While substantial research has examined the role of infant nutrition in early brain and cognitive development, the links between later childhood nutrition, brain development, and cognitive and academic skills remain less explored. In this work, we investigated for the first time the direct and indirect associations between nutrition intake, white matter microstructure and structural connectivity, and cognitive and academic outcomes. Using longitudinal data from typically developing children aged 2 to 14 years, we combined neuroimaging, dietary, and cognitive measures to test direct associations between nutrition and brain structure and connectivity, as well as cognitive and learning outcomes, and to assess whether brain development mediated these relationships. We found that specific nutrients, including DHA, sphingomyelin, iron, niacin, choline, and palmitoleic acid (omega-7), were associated with improved brain structure and connectivity, as well as better cognitive and learning outcomes. We also found that brain development partly mediated the association between childhood nutrition and learning outcomes. To our knowledge, this is the first study to show such a pathway in school-age children. These results add to the growing literature demonstrating the ongoing importance of nutrition beyond infancy in supporting childhood brain and cognitive development.

CONTEXT:Nutrition plays a fundamental role in the growth and healthy upbringing of children. While substantial evidence highlights the significance of nutrition during early life, the understanding of its impact on brain development and function, cognition, behavior, and learning throughout childhood and beyond is limited. OBJECTIVE:In this systematic review we addressed this knowledge gap by assessing the existing evidence on how nutrition influences brain structure and function, cognitive abilities, behavior, and learning skills in school-aged children (ages 5-18 years). DATA SOURCES:A systematic search of MEDLINE (via PubMed, Science Direct, and Google Scholar) for published and clinical nutrition-based intervention studies was performed with the focus on effects significantly improving brain, cognition, behavior, and learning in children 5-18 years old for relevant studies published after January 2010. DATA EXTRACTION:A total of 977 studies were identified, out of which 76 studies fit the inclusion criteria and were included in the systematic analysis. DATA ANALYSIS:Included studies were systematically assessed to provide a comprehensive overview of the relationship between nutritional intake and its impact on brain structure and function, cognition, behavior, and learning skills. In addition, for intervention studies, quality assessment was performed. CONCLUSIONS:Findings suggest that, despite the limited number of studies specifically examining brain-related benefits, nutrition plays a significant role in enhancing and supporting typical neurocognitive development during school age. Current results indicate that diet quality (eg, Mediterranean and Nordic) and the intake of specific nutrients, such as lipids, seem to have the most promising impact and are associated with positive effects. However studies' diversity (ie, intervention versus observational) and methodologies employed, limits drawing strong conclusions regarding the most effective nutritional interventions and their underlying causative mechanisms. In sum, this work provides a systematic summary of the available evidence, by identifying common findings across multiple studies, and suggesting avenues for future research in this important, yet underexplored, area. SYSTEMATIC REVIEW REGISTRATION:PROSPERO registration No. 580224.

Polyamines (PAs), specifically putrescine (PUT), spermidine (SPD) and spermine (SPM), are bioactive compounds which are important in various physiological processes, supporting the growth and development of infants. Previous studies have demonstrated significant differences in the PA content and profiles between human milk and infant formulas. The objective of this study was to enhance understanding of the PA content and profiles in human milk, as well as in dairy ingredients commonly utilized in the production of infant formula. PA precursors, individual PAs and their acetylated derivatives were analysed in human milk collected from a cohort of US mothers. SPD was determined as the most abundant PA in this human milk cohort, followed by SPM and PUT. A comprehensive analysis of the individual PA contents was also conducted in multiple dairy ingredients which were categorised based on their protein content (low: similar to 0-13 %, medium: 25-35 %, and high: 70-90 %). Notably, PUT was the most abundant PA in the medium and low protein content dairy ingredients, while SPM was predominant in the high protein content ingredients. The insights gained from this study will not only inform the development of next-generation infant nutritional formulations but will also guide future research on the nutritional adequacy of infant formulas.

