Iron deficiency anemia (IDA) is common among infants and children in Sub-Saharan Africa and is a leading contributor to the global burden of disease, as well as a hindrance to national development. ...In-home iron fortification of complementary foods using micronutrient powders (MNPs) effectively reduces the risk for IDA by ensuring that the iron needs of infants and young children are met without changing their traditional diet. However, the iron dose delivered by MNPs is high, and comparable on a mg iron per kg body weight to the supplemental doses (2 mg/kg) typically given to older children, which increases diarrhea risk. In controlled studies, iron-containing MNPs modestly increase risk for diarrhea in infants; in some cases, the diarrhea is severe and may require hospitalization. Recent in vitro and in vivo studies provide insights into the mechanism of this effect. Provision of iron fortificants to school-age children and iron-containing MNPs to weaning infants decreases the number of beneficial 'barrier' commensal gut bacteria (e.g., bifidobacteria), increases the enterobacteria to bifidobacteria ratio and abundances of opportunistic pathogens (e.g., pathogenic Escherichia coli), and induces gut inflammation. Thus, although iron-containing MNPs are highly effective in reducing IDA, they may increase gastrointestinal morbidity in infants, and safer formulations are needed.
Iron-containing micronutrient powders (MNPs) reduce anaemia in African infants, but the current high iron dose (12.5 mg/day) may decrease gut
and
, and increase enteropathogens, diarrhoea and ...respiratory tract infections (RTIs). We evaluated the efficacy and safety of a new MNP formula with prebiotic galacto-oligosaccharides (GOS) combined with a low dose (5 mg/day) of highly bioavailable iron.
In a 4-month, controlled, double-blind trial, we randomised Kenyan infants aged 6.5-9.5 months (n=155) to receive daily (1) a MNP without iron (control); (2) the identical MNP but with 5 mg iron (2.5 mg as sodium iron ethylenediaminetetraacetate and 2.5 mg as ferrous fumarate) (Fe group); or (3) the identical MNP as the Fe group but with 7.5 g GOS (FeGOS group).
Anaemia decreased by ≈50% in the Fe and FeGOS groups (p<0.001). Compared with the control or FeGOS group, in the Fe group there were (1) lower abundances of
and
and higher abundances of
(p<0.01); (2) higher abundances of virulence and toxin genes (VTGs) of pathogens (p<0.01); (3) higher plasma intestinal fatty acid-binding protein (a biomarker of enterocyte damage) (p<0.05); and (4) a higher incidence of treated RTIs (p<0.05). In contrast, there were no significant differences in these variables comparing the control and FeGOS groups, with the exception that the abundance of VTGs of all pathogens was significantly lower in the FeGOS group compared with the control and Fe groups (p<0.01).
A MNP containing a low dose of highly bioavailable iron reduces anaemia, and the addition of GOS mitigates most of the adverse effects of iron on the gut microbiome and morbidity in African infants.
NCT02118402.
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.
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.
Our objective was to compare iron absorption from a maize-based porridge containing:1) labeled ferrous sulfate (FeSO4) alone;2) labeled FeSO4given with bovine apo-Lf; and3) intrinsically labeled bovine holo-Lf.
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 as54Fe-labeled FeSO4;2) 1.42 mg of iron as58Fe-labeled FeSO4, given with 1.41 g apo-Lf (containing 0.08 mg iron); and3) 1.41 g holo-Lf carrying 1.5 mg iron as57Fe. 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.
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 FeSO4alone (P = 0.24).
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 FeSO4significantly 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.
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.
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.
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).
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.
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.
Whether consumption of prebiotics increases iron absorption in infants is unclear.
We set out to determine whether prebiotic consumption affects iron absorption from a micronutrient powder (MNP) ...containing a mixture of ferrous fumarate and sodium iron EDTA (FeFum+NaFeEDTA) in Kenyan infants.
