iron absorption and may increase their risk for iron deficiency. The trial was registered at www.clinicaltrials.gov as NCT03317873, and funded by the Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, (grant CMRPG8F0721) and ETH Zurich, Switzerland.
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http://dx.doi.org/10.3324/haematol.2020.264556DOI Listing
October 2020

Iron Absorption is Greater from Apo-Lactoferrin and is Similar Between Holo-Lactoferrin and Ferrous Sulfate: Stable Iron Isotope Studies in Kenyan Infants.

J Nutr 2020 12;150(12):3200-3207

Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland.

Background: Whether lactoferrin (Lf) binds iron to facilitate its absorption or to sequester iron from potential enteropathogens remains uncertain. Bovine Lf is added to many infant formulas, but previous studies in infants reported that Lf had no effect on or inhibited iron absorption. The effects of the apo (iron-free) or the holo (iron-loaded) forms of Lf on iron absorption are unclear.

Objectives: Our objective was to compare iron absorption from a maize-based porridge containing: 1) labeled ferrous sulfate (FeSO4) alone; 2) labeled FeSO4 given with bovine apo-Lf; and 3) intrinsically labeled bovine holo-Lf.

Methods: In a crossover study, we measured iron absorption in Kenyan infants (n = 25; mean ± SD age 4.2 ± 0.9 months; mean ± SD hemoglobin 109 ± 11 g/L) from maize-based test meals containing: 1) 1.5 mg of iron as 54Fe-labeled FeSO4; 2) 1.42 mg of iron as 58Fe-labeled FeSO4, given with 1.41 g apo-Lf (containing 0.08 mg iron); and 3) 1.41 g holo-Lf carrying 1.5 mg iron as 57Fe. The iron saturation levels of apo- and holo-Lf were 0.56% and 47.26%, respectively primary outcome was fractional iron absorption (FIA), assessed by erythrocyte incorporation of isotopic labels.

Results: The FIA from the meal containing apo-Lf + FeSO4 (geometric mean, 9.8%; -SD and +SD, 5.4% and 17.5%) was higher than from the meals containing FeSO4 (geometric mean, 6.3%; -SD and +SD, 3.2% and 12.6%; P = 0.002) or holo-Lf (geometric mean, 5.0%; -SD and +SD, 2.8% and 8.9%; P <0.0001). There was no significant difference in FIA when comparing the meals containing holo-Lf versus FeSO4 alone (P = 0.24).

Conclusions: The amount of iron absorbed from holo-Lf was comparable to that of FeSO4, and the addition of apo-Lf to a test meal containing FeSO4 significantly increased (+56%) iron absorption. These findings suggest that Lf facilitates iron absorption in young infants. Because Lf binds iron with high affinity, it could be a safe way to provide iron to infants in low-income countries, where iron fortificants can adversely affect the gut microbiome and cause diarrhea. This study was registered at clinicaltrials.gov as NCT03617575.
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http://dx.doi.org/10.1093/jn/nxaa226DOI Listing
December 2020

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

Br J Haematol 2021 01 30;192(1):179-189. Epub 2020 Aug 30.

Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zürich, Zurich, Switzerland.

We report the first measurements of long-term iron absorption and loss during iron supplementation in African children using a stable isotope of iron ( Fe). After uniform labelling of body iron with Fe, iron absorption is proportional to the rate of decrease in the Fe tracer concentration, while iron loss is proportional to the rate of decrease in the Fe tracer amount. Anaemic Gambian toddlers were given 2 mg 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.
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http://dx.doi.org/10.1111/bjh.17039DOI Listing
January 2021

Addition of Whole Wheat Flour During Injera Fermentation Degrades Phytic Acid and Triples Iron Absorption from Fortified Tef in Young Women.

J Nutr 2020 10;150(10):2666-2672

Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland.

Background: Iron deficiency is a major public health concern in Ethiopia, where the traditional diet is based on tef injera. Iron absorption from injera is low due to its high phytic acid (PA) content.

Objectives: We investigated ways to increase iron absorption from FeSO4-fortified tef injera in normal-weight healthy women (aged 21-29 y).

Methods: Study A (n = 22) investigated the influence on fractional iron absorption (FIA) from FeSO4-fortified injera of 1) replacing 10% tef flour with whole wheat flour (a source of wheat phytase), or 2) adding an isolated phytase from Aspergillus niger. Study B (n = 18) investigated the influence on FIA of replacing FeSO4 in tef injera with different amounts of NaFeEDTA. In both studies, the iron fortificants were labeled with stable isotopes and FIA was calculated from erythrocyte incorporation of stable iron isotopes 14 d after administration.