Background:Nutritional deficiencies are one of the main factors that affect cognitive development. In Côte d'Ivoire, although nutritional deficiencies have been reported among schoolchildren, their association with cognitive function or academic performance remains unexplored. Objective:The objective of this study was to investigate the relationship between nutritional status, cognition, and school performance in school-aged children from Taabo, Côte d'Ivoire. Methods:A sample of 252 schoolchildren (6-12 years) was recruited. Nutrient biomarkers were measured in blood samples, cognition (fluid intelligence) was assessed using the Raven's Colored Progressive Matrices (RCPM), and school performance was quantified based on academic results in mathematics and literature. Results:Overall scores were 15.4 ± 4.4 for the RCPM, 6.0 ± 2.4 for mathematics, and 5.4 ± 1.8 for literature (out of a maximum of 36, 10, and 10, respectively). Most of the children had normal nutritional status, but all had inadequate plasma levels of iron, folate, thiamine, and vitamin B12. Significant correlations (p < 0.05) were found between biomarkers of iron, folate, tryptophan, calcium, potassium, and omega-3 fatty acids with cognition or school performance. In contrast, no associations were found with zinc, iodine, riboflavin, vitamin B12, or vitamin D. After adjusting for sociodemographic factors in regression models, calcium was identified as a predictor of cognitive skills (R 2 = 0.3, p = 0.020; 95% CI: 8.2 × 10-6-9.3 × 105) and folate as a predictor of performance in both mathematics (R 2 = 0.1, p = 0.006; 95% CI: 0.1-0.3) and literature (R 2 = 0.1, p = 0.005; 95% CI: 0.1-0.2). Conclusion:This study found high rates of B vitamins and iron deficiencies in Ivorian school-aged children. Iron, folate, tryptophan, calcium, potassium, and omega-3 fatty acid biomarkers showed promising correlations with cognition and academic performance. Further research aimed at investigating such relationships is needed.

This review focuses on the effects of polyunsaturated fatty acids (FA) supplementation on neurodevelopmental outcomes in the first year of life in low- and middle-income countries (LMIC). Lipids are an essential part of early life diet; they provide crucial FAs for brain development and healthy growth. The high cost of relevant food sources providing specific FAs restricts their use and consumption in LMIC where more than 3 billion people cannot afford a healthy diet. This narrative review summarizes current knowledge extracted from 24 studies on the impact of specific FAs on neurodevelopment from birth to 12 years of age, with a particular focus on LMICs. We illustrate that most studies focus on effects of polyunsaturated FAs supplementation on neurodevelopmental outcomes in the first year of life. The strongest evidence in the literature is on supplementation during pregnancy with omega-3 fatty acids, in particular alpha-linolenic acid (ALA) and omega-6 fatty acids, in particular linoleic acid (LA), which show promising effects on infant neurodevelopmental outcomes in LMIC. These two essential fatty acids (EFAs) are key substrates necessary to synthesize the long-chain poly-unsaturated fatty acids (LC-PUFA) docosahexaenoic acid (DHA) and arachidonic acid (ARA), which have been reported to be important for neurodevelopment. For the postnatal supplementation we did not observe a clear consensus across studies, either due to mixed finding before 2 years of life or due to the low number of studies beyond 2 years of life. Differences across studies in the choice of FAs, dosage, treatment windows, age and type of neurodevelopment assessments likely contribute to the complexity of the results observed in the studies investigating postnatal supplementation. Finally, this review underlies the need for more research into FAs that support optimal development of children in LMICs and highlight the importance to find affordable solutions without compromising on quality.

