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Effects of micronutrients on brain connectivity are incompletely understood. Analyzing human milk samples across global populations, we identified the carbocyclic sugar myo -inositol as a component that promotes brain development. We determined that it is most abundant in human milk during early lactation when neuronal connections rapidly form in the infant brain. Myo -inositol promoted synapse abundance in human excitatory neurons as well as cultured rat neurons and acted in a dose-dependent manner. Mechanistically, myo -inositol enhanced the ability of neurons to respond to transsynaptic interactions that induce synapses. Effects of myo -inositol in the developing brain were tested in mice, and its dietary supplementation enlarged excitatory postsynaptic sites in the maturing cortex. Utilizing an organotypic slice culture system, we additionally determined that myo -inositol is bioactive in mature brain tissue, and treatment of organotypic slices with this carbocyclic sugar increased the number and size of postsynaptic specializations and excitatory synapse density. This study advances our understanding of the impact of human milk on the infant brain and identifies myo -inositol as a breast milk component that promotes the formation of neuronal connections.

Growth patterns of breastfed infants show substantial inter-individual differences, partly influenced by breast milk (BM) nutritional composition. However, BM nutritional composition does not accurately indicate BM nutrient intakes. This study aimed to examine the associations between both BM intake volumes and macronutrient intakes with infant growth. Mother-infant dyads ( n 94) were recruited into the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) from a single maternity hospital at birth; all infants received exclusive breast-feeding (EBF) for at least 6 weeks. Infant weight, length and skinfolds thicknesses (adiposity) were repeatedly measured from birth to 12 months. Post-feed BM samples were collected at 6 weeks to measure TAG (fat), lactose (carbohydrate) (both by 1 H-NMR) and protein concentrations (Dumas method). BM intake volume was estimated from seventy infants between 4 and 6 weeks using dose-to-the-mother deuterium oxide ( 2 H 2 O) turnover. In the full cohort and among sixty infants who received EBF for 3+ months, higher BM intake at 6 weeks was associated with initial faster growth between 0 and 6 weeks ( β + se 3·58 + 0·47 for weight and 4·53 + 0·6 for adiposity gains, both P < 0·0001) but subsequent slower growth between 3 and 12 months ( β + se - 2·27 + 0·7 for weight and -2·65 + 0·69 for adiposity gains, both P < 0·005). BM carbohydrate and protein intakes at 4-6 weeks were positively associated with early (0-6 weeks) but tended to be negatively related with later (3-12 months) adiposity gains, while BM fat intake showed no association, suggesting that carbohydrate and protein intakes may have more functional relevance to later infant growth and adiposity.

Butyrate in human milk (HM) has been suggested to reduce excessive weight and adipo-sity gains during infancy. However, HM butyrate's origins, determinants, and its influencing mechanism on weight gain are not completely understood. These were studied in the prospective longitudinal Cambridge Baby Growth and Breastfeeding Study (CBGS-BF), in which infants ( n = 59) were exclusively breastfed for at least 6 weeks. Infant growth (birth, 2 weeks, 6 weeks, 3 months, 6 months, and 12 months) and HM butyrate concentrations (2 weeks, 6 weeks, 3 months, and 6 months) were measured. At age 6 weeks, HM intake volume was measured by deuterium-labelled water technique and HM microbiota by 16S sequencing. Cross-sectionally at 6 weeks, HM butyrate was associated with HM microbiota composition ( p = 0.036) although no association with the abundance of typical butyrate producers was detected. In longitudinal analyses across all time points, HM butyrate concentrations were overall negatively associated with infant weight and adiposity, and associations were stronger at younger infant ages. HM butyrate concentration was also inversely correlated with HM intake volume, supporting a possible mechanism whereby butyrate might reduce infant growth via appetite regulation and modulation of HM intake.

