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

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

Register-based information on thyroid diseases in Europe: lessons and results from the EUthyroid collaboration.

Objective: Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. Design: Register-based cross-sectional study. Methods: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. Results: Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. Conclusions: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.

Polyphenol-rich tea decreases iron absorption from fortified wheat bread in Senegalese mother-child pairs and bioavailability of ferrous fumarate is sharply lower in children.

BACKGROUND/OBJECTIVES: Fractional iron absorption (FAFe) from ferrous fumarate (FeFum) and ferrous sulfate (FeSO4) in adults is generally comparable. While FeFum is commonly used to fortify infant foods, FAFe from FeFum in young children and infants may be decreased compared with FeSO4 and this effect has not been assessed in inhibitory vs noninhibitory meals. Previous studies also reported FAFe to be strongly correlated in mother-child pairs. Our objective was to measure FAFe from fortified bread labeled with 58FeSO4 and 57FeFum in mother-child pairs with and without a commonly consumed herbal tea of Combretum micranthum (Tisane Kinkéliba, TK). METHODS: Senegalese mother-child pairs (n = 17) were randomly assigned to receive, in a 2 × 2 factorial design, fortified bread with 58FeSO4 or 57FeFum consumed with TK or water. FAFe was assessed by measuring erythrocyte incorporation of stable iron-isotopes 14 days after administration. RESULTS: In children, relative bioavailability (RBV) from FeFum was 51 and 64% compared with FeSO4 when served with TK or water (both, P < 0.05). In mothers, the presence of TK decreased FAFe by 56% (P < 0.05) and 50% (P = 0.077) and in children by 65 and 72% (both, P < 0.0001), in the meals with 58FeSO4 and 57FeFum, respectively. After adjustment for plasma ferritin, there was a positive correlation between FAFe in mothers and children (r = 0.4142, P = 0.001). CONCLUSIONS: In Senegalese women and children, herbal tea decreased FAFe from a wheat-based meal. The RBV of FeFum was low in children but not in their mothers. FAFe was modestly correlated in mother-child pairs, possibly due to shared genetic, epigenetic or environmental background.

Dried Blood Spot Thyroglobulin as a Biomarker of Iodine Status in Pregnant Women.

Context: Thyroglobulin (Tg) could be a sensitive biomarker of iodine nutrition in pregnant women (PW). A dried blood spot (DBS) assay would simplify collection and transport in field studies. Objectives: Our aims were to (1) establish and test a reference range for DBS-Tg in PW; (2) determine whether co-measurement of Tg antibodies (Abs) is necessary to define population iodine status. Design, Setting, and Participants: Standardized cross-sectional studies of 3870 PW from 11 countries. For the DBS-Tg reference range, we included TgAb-negative PW (n = 599) from 3 countries with sufficient iodine intake. Main Outcome Measures: We measured the urinary iodine concentration and DBS thyroid-stimulating hormone, total thyroxin, Tg, and TgAb. Results: In the reference population, the median DBS-Tg was 9.2 µg/L (95% confidence interval, 8.7 to 9.8 µg/L) and was not significantly different among trimesters. The reference range was 0.3 to 43.5 µg/L. Over a range of iodine intake, the Tg concentrations were U-shaped. Within countries, the median DBS-Tg and the presence of elevated DBS-Tg did not differ significantly between all PW and PW who were TgAb-negative. Conclusions: A median DBS-Tg of ∼10 µg/L with <3% of values ≥44 µg/L indicated population iodine sufficiency. Concurrent measurement of TgAb did not appear necessary to assess the population iodine status.

The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements.

BACKGROUND: Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with higher risk of many diseases that affect mortality, including cardiovascular disease (CVD) and cancer. The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A, due to interactions of vitamin A at the level of the vitamin D nuclear receptor. In this prospective cohort study, we investigated whether the association of 25(OH)D with all-cause, cancer, and CVD mortality was modified by circulating vitamin A or preformed vitamin A intake from supplements. METHODS: We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Mortality data for all-cause (n = 3890), cancer (n = 844), and CVD mortality (n = 1715) were assessed through December 2006. Serum 25(OH)D was measured using a radioimmunoassay kit, vitamin A biomarkers were measured by HPLC, and information on supplement use was obtained by self-report. Multivariable hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were estimated by proportional hazards regression. RESULTS: Serum 25(OH)D was significantly inversely associated with all-cause mortality (HR 0.93, 95% CI 0.89, 0.97, per 10 ng/mL increase) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes, but not with cancer mortality. The observed inverse associations remained statistically significant only among participants with serum retinyl esters <7.0 µg/dL. High intake (>5000 IU/day) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality. The observed interactions were not statistically significant. CONCLUSIONS: 25(OH)D was inversely associated with overall mortality, CVD mortality, and mortality due to non-cancer/non-CVD causes, but not with cancer mortality. A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration.

