A hydrolyzed lipid blend diet promotes myelination in neonatal piglets in a region and concentration-dependent manner.

The impact of early life nutrition on myelin development is of interest given that cognitive and behavioral function depends on proper myelination. Evidence shows that myelination can be altered by dietary lipid, but most of these studies have been performed in the context of disease or impairment. Here, we assessed the effects of lipid blends containing various levels of a hydrolyzed fat (HF) system on myelination in healthy piglets. Piglets were sow-reared, fed a control diet, or a diet containing 12%, 25%, or 53% HF consisting of cholesterol, fatty acids, monoglycerides, and phospholipid from lecithin. At postnatal day 28/29, magnetic resonance imaging (MRI) was performed to assess changes to brain development, followed by brain collection for microscopic analyses of myelin in targeted regions using CLARITY tissue clearing, immunohistochemistry, and electron microscopy techniques. Sow-reared piglets exhibited the highest overall brain white matter volume by MRI. However, a 25% HF diet resulted in the greatest total myelin density in the prefrontal cortex based on 3D modeling analysis of myelinated filaments. Nodal gap length and g-ratio were inversely correlated with percentage of HF in the corpus callosum, as well as in the PFC and internal capsule for g-ratio, indicating that a 53% HF diet resulted in the thickest myelin per axon and a 0% HF control diet the thinnest in specific brain regions. These findings indicate that HF promoted myelination in the neonatal piglet in a region- and concentration-dependent manner.

Natural Vitamin E Supplementation during Pregnancy in Rats Increases RRR-α-Tocopherol Stereoisomer Proportion and Enhances Fetal Antioxidant Capacity, Compared to Synthetic Vitamin E Administration.

INTRODUCTION: Low dietary intake of vitamin E is a global public health issue. RRR-α-tocopherol (RRR-αT) is the only naturally occurring vitamin E stereoisomer, but the equimolecular mixture of all eight stereoisomers, synthetic vitamin E (S-αT), is commonly consumed. The objective of this study was to evaluate bioavailability and antioxidant activity of RRR-αT versus S-αT, in both mother and fetus, after maternal supplementation during pregnancy. METHODS: Female rats (7 weeks of age) received a modified AIN-93G diet supplemented with 75 IU/kg of RRR-αT (NVE, n = 20) or S-αT (SVE, n = 17). At delivery, the levels of αT, stereoisomer distribution, and antioxidant capacity were analyzed in maternal and fetal plasma. RESULTS: NVE administration significantly increased the proportion of RRR-αT stereoisomer in maternal and fetal plasma. The percentage of RRR-αT increased from 32.76% to 88.33% in maternal plasma, and 35.25% to 97.94% in fetal plasma, in the NVE group compared to SVE. Fetal plasma from the NVE group was found to have higher total antioxidant capacity compared to SVE. Lastly, fetal plasma RRR-αT stereoisomer percentage was positively associated with expression levels of scavenger receptor class B type 1 (SR-B1) in the placenta. CONCLUSIONS: Both natural and synthetic sources of vitamin E showed similar bioavailability. Still, NVE supplementation increased the proportion of RRR-αT and promoted higher antioxidant activity in fetal plasma at birth. Placental SR-B1 might be involved in the stereoselective transfer of RRR-αT stereoisomer across the placenta and may improve αT bioactivity in the fetus.

Carotenoid profile in breast milk and maternal and cord plasma: a longitudinal study in Southwest China.

Carotenoids are increasingly being implicated to have an important role in brain and eye development. This study aimed to quantify the content and profile of carotenoids in human breast milk, maternal plasma and neonatal umbilical cord plasma in Chengdu, an urban area in Southwest China. In this study, fifty-four healthy mothers were enrolled. Maternal blood, umbilical cord blood, colostrum, transitional milk and mature milk were collected. Concentrations of carotenoids (lutein, zeaxanthin, ß-cryptoxanthin, ß-carotene and lycopene) were analysed by HPLC. We found that carotenoid concentrations decreased from colostrum to mature milk. Hydrocarbon carotenoids with weaker polarity decreased more than the polar carotenoids. Lycopene concentrations dropped by 99 %, ß-carotene by 92 %, ß-cryptoxanthin by 83 %, lutein by 32 % and zeaxanthin by 22 %. Lycopene and ß-carotene accounted for 70 % of the total carotenoids in colostrum, and lutein predominated amongst carotenoids in transitional milk and mature milk (51-55 %). Carotenoid concentrations in maternal plasma were much higher than that in cord plasma. Lutein predominated in cord plasma. The concentrations of all carotenoids in maternal plasma were correlated with those of cord plasma and human milk. These results are consistent with selective transport mechanisms in the mammary gland related to the polarity of carotenoids, and each carotenoid has its own implications, which may have different priorities in the early life development of infants. These findings may help guide dietary recommendations for carotenoid inclusion in infant formulas.