Results: In study A, the median (IQR) FIA from the 100% tef injera meal was 1.5% (0.7-2.8%). This increased significantly (P < 0.05) to 5.3% (2.4-7.1%) on addition of 10% whole wheat flour, and to 3.6% (1.6-6.2%) on addition of A. niger phytase. PA content of the 3 meals was 0.62, 0.20, and 0.02 g/meal, respectively. In study B, the median (IQR) FIA from the 100% tef injera meal was 3.3% (1.1-4.4%) and did not change significantly (P > 0.05) on replacing 50% or 75% of FeSO4 with NaFeEDTA.

Conclusions: FIA from tef injera by young women was very low. NaFeEDTA was ineffective at increasing iron absorption, presumably due to the relatively low EDTA:Fe molar ratios. Phytate degradation, however, greatly increased during tef fermentation on addition of native or isolated phytases. Replacing 10% tef with whole wheat flour during injera fermentation tripled FIA in young women and should be considered as a potential strategy to improve iron status in Ethiopia.
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http://dx.doi.org/10.1093/jn/nxaa211DOI Listing
October 2020

Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants.

Front Immunol 2020 13;11:1313. Epub 2020 Jul 13.

Department of Health Sciences and Technology, Institute of Food, Nutrition and Health, Laboratory of Human Nutrition, ETH Zürich, Zurich, Switzerland.

Iron deficiency may impair adaptive immunity and is common among African infants at time of vaccination. Whether iron deficiency impairs vaccine response and whether iron supplementation improves humoral vaccine response is uncertain. We performed two studies in southern coastal Kenya. In a birth cohort study, we followed infants to age 18 mo and assessed whether anemia or iron deficiency at time of vaccination predicted vaccine response to three-valent oral polio, diphtheria-tetanus-whole cell pertussis- type b vaccine, ten-valent pneumococcal-conjugate vaccine and measles vaccine. Primary outcomes were anti-vaccine-IgG and seroconversion at age 24 wk and 18 mo. In a randomized trial cohort follow-up, children received a micronutrient powder (MNP) with 5 mg iron daily or a MNP without iron for 4 mo starting at age 7.5 mo and received measles vaccine at 9 and 18 mo; primary outcomes were anti-measles IgG, seroconversion and avidity at age 11.5 mo and 4.5 y. In the birth cohort study, 573 infants were enrolled and 303 completed the study. Controlling for sex, birthweight, anthropometric indices and maternal antibodies, hemoglobin at time of vaccination was the strongest positive predictor of: (A) anti-diphtheria and anti-pertussis-IgG at 24 wk ( = 0.0071, = 0.0339) and 18 mo ( = 0.0182, = 0.0360); (B) anti-pertussis filamentous hemagglutinin-IgG at 24 wk ( = 0.0423); and (C) anti-pneumococcus 19 IgG at 18 mo ( = 0.0129). Anemia and serum transferrin receptor at time of vaccination were the strongest predictors of seroconversion against diphtheria ( = 0.0484, = 0.0439) and pneumococcus 19 at 18 mo ( = 0.0199, = 0.0327). In the randomized trial, 155 infants were recruited, 127 and 88 were assessed at age 11.5 mo and 4.5 y. Compared to infants that did not receive iron, those who received iron at time of vaccination had higher anti-measles-IgG ( = 0.0415), seroconversion ( = 0.0531) and IgG avidity ( = 0.0425) at 11.5 mo. In Kenyan infants, anemia and iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines. Primary response to measles vaccine may be increased by iron supplementation at time of vaccination. These findings argue that correction of iron deficiency during early infancy may improve vaccine response.
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http://dx.doi.org/10.3389/fimmu.2020.01313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369313PMC
April 2021

Acute Consumption of Prebiotic Galacto-Oligosaccharides Increases Iron Absorption from Ferrous Fumarate, but not from Ferrous Sulfate and Ferric Pyrophosphate: Stable Iron Isotope Studies in Iron-Depleted Young Women.

J Nutr 2020 09;150(9):2391-2397

Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland.

