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Premature infants, given their limited reserves, heightened energy requirements, and susceptibility to nutritional deficits, require specialized care. AIM: To examine the complex interplay between nutrition and neurodevelopment in premature infants, underscoring the critical need for tailored nutritional approaches to support optimal brain growth and function. DATA SOURCES: PubMed and MeSH and keywords: preterm, early nutrition, macronutrients, micronutrients, human milk, human milk oligosaccharides, probiotics AND neurodevelopment or neurodevelopment outcomes. Recent articles were selected according to the authors' judgment of their relevance. Specific nutrients, including macro (amino acids, glucose, and lipids) and micronutrients, play an important role in promoting neurodevelopment. Early and aggressive nutrition has shown promise, as has recognizing glucose as the primary energy source for the developing brain. Long-chain polyunsaturated fatty acids, such as DHA, contribute to brain maturation, while the benefits of human milk, human milk oligosaccharides, and probiotics on neurodevelopment via the gut-brain axis are explored. This intricate interplay between the gut microbiota and the central nervous system highlights human milk oligosaccharides' role in early brain maturation. CONCLUSIONS: Individualized nutritional approaches and comprehensive nutrient strategies are paramount to enhancing neurodevelopment in premature infants, underscoring human milk's potential as the gold standard of nutrition for preterm infants.

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Oligosaccharides are significant in mammalian milk, where they serve as prebiotics that promote the growth of beneficial gut bacteria in infants. Comprehensive research of milk oligosaccharides requires precise and validated analytical methods for compositional studies. To address this need, the focus of our study was to develop and validate an analytical method using UPLC-MS/MS to quantify seven specific oligosaccharides found in mammalian milk. The developed and optimized method has adequate linearity, accuracy, and precision parameters. The detection (LOD) and quantification (LOQ) limits for the seven compounds ranged from 0.0018 to 0.0030 µg/mL and 0.0054-0.0063 µg/mL, respectively. The sample preparation method yielded recovery rates above 90.5 %. Furthermore, no significant matrix effect was observed. The validated method was successfully applied to human, goat, and bovine milk samples, demonstrating its proficiency in identifying variances in the concentration of oligosaccharides across different mammals. This versatile method will allow future research about factors affecting oligosaccharide composition.

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BACKGROUND: Human milk oligosaccharides (HMOs) are unconjugated glycans associated with infant health and development. OBJECTIVES: To investigate the associations between HMO concentrations at 1 month and infant development throughout the first year of life. METHODS: A prospective cohort of Brazilian women between 18-40 years of age and their infants was studied from baseline (between 28-35 gestational weeks) and followed at 1 (n = 73), 6 (n = 51), and 12 months (n = 45). A total of 19 HMOs were quantified by HPLC with fluorescence detection. Infant development was evaluated by the Brazilian Ages and Stages Questionnaire. A directed acyclic graph was used to define the minimally sufficient adjustment (gestational age at birth, gestational weight gain, prepregnancy BMI, maternal age, parity, and the mode of breastfeeding at 1 month). Cox regression models with HRs and Benjamini-Hochberg multiple corrections were performed to estimate associations of HMOs with the cumulative risk of inadequate development for 5 developmental domains or for ≥2 developmental domains in all women and in the subset of secretor women (defined as the presence or near absence of 2'-fucosyllactose and lacto-N-fucopentaose I). RESULTS: The multivariate models with multiple corrections revealed an inverse association between lacto-N-tetrose (LNT) and the risk of inadequate development for personal-social skills (0.06; 95% CI: 0.01-0.76) and for ≥2 developmental domains (0.06; 95% CI: 0.01-0.59). The secretor mothers analysis also showed inverse associations with slightly different results for personal-social skills (0.09; 95% CI: 0.02-0.84) and ≥2 developmental domains (0.05; 95% CI: 0.01-0.70). CONCLUSIONS: Higher concentrations of LNT HMOs in Brazilian women are associated with their infants being less likely to be at risk of inadequate development for personal-social skills or for ≥2 developmental domains during the first year of life.