Infants (
= 50; aged 6-14 mo) consumed maize porridge that was fortified with an MNP containing FeFum+NaFeEDTA and 7.5 g galacto-oligosaccharides (GOSs) (Fe+GOS group,
= 22) or the same MNP without GOSs (Fe group,
= 28) each day for 3 wk. Then, on 2 consecutive days, we fed all infants isotopically labeled maize porridge and MNP test meals containing 5 mg Fe as
FeFum+Na
FeEDTA or ferrous sulfate (
FeSO
). Iron absorption was measured as the erythrocyte incorporation of stable isotopes. Iron markers, fecal pH, and bacterial groups were assessed at baseline and 3 wk. Comparisons within and between groups were done with the use of mixed-effects models.
There was a significant group-by-compound interaction on iron absorption (
= 0.011). The median percentages of fractional iron absorption from FeFum+NaFeEDTA and from FeSO
in the Fe group were 11.6% (IQR: 6.9-19.9%) and 20.3% (IQR: 14.2-25.7%), respectively, (
< 0.001) and, in the Fe+GOS group, were 18.8% (IQR: 8.3-37.5%) and 25.5% (IQR: 15.1-37.8%), respectively (
= 0.124). Between groups, iron absorption was greater from the FeFum+NaFeEDTA (
= 0.047) in the Fe+GOS group but not from the FeSO
(
= 0.653). The relative iron bioavailability from FeFum+NaFeEDTA compared with FeSO
was higher in the Fe+GOS group than in the Fe group (88% compared with 63%;
= 0.006). There was a significant time-by-group interaction on
spp. (
= 0.008) and
/
/
spp. (
= 0.018);
/
/
spp. decreased in the Fe group (
= 0.013), and there was a nonsignificant trend toward higher
spp. in the Fe+GOS group (
= 0.099). At 3 wk, iron absorption was negatively correlated with fecal pH (
< 0.001) and positively correlated with
/
/
spp. (
= 0.001).
GOS consumption by infants increased iron absorption by 62% from an MNP containing FeFum+NaFeEDTA, thereby possibly reflecting greater colonic iron absorption. This trial was registered at clinicaltrials.gov as NCT02666417.
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.
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).
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.
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).
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.
There is little data on human milk oligosaccharide (HMO) composition in Sub-Saharan Africa. Iron fortificants adversely affect the infant gut microbiota, while co-provision of prebiotic ...galacto-oligosaccharides (GOS) mitigates most of the adverse effects. Whether variations in maternal HMO profile can influence the infant response to iron and/or GOS fortificants is unknown. The aim of this study was to determine HMO profiles and the secretor/non-secretor phenotype of lactating Kenyan mothers and investigate their effects on the maternal and infant gut microbiota, and on the infant response to a fortification intervention with 5 mg iron (2.5 mg as sodium iron ethylenediaminetetraacetate and 2.5 mg as ferrous fumarate) and 7.5 g GOS. We studied mother-infant pairs (
= 80) participating in a 4-month intervention trial in which the infants (aged 6.5-9.5 months) received daily a micronutrient powder without iron, with iron or with iron and GOS. We assessed: (1) maternal secretor status and HMO composition; (2) effects of secretor status on the maternal and infant gut microbiota in a cross-sectional analysis at baseline of the intervention trial; and (3) interactions between secretor status and intervention groups during the intervention trial on the infant gut microbiota, gut inflammation, iron status, growth and infectious morbidity. Secretor prevalence was 72% and HMOs differed between secretors and non-secretors and over time of lactation. Secretor status did not predict the baseline composition of the maternal and infant gut microbiota. There was a secretor-status-by-intervention-group interaction on
(
= 0.021), Z-scores for length-for-age (
= 0.022) and weight-for-age (
= 0.018), and soluble transferrin receptor (
= 0.041). In the no iron group, longitudinal prevalence of diarrhea was higher among infants of non-secretors (23.8%) than of secretors (10.4%) (
= 0.001). In conclusion, HMO profile may modulate the infant gut microbiota response to fortificant iron; compared to infants of secretor mothers, infants of non-secretor mothers may be more vulnerable to the adverse effect of iron but also benefit more from the co-provision of GOS.