Background: Although acute consumption of high doses of prebiotic galacto-oligosaccharides (GOS) increases fractional iron absorption (FIA) from ferrous fumarate (FeFum), it is uncertain if low doses of GOS have this effect. Furthermore, whether GOS improve iron absorption from other commonly used iron compounds and whether ascorbic acid (AA) enhances the effect of GOS on iron absorption from FeFum is unclear.

Objectives: In iron-depleted women [serum ferritin (SF) <30 μg/L], we assessed: 1) whether the acute enhancing effect of GOS on FeFum is dose dependent; 2) if GOS would affect FIA from ferrous sulfate (FeSO4) or ferric pyrophosphate (FePP); and 3) if AA and GOS given together enhance FIA from FeFum to a greater extent compared with GOS alone.

Methods: We recruited 46 women (mean age 22.0 y, mean BMI 21.3 kg/m2, median SF 17.1 μg/L), and measured FIA from 14 mg iron labeled with stable isotopes in the following conditions: 1) FIA from FeFum given with 3.5 g, 7 g GOS, and without GOS; 2) FIA from FeSO4 and FePP given with and without 15 g GOS; and 3) FIA from FeFum given with 7 g GOS with and without 93 mg AA. FIA was measured as erythrocyte incorporation of stable isotopes after 14 d. Comparisons were made using paired samples t-test or Wilcoxon rank sum test where appropriate.

Results: Giving 7 g of GOS significantly increased FIA from FeFum (+26%; P = 0.039), whereas 3.5 g GOS did not (P = 0.130). GOS did not significantly increase FIA from FeSO4 (P = 0.998) or FePP (P = 0.059). FIA from FeFum given with GOS and AA was significantly higher compared with FeFum given with GOS alone (+30%; P <0.001).

Conclusions: In iron-depleted women, GOS does not increase FIA from FeSO4 or FePP, but it increases FIA from FeFum. Thus, a combination of FeFum and GOS may be a well-absorbed formula for iron supplements. The study was registered at clinicaltrials.gov as NCT03762148.
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http://dx.doi.org/10.1093/jn/nxaa199DOI Listing
September 2020

The effect of iron dosing schedules on plasma hepcidin and iron absorption in Kenyan infants.

Am J Clin Nutr 2020 10;112(4):1132-1141

Laboratory of Human Nutrition, ETH Zurich, Switzerland.

Background: In adults, oral iron doses increase plasma hepcidin (PHep) for 24 h, but not for 48 h, and there is a circadian increase in PHep over the day. Because high PHep decreases fractional iron absorption (FIA), alternate day iron dosing in the morning may be preferable to consecutive day dosing. Whether these effects occur in infants is uncertain.

Objective: Using stable iron isotopes in Kenyan infants, we compared FIA from morning and afternoon doses and from consecutive, alternate (every second day) and every third day iron doses.

Methods: In prospective studies, we measured and compared FIA and the PHep response from 1) meals fortified with a 12-mg iron micronutrient powder given in the morning or afternoon (n = 22); 2) the same given on consecutive or alternate days (n = 21); and 3) a 12-mg iron supplement given on alternate days or every third day (n = 24).

Results: In total, 65.7% of infants were anemic. In study 1, PHep did not differ between morning and afternoon (P = 0.072), and geometric mean FIA[-SD, +SD](%) did not differ between the morning and afternoon doses [15.9 (8.9, 28.6) and 16.1 (8.7, 29.8), P = 0.877]. In study 2, PHep was increased 24 h after oral iron (P = 0.014), and mean FIA [±SD](%) from the baseline dose [23.3 (10.9)] was greater than that from the consecutive day dose (at 24 h) [20.1 (10.4); P = 0.042] but did not differ from the alternate day dose (at 48 h) [20.9 (13.4); P = 0.145]. In study 3, PHep was not increased 48 and 72 h after oral iron (P = 0.384), and the geometric mean FIA[-SD, +SD](%) from doses given at baseline, alternate days, and every third day did not differ [12.7 (7.3, 21.9), 13.8 (7.8, 24.2), and 14.8 (8.8, 24.8), respectively; P = 0.080].

Conclusions: In Kenyan infants given 12 mg oral iron, morning and afternoon doses are comparably absorbed, dosing on consecutive days increases PHep and modestly decreases iron absorption compared with alternate day dosing, and dosing on alternate days or every third day does not increase PHep or decrease absorption. This trial was registered at clinicaltrials.gov as NCT02989311 and NCT03617575.
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http://dx.doi.org/10.1093/ajcn/nqaa174DOI Listing
October 2020

Oral iron supplementation in iron-deficient women: How much and how often?