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BACKGROUND: Oligosaccharides are the third most abundant component in human milk. They are a potential protective agent against neonatal sepsis. OBJECTIVES: We aimed to explore the association between human milk oligosaccharides (HMOs) and late-onset sepsis in very-low-birth-weight infants, and to describe the composition and characteristics of HMOs in Peruvian mothers of these infants. METHODS: This is a secondary data analysis of a randomized clinical trial. We conducted a retrospective cohort study of mothers and their very-low-birth-weight (<1500 g) infants with ≥1 milk sample and follow-up data for >30 d. HMOs were measured by high performance liquid chromatography (HPLC). We used factor analysis and the Mantel-Cox test to explore the association between HMOs and late-onset neonatal sepsis. RESULTS: We included 153 mother-infant pairs and 208 milk samples. Overall, the frequency of the secretor phenotype was 93%. Secretors and nonsecretors were defined by the presence and near-absence of α1-2-fucosylated HMOs, respectively. The most abundant oligosaccharides were 2'-fucosyllactose, lacto-N-fucopentaose (LNFP) I, and difucosyllacto-N-tetraose in secretors and lacto-N-tetraose and LNFP II in nonsecretors. Secretors had higher amounts of total oligosaccharides than nonsecretors (11.45 g/L; IQR: 0.773 g/L compared with 8.04 g/L; IQR: 0.449 g/L). Mature milk samples were more diverse in terms of HMOs than colostrum (Simpson's Reciprocal Diversity Index). We found an association of factor 3 in colostrum with a reduced risk of late-onset sepsis (HR: 0.63; 95% CI: 0.41, 0.97). Fucosyl-disialyllacto-N-hexose (FDSLNH) was the only oligosaccharide correlated to factor 3. CONCLUSIONS: These findings suggest that concentrations of different HMOs vary from one individual to another according to their lactation period and secretor status. We also found that FDSLNH might protect infants with very low birth weight from late-onset neonatal sepsis. Confirming this association could prove 1 more mechanism by which human milk protects infants against infections and open the door to clinical applications of HMOs.This trial was registered at clinicaltrials.gov as NCT01525316.

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Human milk oligosaccharide (HMO) composition varies throughout lactation and can be influenced by maternal characteristics. This study describes HMO variation up to three months postpartum and explores the influences of maternal sociodemographic and anthropometric characteristics in a Brazilian prospective cohort. We followed 101 subjects from 28-35 gestational weeks (baseline) and throughout lactation at 2-8 (visit 1), 28-50 (visit 2) and 88-119 days postpartum (visit 3). Milk samples were collected at visits 1, 2 and 3, and 19 HMOs were quantified usinghigh-performance liquid chromatography with fluorescence detection (HPLC-FL). Friedman post-hoc test, Spearman rank correlation for maternal characteristics and HMOs and non-negative matrix factorization (NMF) were used to define the HMO profile. Most women were secretors (89.1%) and presented high proportion of 2'-fucosyllactose (2ꞌFL) at all three sample times, while lacto-N-tetraose (LNT, 2-8 days) and lacto-N-fucopentaose II (LNFPII, 28-50 and 88-119 days) were the most abundant HMOs in non-secretor women. Over the course of lactation, total HMO weight concentrations (g/L) decreased, but total HMO molar concentrations (mmol/L) increased, highlighting differential changes in HMO composition over time. In addition, maternal pre-pregnancy body mass index (BMI) and parity influence the HMO composition in healthy women in this Brazilian cohort.

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Los oligosacáridos de la leche materna (HMOs) son unas 200 moléculas distintas sintetizadas y secretadas por la glándula mamaria a partir de lactosa a la que diversos enzimas unen monosacáridos simples (glucosa, galactosa, n-acetil galactosamina, fucosa y ácido siálico). Estas uniones y sus diferentes orientaciones espaciales generan una gran diversidad de estructuras químicas y de funcionalidades. La concentración de los HMOs es mayor en el calostro (± 25 g/L), está relacionada con la duración del embarazo y la lactancia: disminuyen progresivamente hasta la mitad de los niveles iniciales. La genética materna influye en el perfil de algunos HMOs; el gen FUT2, que codifica la síntesis de la fucosiltransferasa 2 (FUT2) condiciona el llamado carácter secretor en 75-85% de las mujeres y hace que los antígenos del grupo ABO(H) sean secretados en los líquidos orgánicos (saliva, lágrimas, semen). La ausencia de actividad del gen FUT2 condiciona el carácter no-secretor (15-25% de las mujeres). La actividad del gen FUT3 condiciona la actividad de la fucosiltransferasa 3 (FUT3) que se asocia con el grupo sanguíneo Lewis+ mientras que su ausencia caracteriza a los portadores como Lewis 0. Los HMOs son absorbidos a nivel del intestino como trazas (1%) pero incluso en esas cantidades ejercerían efectos sistémicos.