Maternal Dietary Intake of Omega-3 Fatty Acids Correlates Positively with Regional Brain Volumes in 1-Month-Old Term Infants.

Maternal nutrition is an important factor for infant neurodevelopment. However, prior magnetic resonance imaging (MRI) studies on maternal nutrients and infant brain have focused mostly on preterm infants or on few specific nutrients and few specific brain regions. We present a first study in term-born infants, comprehensively correlating 73 maternal nutrients with infant brain morphometry at the regional (61 regions) and voxel (over 300 000 voxel) levels. Both maternal nutrition intake diaries and infant MRI were collected at 1 month of life (0.9 ± 0.5 months) for 92 term-born infants (among them, 54 infants were purely breastfed and 19 were breastfed most of the time). Intake of nutrients was assessed via standardized food frequency questionnaire. No nutrient was significantly correlated with any of the volumes of the 61 autosegmented brain regions. However, increased volumes within subregions of the frontal cortex and corpus callosum at the voxel level were positively correlated with maternal intake of omega-3 fatty acids, retinol (vitamin A) and vitamin B12, both with and without correction for postmenstrual age and sex (P < 0.05, q < 0.05 after false discovery rate correction). Omega-3 fatty acids remained significantly correlated with infant brain volumes after subsetting to the 54 infants who were exclusively breastfed, but retinol and vitamin B12 did not. This provides an impetus for future larger studies to better characterize the effect size of dietary variation and correlation with neurodevelopmental outcomes, which can lead to improved nutritional guidance during pregnancy and lactation.

Synthetic α-Tocopherol, Compared with Natural α-Tocopherol, Downregulates Myelin Genes in Cerebella of Adolescent Ttpa-null Mice.

BACKGROUND: Vitamin E (α-tocopherol; α-T) deficiency causes spinocerebellar ataxia. α-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic α-T during early life. OBJECTIVE: We assessed the effects of dietary α-T dose and source on tissue α-T accumulation and gene expression in adolescent α-tocopherol transfer protein-null (Ttpa-/-) mice. METHODS: Three-week-old male Ttpa-/- mice (n  = 7/group) were fed 1 of 4 AIN-93G-based diets for 4 wk: vitamin E deficient (VED; below α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+ littermates fed AIN-93G [75 mg synthetic α-T (CON)] served as controls (n  = 7). At 7 wk of age, tissue α-T concentrations and stereoisomer profiles were measured for all groups. RNA-sequencing was performed on cerebella of Ttpa-/- groups. RESULTS: Ttpa-/- mice fed VED had undetectable brain α-T concentrations. Cerebral cortex α-T concentrations were greater in Ttpa-/- mice fed NAT (9.1 ± 0.7 nmol/g), SYN (10.8 ± 1.0 nmol/g), and HSYN (13.9 ± 1.6 nmol/g) compared with the VED group but were significantly lower than in Ttpa+/+ mice fed CON (24.6 ± 1.2 nmol/g) (P < 0.001). RRR-α-T was the predominant stereoisomer in brains of Ttpa+/+ mice (∼40%) and Ttpa-/- mice fed NAT (∼94%). α-T stereoisomer composition was similar in brains of Ttpa-/- mice fed SYN and HSYN (2R: ∼53%; 2S: ∼47%). Very few of the 16,774 genes measured were differentially expressed. However, compared with the NAT diet, HSYN significantly downregulated 20 myelin genes, including 2 transcription factors: SRY-box transcription factor 10 (Sox10) and myelin regulatory factor (Myrf), and several downstream target genes (false discovery rate <0.05). CONCLUSIONS: High-dose synthetic α-T compared with natural α-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.

Brain α-Tocopherol Concentration and Stereoisomer Profile Alter Hippocampal Gene Expression in Weanling Mice.