Mol Aspects Med 2020 10 7;75:100865. Epub 2020 Jul 7.

ETH Zurich, Laboratory of Human Nutrition, Institute of Food Nutrition and Health, Schmelzbergstrasse 7, CH-8092, Zurich, Switzerland. Electronic address:

Iron deficiency and iron deficiency anemia (IDA) are major public health problems worldwide, especially in young women. Oral iron supplementation can be an effective strategy to treat and prevent IDA, but guidelines vary. Some experts recommend doses of 150-200 mg elemental iron per day, with the dose split through the day. However, recent studies suggest this may not be an optimal regimen. The fraction of iron absorbed from high doses of oral iron is low, and unabsorbed iron can cause gut irritation, inflammation and dysbiosis, and these reduce compliance. In recent studies using serum hepcidin profiles and stable iron isotopes to quantify iron absorption in young women, we have shown that: (a) oral iron doses ≥60 mg in iron-deficient women, and doses ≥100 mg in women with IDA, stimulate an acute increase in hepcidin that persists 24 h after the dose, but subsides by 48 h; (b) therefore, to maximize fractional iron absorption, oral doses ≥60 mg should be given on alternate days; (c) the circadian increase in plasma hepcidin is augmented by a morning iron dose; therefore, iron doses should not be given in the afternoon or evening after a morning dose. If rate of Hb response is important, a pooled analysis of our data done for this review indicates that total iron absorption is also higher if twice the target daily iron dose is given on alternate days. In summary, these studies suggest changing from daily to alternate-day schedules and from divided to morning single doses increases iron absorption and may reduce side effects. Thus, providing morning doses of 60-120 mg iron as a ferrous salt given with ascorbic acid on alternate days may be an optimal oral dosing regimen for women with iron-deficiency and mild IDA.
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http://dx.doi.org/10.1016/j.mam.2020.100865DOI Listing
October 2020

Estimating the Health and Economic Benefits of Universal Salt Iodization Programs to Correct Iodine Deficiency Disorders.

Thyroid 2020 12 17;30(12):1802-1809. Epub 2020 Jul 17.

Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.

There has been tremendous progress over the past 25 years to control iodine deficiency disorders (IDDs) through universal salt iodization (USI). In 2019, using the median urinary iodine concentration (MUIC), only 19 countries in the world are classified as iodine deficient; in contrast in 1993, using the total goiter rate (TGR), 113 countries were classified as iodine deficient. However, few analyses have tried to quantify the global health and economic benefits of USI programs, and the shift from TGR to MUIC as the main indicator of IDDs complicates assessment of progress. We used a novel approach to estimate the impact of USI on IDDs, applying a regression model derived from observational data on the relationship between the TGR and the MUIC from 24 countries. The model was used to generate hypothetical national TGR values for 2019 based on current MUIC data. TGR in 1993 and modeled TGR in 2019 were then compared for 139 countries, and using consequence modeling, the potential health and economic benefits realized between 1993 and 2019 were estimated. Based on this approach, the global prevalence of clinical IDDs (as assessed by the TGR) fell from 13.1% to 3.2%, and 720 million cases of clinical IDDs have been prevented by USI (a reduction of 75.9%). USI has significantly reduced the number of newborns affected by IDDs, with 20.5 million cases prevented annually. The resulting improvement in cognitive development and future earnings suggest a potential global economic benefit of nearly $33 billion. However, 4.8 million newborns will be affected by IDDs in 2019, who will experience life-long productivity losses totaling a net present value of $12.5 billion. The global improvements in iodine status over the past 25 years have resulted in major health and economic benefits, mainly in low- and middle-income countries. Efforts should now focus on sustaining this achievement and expanding USI to reach the continuing large number of infants who remain unprotected from IDDs.
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http://dx.doi.org/10.1089/thy.2019.0719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757618PMC
December 2020

Iodine supplements for mildly iodine-deficient pregnant women: are they worthwhile?

Am J Clin Nutr 2020 08;112(2):247-248

Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/ajcn/nqaa116DOI Listing
August 2020

High prevalence of TPO-Abs and subclinical hypothyroidism in iodine-sufficient pregnant women in Northern Algeria.

J Trace Elem Med Biol 2020 Apr 29;61:126533. Epub 2020 Apr 29.

Endocrinology Department, Public Hospital Etablishment IbnZiri, Bologhine, 16090 Algiers, Algeria.