Human milk oligosaccharides (HMOs) are a family of some 200 different molecules synthesized by the mammary gland. At the core is a molecule of lactose, which is linked by different enzymes to glucose, galactose, n-acetyl galactosamine, fucose or sialic acid. These linkages and their different spatial orientation generate, besides the possibilities of numerous chemical structures, the potential for different spatial isomers. The concentration of HMOs in human milk depends on pregnancy and breastfeeding duration. They are highest in colostrum (± 25 g/L) and decrease over time to half this initial level. Maternal genetics modifies the concentration and profile of some oligosaccharides. For example, the FUT2 gene codifies the synthesis of fucosyltransferase 2 (FUT2) whose activity generates the secretor status for antigens of the ABO(H) blood group in organic fluids (saliva, milk, tears, semen) among 75-85% of the carriers of the trait. The absence of activity of the FUT2 gene conditions the non-secretor status (15-25% of women). The FUT3 gene regulates the activity of the fucosyltransferase 3 (FUT3) that is associated with the Lewis blood group. Traces of HMOs (1%) are absorbed in the intestinal tract, however, they exert important systemic effects even at low concentrations.

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Durante los primeros meses de vida, los oligosacáridos de la leche materna (HMOs) aportados por la leche materna participan en procesos asociados con la maduración de tejidos y sistemas del tubo digestivo, modulan algunos de sus procesos metabólicos y ejercen efectos prebióticos y antimicrobianos. Otros efectos estudiados son su contribución a la instalación, desarrollo y estimulación de la microbiota residente con predomino de Bifidobacterium y Bacteroides, con efectos protectores frente a posibles colonizaciones o patologías por enteropatógenos (bacterianas, virus o parásitarias) que pueden actuar nivel local en el tubo digestivo, pero también pueden influir a nivel sistémico. Los HMOs modularían el desarrollo de la inmunidad innata y adaptativa, y probablemente previenen el desarrollo de fenómenos de atopia/alergia. Una patología propia de la etapa neonatal de los prematuros es la enterocolitis necrosante y algunos HMOs podrían disminuir el riesgo de su manifestación. Las actividades de los oligosacáridos de la leche materna contribuyen a la adaptación del lactante a los desafíos que plantea su entorno incluyendo la prevención de algunas patologías en edades posteriores, como es el caso de la diabetes tipo 1 y la obesidad.

During the first months of life, breast milk oligosaccharides (HMOs) stimulate development of the gastrointestinal tract in newborns and young infants; they modulate its metabolism and transport capabilities. Additionally, they exert prebiotic and antimicrobial activities and contribute to the development of the resident intestinal microbiota with a predominance of Bifidobacterium and Bacteroides and protect from colonization and infections by enteropathogens (bacteria, virus or parasites). It is highly probable that their activities extend beyond infancy and persist into adult life. HMOs stimulate the development of the innate and adaptive immune systems and decrease the risk of atopy/allergy. Their intake has been associated with a degree of protection against as necrotizing enterocolitis among premature infants. HMOs contribute to the long term adaptation and protection of newborn infants to unfavorable conditions of their environment and in this way may contribute to protect breastfed infants from type 1 diabetes and obesity.

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Actualmente existe la capacidad de sintetizar oligosacáridos de leche materna (HMOs) en cantidades importantes a partir de hidratos de carbono simples para emplear en estudios en lactantes e incluso en adultos. En los lactantes las fórmulas que contienen HMOs mantienen velocidades normales de incremento del peso, largo corporal y perímetro cefálico con variaciones del largo corporal, el peso y las masas magra y grasa característicos de ciertos HMOs. Algunos HMOs estimulan in vitro en monocitos estimulan en sangre periférica marcadores de inflamación semejantes a los observados con estímulos iguales en lactantes amamantados. Los HMOs están asociados con disminuciones del riesgo de enterocolitis necrosante en prematuros y en ratones. En seguimientos por cuatro meses, lactantes alimentados con una fórmula con 2' fucosil lactosa (2'FL) y lacto-N- neotetraosa (LNnT), mostraron patrones de crecimiento del peso, el largo corporal y el perímetro cefálico comparables a los de un grupo control que recibió la misma fórmula sin HMOs; tampoco hubo diferencias en sus patologías intercurrentes. Las concentraciones de HMOs en la leche pueden variar dependiendo de la localidad geográfica donde fueron obtenidas o el estado de la nutrición materna estos factores deben ser tenidos en cuenta al planificar estudios en grupos de población.