BACKGROUND: Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood. OBJECTIVES: The objective was to determine the impact of bio-potency-adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice. METHODS: Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams. RESULTS: A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz). CONCLUSIONS: In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.

Infant Rhesus Macaque Brain α-Tocopherol Stereoisomer Profile Is Differentially Impacted by the Source of α-Tocopherol in Infant Formula.

BACKGROUND: α-Tocopherol (αT) in its natural form [2'R, 4'R, 8'R αT (RRR-αT)] is more bioactive than synthetic α-tocopherol (all rac-αT). All rac-αT is widely used in infant formulas, but its accretion in formula-fed infant brain is unknown. OBJECTIVE: We sought to compare αT and stereoisomer status in infant rhesus macaques (Macaca mulatta) fed infant formula (RRR-αT or all rac-αT) with a reference group fed a mixed diet of breast milk and maternal diet. METHODS: From 1 d after birth until 6 mo of age, infants (n = 23) were either nursery reared and exclusively fed 1 of 2 formulas by staff personnel or were community housed with their mothers and consumed a mixed reference diet of breast milk (69 mL/d at 6 mo) transitioning to monkey diet at ∼2 mo (MF; n = 8). Formulas contained either 21 µmol RRR-αT/L (NAT-F; n = 8) or 30 µmol all rac-αT/L (SYN-F; n = 7). Total αT and αT stereoisomers were analyzed in breast milk at 2, 4, and 6 mo and in monkey plasma and liver and 6 brain regions at 6 mo of age. α-Tocopherol transfer protein (α-TTP), lipoprotein αT, and urinary α-carboxyethyl-hydroxychroman (α-CEHC) were measured. One-way ANOVA with Tukey's post-hoc test was used for analysis. RESULTS: At study termination, plasma, liver, lipoprotein, and brain total αT did not differ between groups. However, the NAT-F-fed group had higher RRR-αT than the SYN-F-fed group (P < 0.01) and the MF group (P < 0.0001) in plasma (1.7- and 2.7-fold) and brain (1.5- and 2.5-fold). Synthetic αT 2R stereoisomers (SYNTH-2R) were generally 3- and 7-fold lower in brain regions of the NAT-F group compared with those of the SYN-F and MF groups (P < 0.05). SYNTH-2R stereoisomers were 2-fold higher in MF than SYN-F (P < 0.0001). The plasma percentage of SYNTH-2R was negatively correlated with the brain percentage of RRR-αT (r = -0.99, P < 0.0001). Brain αT profiles were not explained by α-TTP mRNA or protein expression. Urine α-CEHC was 3 times higher in the NAT-F than in the MF group (P < 0.01). CONCLUSIONS: Consumption of infant formulas with natural (NAT-F) compared with synthetic (SYN-F) αT differentially impacted brain αT stereoisomer profiles in infant rhesus macaques. Future studies should assess the functional implications of αT stereoisomer profiles on brain health.

The effects of breastfeeding versus formula-feeding on cerebral cortex maturation in infant rhesus macaques.

Breastfeeding is positively associated with several outcomes reflecting early brain development and cognitive functioning. Brain neuroimaging studies have shown that exclusively breastfed children have increased white matter and subcortical gray matter volume compared to formula-fed children. However, it is difficult to disentangle the effects of nutrition in breast milk from other confounding factors that affect brain development, particularly in studies of human subjects. Among the nutrients provided by human breast milk are the carotenoid lutein and the natural form of tocopherol, both of which are selectively deposited in brain. Lutein is the predominant carotenoid in breast milk but not in most infant formulas, whereas infant formulas are supplemented with the synthetic form of tocopherol. In this study, a non-human primate model was used to investigate the effects of breastfeeding versus formula-feeding, as well as lutein and natural RRR-α-tocopherol supplementation of infant formula, on brain maturation under controlled experimental conditions. Infant rhesus macaques (Macaca mulatta) were exclusively breastfed, or were fed infant formulas with different levels and sources of lutein and α-tocopherol. Of note, the breastfed group were mother-reared whereas the formula-fed infants were nursery-reared. Brain structural and diffusion MR images were collected, and brain T2 was measured, at two, four and six months of age. The mother-reared breastfed group was observed to differ from the formula-fed groups by possessing higher diffusion fractional anisotropy (FA) in the corpus callosum, and lower FA in the cerebral cortex at four and six months of age. Cortical regions exhibiting the largest differences include primary motor, premotor, lateral prefrontal, and inferior temporal cortices. No differences were found between the formula groups. Although this study did not identify a nutritional component of breast milk that could be provided to infant formula to facilitate brain maturation consistent with that observed in breastfed animals, our findings indicate that breastfeeding promoted maturation of the corpus callosum and cerebral cortical gray matter in the absence of several confounding factors that affect studies in human infants. However, differences in rearing experience remain as a potential contributor to brain structural differences between breastfed and formula fed infants.