Growth and nutrition during early life have been strongly linked to future health and metabolic risks. The Cambridge Baby Growth Study (CBGS), a longitudinal birth cohort of 2229 mother-infant pairs, was set up in 2001 to investigate early life determinant factors of infant growth and body composition in the UK setting. To carry out extensive profiling of breastmilk intakes and composition in relation to infancy growth, the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) was established upon the original CBGS. The strict inclusion criteria were applied, focusing on a normal birth weight vaginally delivered infant cohort born of healthy and non-obese mothers. Crucially, only infants who were exclusively breastfed for the first 6 weeks of life were retained in the analysed study sample. At each visit from birth, 2 weeks, 6 weeks, and then at 3, 6, 12, 24, and 36 months, longitudinal anthropometric measurements and blood spot collections were conducted. Infant body composition was assessed using air displacement plethysmography (ADP) at 6 weeks and 3 months of age. Breast milk was collected for macronutrients and human milk oligosaccharides (HMO) measurements. Breast milk intake volume was also estimated, as well as sterile breastmilk and infant stool collection for microbiome study.

A bstract: Since originally isolated in 1899, the genus Bifidobacterium has been demonstrated to predominate in the gut microbiota of breastfed infants and to benefit the host by accelerating maturation of the immune response, balancing the immune system to suppress inflammation, improving intestinal barrier function, and increasing acetate production. In particular, Bifidobacterium longum subspecies infantis ( B. infantis ) is well adapted to the infant gut and has co-evolved with the mother-infant dyad and gut microbiome, in part due to its ability to consume complex carbohydrates found in human milk. B. infantis and its human host have a symbiotic relationship that protects the preterm or term neonate and nourishes a healthy gut microbiota prior to weaning. To provide benefits associated with B. infantis to all infants, a number of commercialized strains have been developed over the past decades. As new ingredients become available, safety and suitability must be assessed in preclinical and clinical studies. Consideration of the full clinical evidence for B. infantis use in pediatric nutrition is critical to better understand its potential impacts on infant health and development. Herein we summarize the recent clinical studies utilizing select strains of commercialized B. infantis ., Competing Interests: M.C., N.S., J.L.W. and S.S.W. are employed by the study sponsor, Mead Johnson Nutrition. Mead Johnson Nutrition’s parent company, Reckitt Benckiser, entered into a partnership with Evolve Biosystems in December 2019; however, this had no influence on the outcome of the review. J.A.V. has been a consultant for Mead Johnson Nutrition.

Background: This study was carried out to evaluate enteral feeding advancement and tolerance in preterm infants receiving one of two marketed formulas: intact protein preterm formula (IPF) or extensively hydrolyzed formula (EHF) for the first 14 feeding days., Methods: Primary outcome was days to full enteral feeding (≥140 mL/kg/day). Per protocol analyses included the following: all participants who met study entrance criteria and completed study feeding (primary) and those who received ≥75% enteral intake from study formula (subset). Mothers were encouraged to provide their breast milk., Results: Of the 65 enrolled (IPF: n = 32; EHF: n = 33), 60 completed study feeding per protocol (IPF: n = 30; EHF: n = 30), 37 (62%) received predominantly breast milk, and 23 (38%) received ≥75% study formula intake (IPF: n = 11; EHF: n = 12). No group differences were detected in tolerance measures. No necrotizing enterocolitis (NEC) was reported. Median time to achievement of full enteral feeding was significantly shorter for the IPF vs. EHF group (day 10 vs. 14, p < 0.05) (subset analysis). Mean enteral intake significantly increased by day 14 for the IPF group ( p < 0.05), reflecting group divergence as achieved feeding volumes increased., Conclusions: Results suggest shorter time to full enteral feeding and higher feeding volume achieved by study end in preterm infants receiving intact protein preterm formula versus extensively hydrolyzed formula.