Human milk oligosaccharides (HMOs) are currently synthesized in amounts allowing studies with large numbers and longer follow ups of infants and adults. HMOs have been administered to adults in amounts of up to 20 grams per day without associated symptoms of gastrointestinal fermentation. The microbiota of these individuals presents changes considered positive: increases of Bifidobacterium and decreases of Firmicutes and Proteabacteria. A recent study in infants showed that specific HMOs modulate the growth of lean and fat mass or, on the contrary, decrease adipose tissue mass through not well characterized mechanisms. A study in infants fed for 4 months a formula containing both 2'-O-Fucosyllactose (2'-FL) and Lacto-N-neotetraose (LNnT) with a follow up of 8 months showed that body length, weight gain and head perimeter increased at rates comparable to those of breastfed infants or those fed a control formula. No differences in the incidence of upper and lower respiratory tract infections, skin allergies or use of antibiotics was observed. In the planning of population studies it is important to consider that in ethnically different populations breast milk may contain different profiles of HMOs depending on the area where live, suggesting that some of these profiles may be influenced by consanguinity.

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Human milk oligosaccharides (HMOs) are multifunctional carbohydrates naturally present in human milk that act as prebiotics, prevent pathogen binding and infections, modulate the immune system and may support brain development in infants. HMOs composition is very individualized and differences in HMOs concentrations may affect the infant's health. HMOs variability can be partially explained by the activity of Secretor (Se) and Lewis (Le) genes in the mother, but non-genetic maternal factors may also be involved. In this cross-sectional, observational study, 78 single human milk samples ranging from 17 to 76 days postpartum (median: 32 days, IQR: 25-46 days) were collected from breastfeeding Brazilian women, analyzed for 16 representative HMOs by liquid chromatography coupled to mass spectrometry and associations between maternal and infant factors with HMOs concentrations were investigated. HMOs concentrations presented a high variability even in women with the same SeLe phenotype and associations with maternal allergic disease, time postpartum and with infant's weight, weight gain and sex. Overall, we present unprecedented data on HMOs concentrations from breastfeeding Brazilian women and novel associations of maternal allergic disease and infant's sex with HMOs concentrations. Differences in HMOs composition attributed to maternal SeLe phenotype do not impact infant growth, but higher concentrations of specific HMOs may protect against excessive weight gain.

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Human milk oligosaccharides (HMOs) are free glycans naturally present in human milk that act as prebiotics, prevent pathogen binding, modulate the immune system and support brain development in infants. The HMOs composition and concentrations vary significantly among different women mainly because of the direct influence of the Secretor and Lewis phenotypes on HMOs biosynthesis. Analytical methods that can identify the differences in the HMOs composition and concentrations are a fundamental tool in HMOs research. This paper describes a simple HMOs extraction and analysis for the simultaneous and absolute quantification of neutral and acidic HMOs by graphitized carbon liquid chromatography-electrospray ionization-mass spectrometry. This method was validated and applied to analyze HMOs in the human milk obtained from 10 women. This method allows accurate and reliable quantification of HMOs and can be used to determine differences in HMOs concentrations throughout lactation and among women with different Secretor and Lewis phenotypes.

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Breast milk is the gold standard in infant nutrition. In addition to provide essential nutrients for the newborn, it contains multiple bioactive molecules that provide protection and stimulate proper development. Human milk oligosaccharides (HMO) are complex carbohydrates abundant in breast milk. Intriguingly, these molecules do not provide energy to the infant. Instead, these oligosaccharides are key to guide and support the assembly of a healthy gut microbiome in the infant, dominated by beneficial gut microbes such as Bifidobacterium. New analytical methods for glycan analysis, and next-generation sequencing of microbial communities, have been instrumental in advancing our understanding of the positive role of breast milk oligosaccharides on the gut microbiome, and the genomics and molecular strategies of Bifidobacterium to utilize these oligosaccharides. Moreover, novel approaches to simulate the impact of HMO on the gut microbiome have been described and successfully validated, including the incorporation of synthetic HMO and bovine milk oligosaccharides to infant formula. This review discusses recent advances regarding the influence of HMO in promoting a healthy gut microbiome, with emphasis in the molecular basis of the enrichment in beneficial Bifidobacterium, and novel approaches to replicate the effect of HMO using synthetic or bovine oligosaccharides.