Lactoferrin (LF) and osteopontin (OPN) are bioactive milk proteins which can form heteroprotein complexes and complex coacervates. This research studied the effect of LF-OPN complexation and complex coacervation on the simulated infant gastrointestinal digestion of LF with subsequent examination of gut and bone health bioactivities in preclinical models. In an infant digestion model, the proteolytic profile of LF was unaltered by the pre-association of LF and OPN. Gastric proteolysis of LF was increased when the model gastric pH was reduced from 5.3 to 4.0, but less so when complexed with OPN. In a model of intestinal inflammation, undigested (79% inhibition) and gastric digestates (26% inhibition) of LF, but not gastrointestinal digestates, inhibited lipopolysaccharide (LPS)-induced NF-kappa B activation in intestinal epithelial cells. LF-OPN complexation sustained the inhibitory effect (21-43% of the undigested effect, depending on the type of complex) of LF after gastrointestinal digestion, suggesting that the peptides produced were different. In a neonatal rodent model used to study bone development, coacervating LF and OPN improved bone structures with a significant increase of trabecular proportion (BV/TV increase by 21.7%). This resulted in an 11.3% increase in stiffness of bones. Feeding the LF and OPN proteins in coacervate format also increased the levels of OPN, P1NP and M-CSF in blood, signifying a more pronounced impact on bone development. This research demonstrated that LF-OPN complexation and complex coacervation can delay simulated infant gastrointestinal digestion of LF and protect or improve the bioactivity of the proteins.

Infancy is a critical period for neurodevelopment, which includes myelination, synaptogenesis, synaptic pruning, and the development of motor, social-emotional, and cognitive functions. Human milk provides essential nutrients to the infant’s developing brain, especially during the first postnatal months. Human milk oligosaccharides (HMOs) are a major component of human milk, and there is growing evidence of the association of individual HMOs with cognitive development in early life. However, to our knowledge, no study has explained these associations with a mechanism of action. Here, we investigated possible mediating associations between HMOs in human milk, brain myelination (measured via myelin water fraction), and measures of motor, language (collected via the Bayley Scales of Infant and Toddler Development (Bayley-III)), and socioemotional development (collected via the Ages and Stages Questionnaire: Social-Emotional Version (ASQ-SE)) in healthy term-born breast-fed infants. The results revealed an association between 6′Sialyllactose and social skills that was mediated by myelination. Furthermore, associations of fucosylated HMOs with language outcomes were observed that were not mediated by myelination. These observations indicate the roles of specific HMOs in neurodevelopment and associated functional outcomes, such as social-emotional function and language development.

Breast milk (BM) is the optimal source of nutrition for mammals' early life. It exerts multiple benefits, including the development of cognitive capabilities and protection against several diseases like obesity and infection of the respiratory tract. However, which components of BM are involved in individual development has remained elusive. Sialylated human milk oligosaccharides (HMOs) may constitute a valid candidate, whereby they represent the principal source of sialic acid and act as building blocks for brain development. We hypothesize that the reduced availability of two HMOs, sialyl(alpha2,6)lactose (6 ' SL) and sialyl(alpha2,3)lactose (3 ' SL), may impair attention, cognitive flexibility, and memory in a preclinical model and that the exogenous supplementation of these compounds may contrast the observed deficits. We evaluated cognitive capabilities in a preclinical model exposed to maternal milk containing reduced concentrations of 6 ' SL and 3 ' SL during lactation. To modulate their concentrations, we utilized a preclinical model characterized by the absence of genes that synthesize 3 ' SL and 6 ' SL (B6.129-St3gal4(tm1.1Jxm) and St6gal1(tm2Jxm), double genetic deletion), producing milk lacking 3 ' SL and 6 ' SL. Then, to ensure exposure to 3 ' SL-6 ' SL-poor milk in early life, we adopted a cross-fostering protocol. The outcomes assessed in adulthood were different types of memory, attention and information processing, some of which are part of executive functions. Then, in the second study, we evaluated the long-term compensatory potential of the exogenous oral supplementation of 3 ' SL and 6 ' SL during lactation. In the first study, exposure to HMO-poor milk resulted in reduced memory and attention. Specifically, it resulted in impaired working memory in the T-maze test, in reduced spatial memory in the Barnes maze, and in impaired attentional capabilities in the Attentional set-shifting task. In the second part of the study, we did not observe any difference between experimental groups. We hypothesize that the experimental procedures utilized for the exogenous supplementation may have impacted our ability to observe the cognitive read-out in vivo. This study suggests that early life dietary sialylated HMOs play a crucial role in the development of cognitive functions. Future studies are needed to clarify if an exogenous supplementation of these oligosaccharides may compensate for these affected phenotypes.