Milk and Plasma Lutein and Zeaxanthin Concentrations in Chinese Breast-Feeding Mother-Infant Dyads With Healthy Maternal Fruit and Vegetable Intake.

OBJECTIVES: While others have reported that milk from coastal Chinese women contains high levels of lutein and zeaxanthin, no research has determined the corresponding infant plasma response. Whether infant plasma levels increase commensurately provides important guidance for supplementation of these increasingly intriguing carotenoids in breast-feeding mothers and formula-fed infants. METHODS: Fifty-six mother-infant pairs with a maternal diet rich in eggs, green leafy vegetables, and fruit were enrolled between 6 and 16 weeks of lactation. Milk samples and blood samples from both the mother and infant were collected at entry. Maternal 3-day dietary records and a second milk sample were collected 1 to 3 weeks later. RESULTS: Mean milk lutein concentrations in samples 1 and 2 were 6.5 and 7.7 µg/dL (range 1-22.5 µg/dL), and for zeaxanthin, 1.6 and 1.7 µg/dL (range 1-5.9 µg/dL). Lutein concentrations in infant plasma (18.2 µg/dL) were similar to those in maternal plasma (21.6 µg/dL); zeaxanthin was lower than lutein in both maternal (3.1 µg/dL) and infant (2.9 µg/dL) plasma. Infant and maternal mean plasma lutein and zeaxanthin concentrations were higher than those in both milk samples 1 and 2 (lutein, 6.9 and 8.2 µg/dL; zeaxanthin, 1.9 and 2.0 µg/dL). Infant plasma lutein and zeaxanthin concentrations positively correlated with those in milk sample 1 (lutein, r2 = 0.15, p = 0.004; zeaxanthin, r2 = 0.21, p < 0.001). CONCLUSIONS: Together, these results reveal that high milk concentrations of lutein and zeaxanthin driven by healthy maternal intakes of xanthophyll rich foods are associated with high infant plasma concentrations. These findings will be useful for determining appropriate lutein fortification strategies. Clinical Study.gov registration number: NCT01669655.

Relationships of carotenoid-related gene expression and serum cholesterol and lipoprotein levels to retina and brain lutein deposition in infant rhesus macaques following 6 months of breastfeeding or formula feeding.

The purpose of this study was to investigate if the enhanced bioaccumulation of lutein in retina and brain of breastfed, compared to formula-fed, infant monkeys was associated with higher levels of serum total and HDL cholesterol, apolipoproteins, or mRNA/protein expression of carotenoid-related genes. Newborn rhesus macaques were either breastfed, fed a carotenoid-supplemented formula, or fed an unsupplemented formula for 6 months (n = 8, 8, 7). Real-time qPCR and western blotting were performed in two brain regions (occipital cortex and cerebellum) and two retina regions (macular and peripheral retina). Breastfed infants had higher serum total cholesterol, HDL cholesterol, apoA-I, and apoB-100 levels than the combined formula-fed groups (P < 0.05). Breast milk or infant formulas did not alter expression of the nine genes (CD36, SCARB1, SCARB2, LDLR, STARD3, GSTP1, BCO1, BCO2, RPE65) examined except for SCARB2 in the retina and brain regions. In conclusion, dietary regimen did not impact the expression of carotenoid-related genes except for SCARB2. However, carotenoid-related genes were differentially expressed across brain and retina regions. Breastfed infants had higher serum total and HDL cholesterol, and apolipoproteins, suggesting that lipoprotein levels might be important for delivering lutein to tissues, especially the macular retina, during infancy.

Lutein Is Differentially Deposited across Brain Regions following Formula or Breast Feeding of Infant Rhesus Macaques.