Background: Human milk feeding is encouraged for all infants; however, the mammary gland depends on maternal dietary intake of vitamins A, B1, B2, B6, B12, D, docosahexaenoic acid (DHA), choline, and iodine. Nutrition support team knowledge of maternal feeding guidelines for these nutrient sources can therefore impact infant intake. We hypothesized that these key nutrients for lactation in the mother's diet would be less than the dietary guidelines in the United States., Methods: This was a secondary analysis of nutrition data collected during a randomized, controlled trial. Dietary records were analyzed from 16 mothers (13 with singleton and 3 with multiple births) completing the study. Mean dietary intakes of selected nutrients were calculated and compared with the current dietary reference intakes., Results: Mean maternal dietary intake for singletons was significantly (P < .05) lower than the dietary reference intakes for (vitamin A (58%), vitamin D (44%), and choline (58%);) DHA comprised only 5% of the current expert recommendation. Based on singleton recommendations, mothers to twins consumed an adequate intake except for DHA., Conclusions: Women providing breast milk for singleton preterm infants did not consume dietary reference intakes for key nutrients. Twin mothers' diets were adequate except for DHA, but these guidelines are based on singleton pregnancies and remain poorly understood for twin needs. The nutrition support team can have a unique role in maternal dietary education to impact human milk nutrient delivery to the infant., (© 2018 American Society for Parenteral and Enteral Nutrition.)

Background: An understudied component of the diet, branched-chain fatty acids (BCFAs) are distinctive saturated fatty acids that may have an important influence on health. Human-milk fatty acid composition is known to differ worldwide, but comparative data are lacking on BCFAs., Objective: We tested the hypotheses that concentrations of BCFAs in human milk differ between populations and are associated with maternal diet., Design: We surveyed the BCFA composition of samples collected as part of a standardized, prospective study of human-milk composition. Mothers were enrolled from 3 urban populations with differing diets: Cincinnati, Ohio; Shanghai, China; and Mexico City, Mexico. Enrollment was limited to healthy mothers of term singleton infants. We undertook a cross-sectional analysis of milk from all women with samples at postpartum week 4 (n = 359; ∼120 women/site). Fatty acids were extracted from milk by using a modified Bligh-Dyer technique and analyzed by gas chromatography. Statistical analysis was performed by ANOVA and Tobit regression. For Cincinnati mothers, 24-h diet recalls were analyzed in relation to the individual BCFA concentrations measured in milk samples., Results: Total BCFAs in milk differed by site, with the highest concentration in Cincinnati followed by Mexico City and Shanghai (mean ± SE: 7.90 ± 0.41, 6.10 ± 0.36, and 4.27 ± 0.25 mg/100 mL, respectively; P < 0.001). Site differences persisted after delivery mode, maternal age, and body mass index were controlled for. The individual concentrations of iso-14:0, iso-16:0, iso-18:0, anteiso-15:0, and anteiso-17:0 also differed between sites. Milk concentrations of iso-14:0 and anteiso-15:0 were associated with maternal intake of dairy; iso-16:0 was associated with maternal intakes of dairy and beef., Conclusions: BCFA concentrations in milk at 4 wk postpartum differed between mothers from Cincinnati, Shanghai, and Mexico City. Variations in human-milk BCFAs are influenced by diet. The impact of BCFAs on infant health warrants investigation., (© 2017 American Society for Nutrition.)

Emerging evidence indicates that carotenoids may have particular roles in infant nutrition and development, yet data on the profile and bioavailability of carotenoids from human milk remain sparse. Milk was longitudinally collected at 2, 4, 13, and 26 weeks postpartum from twenty mothers each in China, Mexico, and the USA in the Global Exploration of Human Milk Study (n = 60 donors, n = 240 samples). Maternal and neonatal plasma was analyzed for carotenoids from the USA cohort at 4 weeks postpartum. Carotenoids were analyzed by HPLC and total lipids by Creamatocrit. Across all countries and lactation stages, the top four carotenoids were lutein (median 114.4 nmol/L), β-carotene (49.4 nmol/L), β-cryptoxanthin (33.8 nmol/L), and lycopene (33.7 nmol/L). Non-provitamin A carotenoids (nmol/L) and total lipids (g/L) decreased (p<0.05) with increasing lactation stage, except the provitamin A carotenoids α- and β-cryptoxanthin and β-carotene did not significantly change (p>0.05) with lactation stage. Total carotenoid content and lutein content were greatest from China, yet lycopene was lowest from China (p<0.0001). Lutein, β-cryptoxanthin, and β-carotene, and lycopene concentrations in milk were significantly correlated to maternal plasma and neonatal plasma concentrations (p<0.05), with the exception that lycopene was not significantly associated between human milk and neonatal plasma (p>0.3). This enhanced understanding of neonatal exposure to carotenoids during development may help guide dietary recommendations and design of human milk mimetics.