IntroductionHuman milk contains structurally diverse oligosaccharides (HMO), which are multifunctional modulators of neonatal immune development. Our objective was to investigate formula supplemented with fucosylated (2’FL) + neutral (lacto-N-neotetraose, LNnt) oligosaccharides and/or sialylated bovine milk oligosaccharides (BMOS) on immunological outcomes.MethodsPigs (n=46) were randomized at 48h of age to four diets: sow milk replacer formula (CON), BMOS (CON + 6.5 g/L BMOS), HMO (CON + 1.0 g/L 2’FL + 0.5 g/L LNnT), or BMOS+HMO (CON + 6.5 g/L BMOS + 1.0 g/L 2’FL + 0.5 g/L LNnT). Blood and tissues were collected on postnatal day 33 for measurement of cytokines and IgG, phenotypic identification of immune cells, and ex vivo lipopolysaccharide (LPS)-stimulation of immune cells.ResultsSerum IgG was significantly lower in the HMO group than BMOS+HMO but did not differ from CON or BMOS. The percentage of PBMC T-helper cells was lower in BMOS+HMO than the other groups. Splenocytes from the BMOS group secreted more IL-1β when stimulated ex vivo with LPS compared to CON or HMO groups. For PBMCs, a statistical interaction of BMOS*HMO was observed for IL-10 secretion (p=0.037), with BMOS+HMO and HMO groups differing at p=0.1.DiscussionThe addition of a mix of fucosylated and sialylated oligosaccharides to infant formula provides specific activities in the immune system that differ from formulations supplemented with one oligosaccharide structure.

While ample research on independent associations between infant cognition and gut microbiota composition and human milk (HM) oligosaccharides (HMOs) has been reported, studies on how the interactions between gut microbiota and HMOs may yield associations with cognitive development in infancy are lacking. We aimed to determine how HMOs and species of Bacteroides and Bifidobacterium genera interact with each other and their associations with cognitive development in typically developing infants. A total of 105 mother-infant dyads were included in this study. The enrolled infants [2.9–12 months old (8.09 ± 2.48)] were at least predominantly breastfed at 4 months old. A total of 170 HM samples from the mothers and fecal samples of the children were collected longitudinally. Using the Mullen Scales of Early Learning to assess cognition and the scores as the outcomes, linear mixed effects models including both the levels of eight HMOs and relative abundance of Bacteroides and Bifidobacterium species as main associations and their interactions were employed with adjusting covariates; infant sex, delivery mode, maternal education, site, and batch effects of HMOs. Additionally, regression models stratifying infants based on the A-tetrasaccharide (A-tetra) status of the HM they received were also employed to determine if the associations depend on the A-tetra status. With Bacteroides species, we observed significant associations with motor functions, while Bif. catenulatum showed a negative association with visual reception in the detectable A-tetra group both as main effect (value of p = 0.012) and in interaction with LNFP-I (value of p = 0.007). Additionally, 3-FL showed a positive association with gross motor (p = 0.027) and visual reception (p = 0.041). Furthermore, significant associations were observed with the interaction terms mainly in the undetectable A-tetra group. Specifically, we observed negative associations for Bifidobacterium species and LNT [breve (p = 0.011) and longum (p = 0.022)], and positive associations for expressive language with 3′-SL and Bif. bifidum (p = 0.01), 6′-SL and B. fragilis (p = 0.019), and LNFP-I and Bif. kashiwanohense (p = 0.048), respectively. Our findings suggest that gut microbiota and HMOs are both independently and interactively associated with early cognitive development. In particular, the diverse interactions between HMOs and Bacteroides and Bifidobacterium species reveal different candidate pathways through which HMOs, Bifidobacterium and Bacteroides species potentially interact to impact cognitive development in infancy.