Iron Modulates Butyrate Production by a Child Gut Microbiota In Vitro.

UNLABELLED: The aim of this study was to investigate the effect of iron (Fe) availability on butyrate production in the complex bacterial ecosystem of the human gut. Hence, different Fe availabilities were mimicked in an in vitro colonic fermentation model (the polyfermenter intestinal model called PolyFermS) inoculated with immobilized gut microbiota from a child and in batch cultures of the butyrate producer Roseburia intestinalis. Shifts in the microbial community (16S rRNA sequencing and quantitative PCR), metabolic activity (high-performance liquid chromatography), and expression of genes involved in butyrate production were assessed. In the PolyFermS, moderate Fe deficiency resulted in a 1.4-fold increase in butyrate production and a 5-fold increase in butyryl-coenzyme A (CoA):acetate CoA-transferase gene expression, while very strong Fe deficiency significantly decreased butyrate concentrations and butyrate-producing bacteria compared with the results under normal Fe conditions. Batch cultures of R. intestinalis grown in a low-Fe environment preferentially produced lactate and had reduced butyrate and hydrogen production, in parallel with upregulation of the lactate dehydrogenase gene and downregulation of the pyruvate:ferredoxin-oxidoreductase gene. In contrast, under high-Fe conditions, R. intestinalis cultures showed enhanced butyrate and hydrogen production, along with increased expression of the corresponding genes, compared with the results under normal-Fe conditions. Our data reveal the strong regulatory effect of Fe on gut microbiota butyrate producers and on the concentrations of butyrate, which contributes to the maintenance of host gut health. IMPORTANCE: Fe deficiency is one of the most common nutritional deficiencies worldwide and can be corrected by Fe supplementation. In this in vitro study, we show that environmental Fe concentrations in a continuous gut fermentation model closely mimicking a child's gut microbiota strongly affect the composition of the gut microbiome and its metabolic activity, particularly butyrate production. The differential expression of genes involved in the butyrate production pathway under different Fe conditions and the enzyme cofactor role of Fe explain the observed modulation of butyrate production. Our data reveal that the level of dietary Fe reaching the colon affects the microbiome, and its essential function of providing the host with beneficial butyrate.

Subclinical Hypothyroidism and Elevated Thyroglobulin in Infants with Chronic Excess Iodine Intake.

BACKGROUND: Acute iodine excess in newborns can cause hypothyroidism, but there are limited data on the effects of iodine excess on thyroid function in older infants. The aim of this study was to measure the effects of chronic excess iodine intake on thyroid function in 6-24-month-old infants. METHODS: In this cross-sectional study, infants (n=696) in eastern Nepal were studied. Spot urine samples, venous blood samples, and household salt samples were collected, and urinary iodine concentration (UIC), serum free thyroxine (fT4), thyrotropin (TSH), thyroglobulin (Tg), and titrated household salt iodine concentration (SIC) were measured. Daily iodine intake was calculated from UIC based on estimates of urine volume at this age. RESULTS: Median (25th-75th percentile) household SIC was 89 (70-149) ppm, while national legislation stipulates a fortification level of 50 ppm. Median UIC was 407 (312-491) µg/L; 76% of infants had a UIC >300 µg/L, suggesting iodine excess. Calculated mean iodine intake in 12-24-month-old infants was 220 µg/day, exceeding the recommended safe upper limit for iodine at this age (200 µg/day). Among the infants, 15.8% had an elevated Tg, 7.4% had subclinical hypothyroidism, but <1% had overt hypothyroidism. UIC was not a significant predictor of thyroid function, thyroid hormones, or Tg. CONCLUSION: In 6-24-month-old infants exposed to excessive iodine intake, ∼7% have subclinical hypothyroidism but <1% have overt hypothyroidism. These findings suggest the thyroid in late infancy is already able to adapt to high iodine intakes and, in most cases, maintain euthyroidism.

SUFFICIENT IODINE INTAKE IN SCHOOLCHILDREN FROM THE ZAGREB AREA: ASSESSMENT WITH DRIED BLOD SPOT THYROGLOBULIN AS A NEW FUNCTIONAL BIOMARKER FOR IODINE DEFICIENCY.