Background: Lutein, a yellow xanthophyll, selectively accumulates in primate retina and brain. Lutein may play a critical role in neural and retinal development, but few studies have investigated the impact of dietary source on its bioaccumulation in infants. Objective: We explored the bioaccumulation of lutein in infant rhesus macaques following breastfeeding or formula-feeding. Methods: From birth to 6 mo of age, male and female rhesus macaques (Macaca mulatta) were either breastfed (BF) (n = 8), fed a formula supplemented with lutein, zeaxanthin, ß-carotene, and lycopene (237, 19.0, 74.2, and 338 nmol/kg, supplemented formula-fed; SF) (n = 8), or fed a formula with low amounts of these carotenoids (38.6, 2.3, 21.5, and 0 nmol/kg, unsupplemented formula-fed; UF) (n = 7). The concentrations of carotenoids in serum and tissues were analyzed by HPLC. Results: At 6 mo of age, the BF group exhibited significantly higher lutein concentrations in serum, all brain regions, macular and peripheral retina, adipose tissue, liver, and other tissues compared to both formula-fed groups (P < 0.001). Lutein concentrations were higher in the SF group than in the UF group in serum and all tissues, with the exception of macular retina. Lutein was differentially distributed across brain areas, with the highest concentrations in the occipital cortex, regardless of the diet. Zeaxanthin was present in all brain regions but only in the BF infants; it was present in both retinal regions in all groups but was significantly enhanced in BF infants compared to either formula group (P < 0.001). ß-Carotene accumulated across brain regions in all groups, but was not detected in retina. Although lycopene was found in many tissues of the SF group, it was not detected in the brain or retina. Conclusions: Although carotenoid supplementation of infant formula significantly increased serum and tissue lutein concentrations compared to unsupplemented formula, concentrations were still well below those in BF infants. Regardless of diet, occipital cortex showed selectively higher lutein deposition than other brain regions, suggesting lutein's role in visual processing in early life.

Supplementation with RRR- or all-rac-α-Tocopherol Differentially Affects the α-Tocopherol Stereoisomer Profile in the Milk and Plasma of Lactating Women.

Background: The naturally occurring α-tocopherol stereoisomer RRR-α-tocopherol is known to be more bioactive than synthetic α-tocopherol (all-rac-α-tocopherol). However, the influence of this difference on the α-tocopherol stereoisomer profile of human milk is not understood.Objective: We investigated whether supplemental RRR-α-tocopherol or all-rac-α-tocopherol differentially affected the distribution of α-tocopherol stereoisomers in milk and plasma from lactating women.Methods: Eighty-nine lactating women aged 19-40 y and with a body mass index (in kg/m2) ≤30 were randomly assigned at 4-6 wk postpartum to receive a daily supplement containing 45.5 mg all-rac-α-tocopherol acetate (ARAC), 22.8 mg all-rac-α-tocopherol acetate + 20.1 mg RRR-α-tocopherol (MIX), or 40.2 mg RRR-α-tocopherol (RRR). Milk and plasma were analyzed for α-tocopherol structural isomers and α-tocopherol stereoisomers at baseline and after 6 wk supplementation with the use of chiral HPLC.Results: There were no significant treatment group or time-dependent changes in milk or plasma α, γ, or δ-tocopherol. RRR-α-tocopherol was the most abundant stereoisomer in both milk and plasma in each group. Supplementation changed both milk and plasma percentage RRR-α-tocopherol (RRR > MIX > ARAC) (P < 0.05) and percentage non-RRR-α-tocopherol (ARAC > MIX > RRR) (P < 0.05). In the RRR group, percentage RRR-α-tocopherol increased in milk (mean ± SEM: 78% ± 2.3% compared with 82% ± 1.7%) (P < 0.05) and plasma (mean ± SEM: 77% ± 1.8% compared with 87% ± 1%) (P < 0.05). In contrast, the percentage RRR-α-tocopherol decreased in the MIX and ARAC groups (MIX, P < 0.05; ARAC, P < 0.0001), and percentage non-RRR-α-tocopherol stereoisomers increased (MIX, P < 0.05; ARAC, P < 0.0001) commensurate with an accumulation of 2S-α-tocopherol stereoisomers (P < 0.05) in both milk and plasma. Milk and plasma RRR-α-tocopherol was positively correlated at baseline (r = 0.67; P < 0.0001) and 6 wk (r = 0.80; P < 0.0001).Conclusion: The α-tocopherol supplementation strategy differentially affected the α-tocopherol milk and plasma stereoisomer profile in lactating women. RRR-α-tocopherol increased milk and plasma percentage RRR-α-tocopherol, whereas all-rac-α-tocopherol acetate reduced these percentages. Because RRR-α-tocopherol is the most bioactive stereoisomer, investigating the impact of supplement-driven changes in the milk α-tocopherol stereoisomer profile on the α-tocopherol status of breastfed infants is warranted.