We report the fatty acid composition of mother׳s own human milk from one of the largest US cohorts of lactating mothers of preterm infants. Milk fatty acid data were used as a proxy for intake at enrollment in infants (n=150) who received human milk with a powder human milk fortifier (HMF; Control) or liquid HMF [LHMF; provided additional 12mg docosahexaenoic acid (DHA), 20mg arachidonic acid (ARA)/100mL human milk]. Mothers provided milk samples (n=129) and reported maternal DHA consumption (n=128). Infant blood samples were drawn at study completion (Study Day 28). Human milk and infant PPL fatty acids were analyzed using capillary column gas chromatography. DHA and ARA were within ranges previously published for US term and preterm human milk. Compared to Control HMF (providing no DHA or ARA), human milk fortified with LHMF significantly increased infant PPL DHA and ARA and improved preterm infant DHA and ARA status., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lactoferrin is the second most abundant whey protein in human milk and is known for its functional benefits, particularly antimicrobial activities. We report a comprehensive evaluation of the published literature on quantitative changes in lactoferrin in term and preterm human milk through the course of lactation. We also considered methods used to quantify lactoferrin. We critically evaluated 94 articles on human milk with 52 meeting study inclusion criteria (2724 women). A descriptive analysis of the data was performed. Lactoferrin concentration was highest during early lactation and rapidly declined to remain relatively unchanged from 1 month to 2 years of lactation. The unweighted mean of mean (±SEM) concentrations of lactoferrin in early milk (<28 days lactation) was 4.91 ± 0.31 g/L (range of means 0.34-17.94 g/L; median 4.03). For mature milk, the mean of means was 2.10 ± 0.87 g/L (range of means 0.44-4.4 g/L; median 1.91). The majority of data were derived from Europe with fewer studies from Africa and South America. There was a paucity of data on preterm milk. This comprehensive dataset explains in detail the longitudinal changes of lactoferrin concentrations in human milk throughout the world and briefly describes factors that may influence these concentrations.

Human milk proteins provide essential nutrition for growth and development, and support a number of vital developmental processes in the neonate. A complete understanding of the possible functions of human milk proteins has been limited by incomplete knowledge of the human milk proteome. In this report, we have analyzed the proteomes of whey from human transitional and mature milk using ion-exchange and SDS-PAGE based protein fractionation methods. With a larger-than-normal sample loading approach, we are able to largely extend human milk proteome to 976 proteins. Among them, 152 proteins are found to render significant regulatory changes between transitional milk and mature milk. We further found that immunoglobulins sIgA and IgM are more abundant in transitional milk, whereas IgG is more abundant in mature milk, suggesting a transformation in defense mechanism from newborns to young infants. Additionally, we report a more comprehensive view of a complement system and associated regulatory apparatus in human milk, demonstrating the presence and function of a system similar to that found in the circulation but prevailed by alternative pathway in complement activation. Proteins involved in various aspects of carbohydrate metabolism are also described, revealing either a transition in milk functionality to accommodate carbohydrate-rich secretions as lactation progresses, or a potentially novel way of looking at the metabolic state of the mammary tissue. Lately, a number of extracellular matrix (ECM) proteins are found to be in higher abundance in transitional milk and may be relevant to the development of infants' gastrointestinal tract in early life. In contrast, the ECM protein fibronectin and several of the actin cytoskeleton proteins that it regulates are more abundant in mature milk, which may indicate the important functional role for milk in regulating reactive oxygen species.