Background: Iodine is a trace element whose adequate intakes are essential during gestation to promote the correct growth and development of the fetus. Historically, endemic goiter and cretinism affected northern regions of Algeria, and iodized salt was introduced in 1990. However, there has been no national study of iodine nutrition in Algeria since 1994. The aim of this study was to assess the iodine status and thyroid function of women of reproductive age (WRA) and pregnant women (PW) in northern Algeria.

Methods: Healthy WRA and PW were recruited from an urban area (Algiers) and healthy WRA from a rural area (Tizi-Ouzou). Spot urine and venous blood samples were collected to assess iodine status (urinary iodine concentration, UIC) and serum thyroid hormones (TSH, FT4), thyroglobulin (Tg), and anti-thyroid peroxidase antibodies (TPO-Ab) concentrations.

Results: The median UIC in WRA was 256 μg/L (IQR: 166-354 μg/L; n = 151) in Algiers and 253 μg/L (167-341 μg/L; n = 150) in Tizi-Ouzou. The median UIC for the PW in Algiers was 233 μg/L (IQR: 157-326 μg/L; n = 173).Thirty-five percent of WRA and 30% of PW had an UIC > 300 μg/L. Median TSH, FT4 and Tg concentrations were within reference ranges in all groups of women. Among PW, 72.7%, 75.4% and 75.5% in the first, second and third trimester were TPO-Ab+. Among TPO-Ab + PW in the first, second and third trimesters, 18.7%, 13% and 10.3% had subclinical hypothyroidism.

Conclusion: In northern Algeria, median UICs in PW indicate iodine sufficiency, and in WRA indicate more than adequate intakes. About 75% of PW are TPO-Ab + and the prevalence of subclinical hypothyroidism is high. Monitoring and surveillance of iodine fortification programs is vital to avoid both iodine deficiency and excess. There is an urgent need for a comprehensive national iodine status survey including school-age children and other vulnerable population groups in Algeria.
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http://dx.doi.org/10.1016/j.jtemb.2020.126533DOI Listing
April 2020

Iron bioavailability from bouillon fortified with a novel ferric phytate compound: a stable iron isotope study in healthy women (part II).

Sci Rep 2020 03 24;10(1):5339. Epub 2020 Mar 24.

ETH Zurich, Laboratory of Human Nutrition, Zurich, Switzerland.

Bouillon cubes are widely consumed and when fortified with iron could contribute in preventing iron deficiency. We report the development (part I) and evaluation (current part II) of a novel ferric phytate compound to be used as iron fortificant in condiments such as bouillon. Ferric pyrophosphate (FePP), is the compound of choice due to its high stability in foods, but has a modest absorption in humans. Our objective was to assess iron bioavailability from a novel iron fortificant consisting of ferric iron complexed with phytic acid and hydrolyzed corn protein (Fe-PA-HCP), used in bouillon with and without an inhibitory food matrix. In a randomised single blind, cross-over study, we measured iron absorption in healthy adult women (n = 22). In vitro iron bioaccessibility was assessed using a Caco-2 cell model. Iron absorption from Fe-PA-HCP was 1.5% and 4.1% in bouillon with and without inhibitory matrix, respectively. Relative iron bioavailability to FeSO was 2.4 times higher than from FePP in bouillon (17% vs 7%) and 5.2 times higher when consumed with the inhibitory meal (41% vs 8%). Similar results were found in vitro. Fe-PA-HCP has a higher relative bioavailability versus FePP, especially when bouillon is served with an inhibitory food matrix.
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http://dx.doi.org/10.1038/s41598-020-62307-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093532PMC
March 2020

Effects of an Iodine-Containing Prenatal Multiple Micronutrient on Maternal and Infant Iodine Status and Thyroid Function: A Randomized Trial in The Gambia.

Thyroid 2020 09 28;30(9):1355-1365. Epub 2020 Apr 28.

Department of Women and Children's Health, King's College London, London, United Kingdom.