The naturally occurring α-tocopherol stereoisomer RRR-α-tocopherol is predominant in the human infant brain.

α-Tocopherol is the principal source of vitamin E, an essential nutrient that plays a crucial role in maintaining healthy brain function. Infant formula is routinely supplemented with synthetic α-tocopherol, a racaemic mixture of eight stereoisomers with less bioactivity than the natural stereoisomer RRR-α-tocopherol. α-Tocopherol stereoisomer profiles have not been previously reported in the human brain. In the present study, we analysed total α-tocopherol and α-tocopherol stereoisomers in the frontal cortex (FC), hippocampus (HPC) and visual cortex (VC) of infants (n 36) who died of sudden infant death syndrome or other conditions. RRR-α-tocopherol was the predominant stereoisomer in all brain regions (P<0·0001) and samples, despite a large intra-decedent range in total α-tocopherol (5-17 µg/g). Mean RRR-α-tocopherol concentrations in FC, HPC and VC were 10·5, 6·8 and 5·5 µg/g, respectively. In contrast, mean levels of the synthetic stereoisomers were RRS, 1-1·5; RSR, 0·8-1·0; RSS, 0·7-0·9; and Σ2S 0·2-0·3 µg/g. Samples from all but two decedents contained measurable levels of the synthetic stereoisomers, but the intra-decedent variation was large. The ratio of RRR:the sum of the synthetic 2R stereoisomers (RRS+RSR+RSS) averaged 2·5, 2·3 and 2·4 in FC, HPC and VC, respectively, and ranged from 1 to at least 4·7, indicating that infant brain discriminates against synthetic 2R stereoisomers in favour of RRR. These findings reveal that RRR-α-tocopherol is the predominant stereoisomer in infant brain. These data also indicate that the infant brain discriminates against the synthetic 2R stereoisomers, but is unable to do so completely. On the basis of these findings, investigation into the impact of α-tocopherol stereoisomers on neurodevelopment is warranted.

Milk protein-based infant formula containing rice starch and low lactose reduces common regurgitation in healthy term infants: a randomized, blinded, and prospective trial.

OBJECTIVE: Spit-up (regurgitation) reduction with prethickened milk protein-based infant formulas containing rice starch has been clinically demonstrated in infants with heavy spit-ups but not in otherwise healthy normal infants with common spit-ups. The objective of this study was to evaluate growth, gastrointestinal tolerance, and efficacy to reduce common spit-up in normal, healthy term infants fed an investigational rice starch prethickened lactose-free milk protein-based infant formula. METHODS: This double-blind, randomized, parallel study evaluated the investigational rice starch prethickened lactose-free (low lactose < 100 mg/L) milk protein-based infant formula compared to a standard, commercially available, iso-nutrient, lactose-containing (100% of carbohydrate) milk-based infant formula (control) for growth and gastrointestinal tolerance in healthy term infants (n = 132/group) fed from 14 ± 3 days to 112 days of age. Data were classified and analyzed as evaluable (EV; subjects completing study per protocol) or intent-to-treat data (ITT; all subjects with available data). RESULTS: Growth as indicated by weight gain (primary variable) and formula intake were not significantly different (p > 0.05) between feeding groups (EV or ITT). Though both formulas were well tolerated, spit-up frequency was significantly lower (p < 0.05) in the rice versus control group by 53% at 28 days of age, 54% at 56 days, 48% at 84 days, and 32% at 112 days (EV). Importantly, infants in the rice group were 1.6 to 1.8 times more likely to report zero spit-up than infants in the control group. The rice group also had higher percentages of soft and yellow stools. CONCLUSIONS: The rice starch prethickened lactose-free milk protein-based formula (rice) supported normal growth and safe use as the sole source of feeding for normal infants over the first 4 months of life. The rice formula was efficacious in providing a clinically relevant reduction of spit-up frequency in otherwise healthy term infants.

Lutein and preterm infants with decreased concentrations of brain carotenoids.