Early dietary exposure via human milk nutrients offers a window of opportunity to support cognitive and temperament development. While several studies have focused on associations of few pre-selected human milk nutrients with cognition and temperament, it is highly plausible that human milk nutrients synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of three major classes of human milk nutrients with cognition and temperament during the first 6 months of life when human milk is the primary source of an infant's nutrition and explore whether there were persistent effects up to 18 months old. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of 54 exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12, and 12-18 months old. Human milk samples were obtained from the mothers of the participants at less than 6 months of age and analyzed for fatty acids [total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)], phospholipids [phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin], and choline [free choline, phosphocholine (PCho), glycerophosphocholine]. Feature selection was performed to select nutrients associated with cognition and temperament. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed (p = 0.024). A significant effect of DHA, n-6/n-3, PE, and TSFA concentrations on receptive language (R-2 = 0.39, p = 0.025) and the elevated ARA, PCho, and PI with increased surgency (R-2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of human milk nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months (p = 0.002). Our study highlighted that various human milk nutrients work together to support the development of cognition and temperament traits during early infancy.

ABSTRACT Introduction: Oligosaccharides found in mammalian milk have shown the potential to alter brain development across multiple species. The diversity and concentration of these oligosaccharides is species-specific and varies greatly between individuals, thus understanding their role in cognitive development is warranted. We investigated the impact of early life dietary fucosylated/neutral or sialylated human milk oligosaccharides (HMO) on behaviours in tasks assessing anxiety, motivation, appetite, learning, and memory. Methods: Sixty-four female Göttingen minipigs were artificially reared from 2 weeks postnatal and provided milk replacers. The study used four groups: no additional oligosaccharides (Con), fucosylated and neutral oligosaccharides (FN, 4 g/L), sialylated oligosaccharides (SL, 0.68 g/L), or both FN and SL (FN + SL, 4 g/L) from 2 to 11 weeks postnatal. One reference group was sow-reared. Weaning occurred between 10 and 11 weeks postnatal, and thereafter an obesogenic diet was provided. Behavioral tasks were conducted over three periods: 1) 0–11 weeks; 2) 16–29 weeks; 3) 39–45 weeks. Tasks included a spatial holeboard task, open field task, exposure to a novel object, runway task, single-feed task, and home pen behaviour observation. Results: In the holeboard, the SL group demonstrated improved reference memory during reversal trials between 16-29 weeks. All groups demonstrated equivalent behavior in open field, novel object, runway, and single-feed tasks, as well as in their home pens (Ps > 0.05). Discussion: These results suggest that early life dietary intake of sialylated oligosaccharides may provide an improvement to cognition during the equivalent developmental stage of adolescence.

Early dietary exposure via human milk (HM) components offers a window of opportunity to support cognitive and temperamental development. While several studies have focused on associations of few pre-selected HM components with cognition and temperament, it is highly plausible that HM components synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of a wide array of HM nutrients with cognition and temperament during the first six months of life and explore if there were persistent effects up to 18 months old, when HM is the primary source of an infant’s nutrition. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of fifty-four exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12 and 12-18 months old. HM samples were obtained from the mothers of the participants at less than 6 months of life and analyzed for fatty acids (total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)), phospholipids (phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin) and choline (free choline, phosphocholine (PCho), glycerophosphocholine). Feature selection was performed to select nutrients associated with cognition and temperament, respectively. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed (p = 0.024). Significant effect of DHA, n-6/n-3, PE and TSFA concentrations on receptive language (R2 = 0.39, p = 0.025), and the elevated ARA, PCho, and PI with increased surgency (R2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of HM nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months (p = 0.002). Our studies highlighted that various HM nutrients work together to support the development of cognition and temperament traits during early infancy.