Current methods for assessment of iodine intake in a population comprise measurements of urinary iodine concentration (UIC), thyroid volume by ultrasound (US-Tvol), and newborn TSH. Serum or dried blood spot thyroglobulin (DBS-Tg) is a new promising functional iodine status biomarker in children. In 1996, a new act on universal salt iodination was introduced in Croatia with 25 mg of potassium iodideper kg of salt. In 2002, Croatia finally reached iodine sufficiency. However, in 2009, median UIC in 101 schoolchildren from Zagreb, the capital of Croatia, was 288 µg/L, posing to be excessive. The aim of the study was to assess iodine intake in schoolchildren from the Zagreb area and to evaluate the value of DBS-Tg in schoolchildren as a new functional biomarker of iodine deficiency (and iodine excess). The study was part of a large international study in 6- to 12-year-old children supported by UNICEF, the Swiss Federal Institute of Technology (ETH Zurich) and the International Council for the Control of Iodine Deficiency Disorders (ICCIDD). According to international study results, the median cut-off Tg < 13 µg/L and/or < 3% Tg values > 40 µg/L indicate iodine sufficiency. The study included 159 schoolchildren (median age 9.1 ± 1.4 years) from Zagreb and a nearby small town of Jastrebarsko with measurements of UIC, US-Tvol, DBS-Tg, T4, TSH and iodine content in salt from households of schoolchildren (KI/kg of salt). Overall median UIC was 205 µg/L (range 1-505 µg/L). Thyroid volumes in schoolchildren measured by US were within the normal range according to reference values. Median DBS-Tg in schoolchildren was 12.1 µg/L with 3% of Tg values > 40 µg/L. High Tg values were in the UIC range < 50 µg/L and > 300 µg/L (U-shaped curve of Tg plotted against UIC). All children were euthyroid with geometric mean TSH 0.7 ± 0.3 mU/L and arithmetic mean T4 62 ± 12.5 nmol/L. The mean KI content per kg of salt was 24.9 ± 3.1 mg/kg (range 19-36 mg/kg). Study results indicated iodine sufficiency in schoolchildren from the Zagreb area. Thyroglobulin proved to be a sensitive indicator of both iodine deficiency and iodine excess in children. Iodine content in salt from households of schoolchildren was in good compliance with the Croatian act (20-30 mg KI/kg of salt).

Salmonella adhesion, invasion and cellular immune responses are differentially affected by iron concentrations in a combined in vitro gut fermentation-cell model.

In regions with a high infectious disease burden, concerns have been raised about the safety of iron supplementation because higher iron concentrations in the gut lumen may increase risk of enteropathogen infection. The aim of this study was to investigate interactions of the enteropathogen Salmonella enterica ssp. enterica Typhimurium with intestinal cells under different iron concentrations encountered in the gut lumen during iron deficiency and supplementation using an in vitro colonic fermentation system inoculated with immobilized child gut microbiota combined with Caco-2/HT29-MTX co-culture monolayers. Colonic fermentation effluents obtained during normal, low (chelation by 2,2'-dipyridyl) and high iron (26.5 mg iron/L) fermentation conditions containing Salmonella or pure Salmonella cultures with similar iron conditions were applied to cellular monolayers. Salmonella adhesion and invasion capacity, cellular integrity and immune response were assessed. Under high iron conditions in pure culture, Salmonella adhesion was 8-fold increased compared to normal iron conditions while invasion was not affected leading to decreased invasion efficiency (-86%). Moreover, cellular cytokines IL-1ß, IL-6, IL-8 and TNF-α secretion as well as NF-κB activation in THP-1 cells were attenuated under high iron conditions. Low iron conditions in pure culture increased Salmonella invasion correlating with an increase in IL-8 release. In fermentation effluents, Salmonella adhesion was 12-fold and invasion was 428-fold reduced compared to pure culture. Salmonella in high iron fermentation effluents had decreased invasion efficiency (-77.1%) and cellular TNF-α release compared to normal iron effluent. The presence of commensal microbiota and bacterial metabolites in fermentation effluents reduced adhesion and invasion of Salmonella compared to pure culture highlighting the importance of the gut microbiota as a barrier during pathogen invasion. High iron concentrations as encountered in the gut lumen during iron supplementation attenuated Salmonella invasion efficiency and cellular immune response suggesting that high iron concentrations alone may not lead to an increased Salmonella invasion.