Iodine supplementation is recommended to pregnant women in iodine-deficient populations, but the impact in moderate iodine deficiency is uncertain. We assessed the effect of an iodine-containing prenatal multiple micronutrient (MMN) supplement in a rural Gambian population at risk of moderate iodine deficiency. This study uses data and samples collected as a part of the randomized controlled trial Early Nutrition and Immune Development (ENID; ISRCTN49285450) conducted in Keneba, The Gambia. Pregnant women (<20 weeks gestation) were randomized to either a daily supplement of MMNs containing 300 μg of iodine or an iron and folic acid (FeFol) supplement. Randomization was double blinded (participants and investigators). The coprimary outcomes were maternal urinary iodine concentration (UIC) and serum thyroglobulin (Tg), assessed at baseline and at 30 weeks' gestation. Secondary outcomes were maternal serum thyrotropin (TSH), total triiodothyronine (TT3), total thyroxine (TT4) (assessed at baseline and at 30 weeks' gestation), breast milk iodine concentration (BMIC) (assessed at 8, 12, and 24 weeks postpartum), infant serum Tg (assessed at birth [cord], 12, and 24 weeks postpartum), and serum TSH (assessed at birth [cord]). The effect of supplementation was evaluated using mixed effects models. A total of 875 pregnant women were enrolled between April 2010 and February 2015. In this secondary analysis, we included women from the MMN ( = 219) and FeFol ( = 219) arm of the ENID trial. At baseline, median (interquartile range or IQR) maternal UIC and Tg was 51 μg/L (33-82) and 22 μg/L (12-39), respectively, indicating moderate iodine deficiency. Maternal MMN supplement increased maternal UIC ( < 0.001), decreased maternal Tg ( < 0.001), and cord blood Tg ( < 0.001) compared with FeFol. Maternal thyroid function tests (TSH, TT3, TT4, and TT3/TT4 ratio) and BMIC did not differ according to maternal supplement group over the course of the study. Median (IQR) BMIC, maternal UIC, and infant Tg in the MMN group were 51 μg/L (35-72), 39 μg/L (25-64), and 87 μg/L (59-127), respectively, at 12 weeks postpartum, and did not differ between supplement groups. Supplementing moderately iodine-deficient women during pregnancy improved maternal iodine status and reduced Tg concentration. However, the effects were not attained postpartum and maternal and infant iodine nutrition remained inadequate during the first six months after birth. Consideration should be given to ensuring adequate maternal status through pregnancy and lactation in populations with moderate deficiency.
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http://dx.doi.org/10.1089/thy.2019.0789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482118PMC
September 2020

The effect of central obesity on inflammation, hepcidin, and iron metabolism in young women.

Int J Obes (Lond) 2020 06 23;44(6):1291-1300. Epub 2020 Jan 23.

Department of Health Science and Technology, Laboratory of Human Nutrition, Institute of Food Nutrition and Health, ETH Zurich, Schmelzbergstrasse 7, 8092, Zurich, Switzerland.

Background/objectives: In overweight and obesity (OW/OB), greater total body fat predicts higher serum hepcidin (SHep) which can impair iron homeostasis and increase risk for iron deficiency (ID). However, the effect of body fat distribution on SHep and iron homeostasis is unclear. In central obesity, interleukin (IL)-6 released from visceral adipose tissue into portal blood could strongly stimulate hepatic hepcidin synthesis. Thus, our hypothesis was that higher amounts of android fat, rather than gynoid fat, would predict impaired iron metabolism in OW/OB.

Subjects/methods: In this cross-sectional study, we enrolled 117 otherwise-healthy women into two groups: normal weight; BMI < 25 (n = 36) and OW/OB; BMI ≥ 25 (n = 81); we then subdivided the OW/OB using DEXA into tertiles based on the ratio of android fat/total body fat (AF/TBF). We measured inflammation and iron status, and assessed iron absorption in two ways: by measuring erythrocyte isotope incorporation from a labeled test meal containing 6 mg Fe (representing dietary iron); and by measuring change in serum iron (ΔSeFe) after a 100 mg oral iron challenge (representing supplemental iron).

Results: Greater AF/TBF correlated with higher CRP, AGP, SHep, and TIBC, and lower transferrin saturation and SeFe/SHep ratio (for all, p < 0.05). Greater AF/TBF correlated with lower supplemental iron absorption (ΔSeFe) (p = 0.08) but not lower dietary iron absorption. In multiple regressions, AF/TBF positively predicted CRP (p < 0.001) and SHep (p < 0.05); a model including AF/TBF and serum ferritin as covariates explained 65% of the variance in SHep. AF/TBF negatively predicted TSAT (p < 0.05) and iron absorption (ΔSeFe) (p = 0.07). In contrast, the ratio of gynoid fat/total body fat was not significantly associated with these variables.