OBJECTIVES: Lutein and zeaxanthin are dietary carotenoids that may influence visual and cognitive development. The objective of this study was to provide the first data on distribution of carotenoids in the infant brain and compare concentrations in preterm and term infants. METHODS: Voluntarily donated brain tissues from 30 infants who died during the first 1.5 years of life were obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank. Tissues (hippocampus and prefrontal, frontal, auditory, and occipital cortices) were extracted using standard lipid extraction procedures and analyzed using reverse-phase high-pressure liquid chromatography. RESULTS: Lutein, zeaxanthin, cryptoxanthin, and ß-carotene were the major carotenoids found in the infant brain tissues. Lutein was the predominant carotenoid accounting for 59% of total carotenoids. Preterm infants (n = 8) had significantly lower concentrations of lutein, zeaxanthin, and cryptoxanthin in their brain compared with term infants (n = 22) despite similarity in postmenstrual age. Among formula-fed infants, preterm infants (n = 3) had lower concentrations of lutein and zeaxanthin compared with term infants (n = 5). Brain lutein concentrations were not different between breast milk-fed (n = 3) and formula-fed (n = 5) term decedents. In contrast, term decedents with measurable brain cryptoxanthin, a carotenoid that is inherently low in formula, had higher brain lutein, suggesting that the type of feeding is an important determinant of brain lutein concentrations. CONCLUSIONS: These data reveal preferential accumulation and maintenance of lutein in the infant brain despite underrepresentation in the typical infant diet. Further investigation on the impact of lutein on neural development in preterm infants is warranted.

Longitudinal changes in choline concentration and associated factors in human breast milk.

BACKGROUND: Human breast milk is the primary source of choline and choline-containing compounds for infants at early stages of life. Choline data across lactation in Chinese human milk were limited. OBJECTIVE: This study aimed to quantify the five choline compounds in Chinese human breast milk and explore associated factors. METHODS: A total of 540 lactating mothers from the MUAI (Maternal Nutrition and Infant Investigation) study were included. The content of water-soluble choline (free choline, phosphocholine, glycerophosphocholine) and lipid-soluble choline (phosphatidylcholine, sphingomyelin) in 892 human milk samples collected from 0 to 400 days postpartum were examined, and associated factors were explored. RESULTS: Choline concentrations in human milk varied from postpartum day 0-400 (92.06 ± 65.22 to 171.01 ± 47.84 mg/L). Water-soluble choline was the major component (88.6%-93.8%) in human milk and ranged from 793.03 (659.22) to 1544.43 (443.32) µmol/L. Its trajectory followed that of total choline, increasing from colostrum to transitional milk and then declining in mature milk. In contrast, lipid-soluble choline accounted for 6.2%-11.4% over lactation and had an opposite trajectory. Choline composition varied by delivery mode and parity history. CONCLUSION: The concentrations of individual choline and choline-containing compounds during lactation in Chinese human breast milk were described for the first time. Our results address gaps in extant Chinese human milk choline data and support tailored dietary reference intakes for Chinese lactating women and infants. Our data describes the level and profile of choline from 0 to 400 days postpartum in Chinese human breast milk. This is the most updated data on choline and also the first report of water-soluble choline as the predominant type in Chinese human milk. Our results compensate for the deficiencies in data on choline in Chinese human milk. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry number: ChiCTR1800015387. Web link to study on registry: https://www.chictr.org.cn/index.aspx.

Calcifediol During Pregnancy Improves Maternal and Fetal Availability of Vitamin D Compared to Vitamin D3 in Rats and Modifies Fetal Metabolism.