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Composition of the gut microbiome is influenced by diet. Milk or formula oligosaccharides act as prebiotics, bioactives that promote the growth of beneficial gut microbes. The influence of prebiotics on microbial interactions is not well understood. Here we investigated the transformation of prebiotics by a consortium of four representative species of the infant gut microbiome, and how their interactions changed with dietary substrates. First, we optimized a culture medium resembling certain infant gut parameters. A consortium containing Bifidobacterium longum subsp. infantis, Bacteroides vulgatus, Escherichia coli and Lactobacillus acidophilus was grown on fructooligosaccharides (FOS) or 2'-fucosyllactose (2FL) in mono- or co-culture. While Bi. infantis and Ba. vulgatus dominated growth on 2FL, their combined growth was reduced. Besides, interaction coefficients indicated strong competition, especially on FOS. While FOS was rapidly consumed by the consortium, B. infantis was the only microbe displaying significant consumption of 2FL. Acid production by the consortium resembled the metabolism of microorganisms dominating growth in each substrate. Finally, the consortium was tested in a bioreactor, observing similar predominance but more pronounced acid production and substrate consumption. This study indicates that the chemical nature of prebiotics modulate microbial interactions in a consortium of infant gut species.

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A Organização Mundial da Saúde (OMS) afirma que "aleitamento materno é uma forma inigualável de prover alimento ideal para o crescimento e desenvolvimento saudável das crianças". A utilização de fórmulas infantis é uma alternativa para lactentes que não podem ser ou são parcialmente amamentados, após terem sido utilizadas todas as técnicas possíveis, informativa e de suporte para garantir o aleitamento materno. Inúmeras fórmulas lácteas, com as mais diferentes composições e indicações, têm sido desenvolvidas numa busca incessante de encontrar a fórmula que se aproxime das características do leite materno. Esta multiplicidade de produtos tem exigido, por parte da OMS/FAO, das principais sociedades científicas mundiais e das agências reguladoras de vários países, a elaboração de normas técnicas para a produção e utilização destes alimentos. Sabe-se que a complexidade do leite materno, principalmente no que diz respeito aos seus componentes imunológicos, biodisponibilidade dos nutrientes e oscilação na composição ao longo do aleitamento materno, faz com que seja impossível mimetizar seus incríveis benefícios para o desenvolvimento e saúde do lactente a longo prazo. Porém, diversos avanços já ocorreram no desenvolvimento das fórmulas infantis, principalmente em relação a qualidade do perfil de aminoácidos e redução das concentrações de proteínas, quando comparados às formulações disponíveis no passado. No entanto, futuras inovações em relação a estrutura lipídica, assim como, do microbioma e dos oligossacarídeos do leite humano ainda são esperados nas fórmulas infantis das próximas gerações.

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OBJECTIVE: To determine the impact of 2 probiotic bifidobacteria on the fecal microbiota of premature infants fed either human milk or formula. STUDY DESIGN: In the first of two phase 1 clinical trials, 12 premature infants receiving formula feedings were assigned randomly to receive either Bifidobacterium longum ssp infantis or Bifidobacterium animalis ssp lactis in increasing doses during a 5-week period. In the second, 9 premature infants receiving their mother's milk received each of the two bifidobacteria for 2 weeks separated by a 1-week washout period. Serial stool specimens from each infant were analyzed by terminal restriction fragment-length polymorphism and quantitative polymerase chain reaction for bacterial composition. RESULTS: Among the formula-fed infants, there was a greater increase in fecal bifidobacteria among infants receiving B infantis (Binf) than those receiving B lactis (Blac). This difference was most marked at a dose of 1.4 × 10(9) colony-forming units twice daily (P < .05). Bacterial diversity improved over dose/time in those infants receiving Binf. Among the human milk-fed infants, greater increases in fecal bifidobacteria and decreases in γ-Proteobacteria followed the administration of Binf than Blac. The B longum group (which includes Binf but not Blac) was the dominant bifidobacteria among the human milk-fed infants, regardless of the probiotic administered. CONCLUSIONS: Binf was more effective at colonizing the fecal microbiota than Blac in both formula-fed and human milk-fed premature infants. The combination of human milk plus Binf resulted in the greatest fecal levels of bifidobacteria.

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