The gut microbiota evolves rapidly after birth, responding dynamically to environmental factors and playing a key role in short- and long-term health. Lifestyle and rurality have been shown to ...contribute to differences in the gut microbiome, including Bifidobacterium levels, between infants. We studied the composition, function and variability of the gut microbiomes of 6- to 11-month-old Kenyan infants (n = 105). Shotgun metagenomics showed Bifidobacterium longum to be the dominant species. A pangenomic analysis of B. longum in gut metagenomes revealed a high prevalence of B. longum subsp. infantis (B. infantis) in Kenyan infants (80%), and possible co-existence of this subspecies with B. longum subsp. longum. Stratification of the gut microbiome into community (GMC) types revealed differences in composition and functional features. GMC types with a higher prevalence of B. infantis and abundance of B. breve also had a lower pH and a lower abundance of genes encoding pathogenic features. An analysis of human milk oligosaccharides (HMOs) classified the human milk (HM) samples into four groups defined on the basis of secretor and Lewis polymorphisms revealed a higher prevalence of HM group III (Se+, Le-) (22%) than in most previously studied populations, with an enrichment in 2′-fucosyllactose. Our results show that the gut microbiome of partially breastfed Kenyan infants over the age of six months is enriched in bacteria from the Bifidobacterium community, including B. infantis, and that the high prevalence of a specific HM group may indicate a specific HMO-gut microbiome association. This study sheds light on gut microbiome variation in an understudied population with limited exposure to modern microbiome-altering factors.
Compared with infant cereals based on refined grains, an infant cereal containing whole grains (WGs) and pulses with adequate amounts of ascorbic acid to protect against absorption inhibitors could ...be a healthier source of well-absorbed iron. However, iron absorption from such cereals is uncertain.
We measured iron bioavailability from ferrous fumarate (Fefum) added to commercial infant cereals containing 1) refined wheat flour (reference meal), 2) WG wheat and lentil flour (WG-wheat-lentil), 3) WG wheat and chickpea flour (WG-wheat-chickpeas), and 4) WG oat flour (WG-oat) and from ferrous bisglycinate (FeBG) added to the same oat-based cereal (WG-oat-FeBG).
In a prospective, single-blinded randomized crossover study, 6- to 14-mo-old Malawian children (n = 30) consumed 25-g servings of all 5 test meals containing 2.25 mg stable isotope-labeled iron and 13.5 mg ascorbic acid. Fractional iron absorption (FIA) was assessed by erythrocyte incorporation of isotopes after 14 d. Comparisons were made using linear mixed models.
Seventy percent of the children were anemic and 67% were iron deficient. Geometric mean FIA percentages (–SD, +SD) from the cereals were as follows: 1) refined wheat, 12.1 (4.8, 30.6); 2) WG-wheat-lentil, 15.8 (6.6, 37.6); 3) WG-wheat-chickpeas, 12.8 (5.5, 29.8); and 4) WG-oat, 9.2 (3.9, 21.5) and 7.4 (2.9, 18.9) from WG-oat-FeBG. Meal predicted FIA (P ≤ 0.001), whereas in pairwise comparisons, only WG-oat-FeBG was significantly different compared with the refined wheat meal (P = 0.02). In addition, FIAs from WG-wheat-lentil and WG-wheat-chickpeas were significantly higher than from WG-oat (P = 0.002 and P = 0.04, respectively) and WG-oat-FeBG (P < 0.001 and P = 0.004, respectively).
In Malawian children, when given with ascorbic acid at a molar ratio of 2:1, iron bioavailability from Fefum-fortified infant cereals containing WG wheat and pulses is ≈13−15%, whereas that from FeBG- and Fefum-fortified infant cereals based on WG oats is ≈7−9%.
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