The fetus depends on the transplacental transfer of vitamin D. Calcifediol (25-OH-D3) is the vitamin D metabolite that crosses the placenta. Previously, oral 25-OH-D3 improved serum 25-OH-D3 compared to vitamin D3 in non-pregnant subjects, although no studies are available in pregnant women. We evaluated the availability of oral 25-OH-D3 compared to vitamin D3 during pregnancy, as well as, their levels in the fetus and effect on metabolism-related proteins. Twenty female rats per group were fed with 25 µg/kg of diet of vitamin D3 (1,000 UI vitamin D/kg diet) or with 25 µg/kg diet of 25-OH-D3. We analyzed 25-OH-D3 levels in maternal and fetal plasma; protein levels of vitamin D receptor (VDR), fatty acid translocase (FAT), and scavenger-receptor class B type-1 (SR-B1) in both maternal liver and placenta; and protein levels of VDR and Glutamate decarboxylase (GAD67) in fetal brain. 25-OH-D3 doubled the concentration of 25-OH-D3 in both maternal and fetal plasma compared to vitamin D3. In addition, maternal liver VDR, FAT, and SR-BI increased significantly in the 25-OH-D3 group, but no changes were found in the placenta. Interestingly, 25-OH-D3 decreased GAD67 expression in the fetal brain and it also tended to decrease VDR (P = 0.086). In conclusion, 25-OH-D3 provided better vitamin D availability for both mother and fetus when administered during pregnancy compared to vitamin D3. No adverse effects on pregnancy outcomes were observed. The effects of 25-OH-D3 on the expression of VDR and GAD67 in fetal brain require further investigation.

Increased Breastfeeding Proportion Is Associated with Improved Gross Motor Skills at 3-5 Years of Age: A Pilot Study.

Breastmilk provides key nutrients and bio-active factors that contribute to infant neurodevelopment. Optimizing maternal nutrition could provide further benefit to psychomotor outcomes. Our observational cohort pilot study aims to determine if breastfeeding extent and breastmilk nutrients correlate with psychomotor outcomes at school age. The breastfeeding proportion at 3 months of age and neurodevelopmental outcomes at 3-5 years of age were recorded for 33 typically developing newborns born after uncomplicated pregnancies. The association between categorical breastfeeding proportion and neurodevelopmental outcome scores was determined for the cohort using a Spearman correlation with and without the inclusion of parental factors. Vitamin E and carotenoid levels were determined in breastmilk samples from 14 of the mothers. After the inclusion of parental education and income as covariates, motor skill scores positively correlated with breastmilk contents of α-tocopherol (Spearman coefficient 0.88, p-value = 0.02), translutein (0.98, p-value = 0.0007), total lutein (0.92, p-value = 0.01), and zeaxanthin (0.93, p-value = 0.0068). Problem solving skills negatively correlated with the levels of the RSR enantiomer of α-tocopherol (-0.86, p-value = 0.03). Overall, higher exposure to breastfeeding was associated with improved gross motor and problem-solving skills at 3-5 years of age. The potential of α-tocopherol, lutein, and zeaxanthin intake to provide neurodevelopmental benefit is worthy of further investigation.

A Role for Data Science in Precision Nutrition and Early Brain Development.

Multimodal brain magnetic resonance imaging (MRI) can provide biomarkers of early influences on neurodevelopment such as nutrition, environmental and genetic factors. As the exposure to early influences can be separated from neurodevelopmental outcomes by many months or years, MRI markers can serve as an important intermediate outcome in multivariate analyses of neurodevelopmental determinants. Key to the success of such work are recent advances in data science as well as the growth of relevant data resources. Multimodal MRI assessment of neurodevelopment can be supplemented with other biomarkers of neurodevelopment such as electroencephalograms, magnetoencephalogram, and non-imaging biomarkers. This review focuses on how maternal nutrition impacts infant brain development, with three purposes: (1) to summarize the current knowledge about how nutrition in stages of pregnancy and breastfeeding impact infant brain development; (2) to discuss multimodal MRI and other measures of early neurodevelopment; and (3) to discuss potential opportunities for data science and artificial intelligence to advance precision nutrition. We hope this review can facilitate the collaborative march toward precision nutrition during pregnancy and the first year of life.

Carotenoids improve the development of cerebral cortical networks in formula-fed infant macaques.

Nutrition during the first years of life has a significant impact on brain development. This study characterized differences in brain maturation from birth to 6 months of life in infant macaques fed formulas differing in content of lutein, ß-carotene, and other carotenoids using Magnetic Resonance Imaging to measure functional connectivity. We observed differences in functional connectivity based on the interaction of diet, age and brain networks. Post hoc analysis revealed significant diet-specific differences between insular-opercular and somatomotor networks at 2 months of age, dorsal attention and somatomotor at 4 months of age, and within somatomotor and between somatomotor-visual and auditory-dorsal attention networks at 6 months of age. Overall, we found a larger divergence in connectivity from the breastfeeding group in infant macaques fed formula containing no supplemental carotenoids in comparison to those fed formula supplemented with carotenoids. These findings suggest that carotenoid formula supplementation influences functional brain development.