Conclusion: Body fat distribution affects iron metabolism: women with greater central adiposity have higher SHep, greater impairments in iron homeostasis, and reduced iron absorption from a supplemental iron dose.
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http://dx.doi.org/10.1038/s41366-020-0522-xDOI Listing
June 2020

Iodine bioavailability from cow milk: a randomized, crossover balance study in healthy iodine-replete adults.

Am J Clin Nutr 2019 07;110(1):102-110

ETH Zurich, Institute of Food, Nutrition and Health, Laboratory of Human Nutrition, Zurich, Switzerland.

Background: Milk and dairy products are considered important dietary sources of iodine in many countries. However, to our knowledge, iodine bioavailability from milk has not been directly measured in humans.

Objective: The aim of this study was to compare iodine bioavailability in iodine-replete adults from: 1) cow milk containing a high concentration of native iodine; 2) milk containing a low concentration of native iodine, with the addition of potassium iodide (KI) to assess a potential matrix effect; and 3) an aqueous solution of KI as a comparator; with all 3 containing equal amounts of total iodine (263 µg/250 mL). We also speciated iodine in milk.

Design: We conducted a 3-wk, randomized, crossover balance study in adults (n = 12) consuming directly analyzed, standardized diets. During the 3 test conditions - high intrinsic iodine milk (IIM), extrinsically added iodine in milk (EIM), and aqueous iodine solution (AIS) - subjects collected 24-h urine over 3 d and consumed the test drink on the second day, with 3- or 4-d wash-out periods prior to each treatment. Iodine absorption was calculated as the ratio of urinary iodine excretion (UIE) to total iodine intake. Milk iodine speciation was performed using ion chromatography-mass spectrometry.

Results: Iodine intake from the standardized diet was 195 ± 6 µg/d for males and 107 ± 6 µg/d for females; the test drinks provided an additional 263 µg. Eleven subjects completed the protocol. There was a linear relation between iodine intake and UIE (β = 0.89, SE = 0.04, P < 0.001). There were no significant differences in UIE among the 3 conditions (P = 0.24). Median (range) fractional iodine absorption across the 3 conditions was 91 (51-145), 72 (48-95), and 98 (51-143)% on days 1, 2, and 3, respectively, with day 2 significantly lower compared with days 1 and 3 (P < 0.001). In milk, 80-93% of the total iodine was inorganic iodide.

Conclusion: Nearly all of the iodine in cow milk is iodide and although fractional iodine absorption from milk decreases with increasing dose, its bioavailability is high. The trial was registered at clinicaltrials.gov as NCT03590431.
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http://dx.doi.org/10.1093/ajcn/nqz092DOI Listing
July 2019

A heat-stable microparticle platform for oral micronutrient delivery.

Sci Transl Med 2019 11;11(518)

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Micronutrient deficiencies affect up to 2 billion people and are the leading cause of cognitive and physical disorders in the developing world. Food fortification is effective in treating micronutrient deficiencies; however, its global implementation has been limited by technical challenges in maintaining micronutrient stability during cooking and storage. We hypothesized that polymer-based encapsulation could address this and facilitate micronutrient absorption. We identified poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate) (1:2:1) (BMC) as a material with proven safety, offering stability in boiling water, rapid dissolution in gastric acid, and the ability to encapsulate distinct micronutrients. We encapsulated 11 micronutrients (iron; iodine; zinc; and vitamins A, B2, niacin, biotin, folic acid, B12, C, and D) and co-encapsulated up to 4 micronutrients. Encapsulation improved micronutrient stability against heat, light, moisture, and oxidation. Rodent studies confirmed rapid micronutrient release in the stomach and intestinal absorption. Bioavailability of iron from microparticles, compared to free iron, was lower in an initial human study. An organotypic human intestinal model revealed that increased iron loading and decreased polymer content would improve absorption. Using process development approaches capable of kilogram-scale synthesis, we increased iron loading more than 30-fold. Scaled batches tested in a follow-up human study exhibited up to 89% relative iron bioavailability compared to free iron. Collectively, these studies describe a broad approach for clinical translation of a heat-stable ingestible micronutrient delivery platform with the potential to improve micronutrient deficiency in the developing world. These approaches could potentially be applied toward clinical translation of other materials, such as natural polymers, for encapsulation and oral delivery of micronutrients.
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http://dx.doi.org/10.1126/scitranslmed.aaw3680DOI Listing
November 2019