Early life nutrition critically impacts post-natal brain maturation and cognitive development. Post-natal dietary deficits in specific nutrients, such as lipids, minerals or vitamins are associated with brain maturation and cognitive impairments. Specifically, polar lipids (PL), such as sphingolipids and phospholipids, are important cellular membrane building blocks and are critical for brain connectivity due to their role in neurite outgrowth, synaptic formation, and myelination. In this preclinical study, we assessed the effects of a chronic supplementation with a source of PL extracted from an alpha-lactalbumin enriched whey protein containing 10% lipids from early life (post-natal day (PND) 7) to adulthood (PND 72) on adult motor skills, anxiety, and long-term memory. The motor skills were assessed using open field and rotarod test. Anxiety was assessed using elevated plus maze (EPM). Long-term object and spatial memory were assessed using novel object recognition (NOR) and Morris water maze (MWM). Our results suggest that chronic PL supplementation improved measures of spatial long-term memory accuracy and cognitive flexibility in the MWM in adulthood, with no change in general mobility, anxiety and exploratory behavior. Our results indicate memory specific functional benefits of long-term dietary PL during post-natal brain development.

ABSTRACT Background Genetic polymorphisms leading to variations in human milk oligosaccharide (HMO) composition have been reported. Alpha-Tetrasaccharide (A-tetra), an HMO, has been shown to only be present (>limit of detection; A-tetra+) in the human milk (HM) of women with blood type A, suggesting genetic origins determining the presence or absence (A-tetra-) of A-tetra in HM. Objectives This study aimed to determine whether associations exist between HMO concentrations and cognitive development, and whether the associations vary between A-tetra+ and A-tetra- groups in children (<25 months old). Methods We enrolled typically developing children (2–25 months old; mean, 10 months old) who were at least partially breastfed at the study visit. The Mullen Scales of Early Learning (MSEL) were used as the primary outcome measure to assess early cognitive development. Linear mixed effects models were employed by stratifying children based on A-tetra levels (A-tetra+ or A-tetra-) to assess associations between age-removed HMO concentrations and both MSEL composite scores and the 5 subdomain scores. Results A total of 99 mother-child dyads and 183 HM samples were included (A-tetra+: 57 samples, 33 dyads; A-tetra-: 126 samples, 66 dyads). No significant association was observed between HMOs and MSEL when all samples were analyzed together. The composite score and 3’-sialyllactose (3’-SL) levels were positively associated [P = 0.002; effect size (EF), 13.12; 95% CI, 5.36–20.80] in the A-tetra + group. This association was driven by the receptive (adjusted P = 0.015; EF, 9.95; 95% CI, 3.91–15.99) and expressive (adjusted P = 0.048; EF, 7.53; 95% CI, 2.51–13.79) language subdomain scores. Furthermore, there was an interaction between 3’-SL and age for receptive language (adjusted P = 0.03; EF, -14.93; 95% CI, -25.29 to -4.24). Conclusions Our study reports the association of 3’-SL and cognition, particularly language functions, in typically developing children who received HM containing detectable A-tetra during infancy.

Breast milk exerts pivotal regulatory functions early in development whereby it contributes to the maturation of brain and associated cognitive functions. However, the specific components of maternal milk mediating this process have remained elusive. Sialylated human milk oligosaccharides (HMOs) represent likely candidates since they constitute the principal neonatal dietary source of sialic acid, which is crucial for brain development and neuronal patterning. We hypothesize that the selective neonatal lactational deprivation of a specific sialylated HMOs, sialyl(alpha2,3)lactose (3′SL), may impair cognitive capabilities (attention, cognitive flexibility, and memory) in adulthood in a preclinical model. To operationalize this hypothesis, we cross-fostered wild-type (WT) mouse pups to B6.129-St3gal4tm1.1Jxm/J dams, knock-out (KO) for the gene synthesizing 3′SL, thereby providing milk with approximately 80% 3′SL content reduction. We thus exposed lactating WT pups to a selective reduction of 3′SL and investigated multiple cognitive domains (including memory and attention) in adulthood. Furthermore, to account for the underlying electrophysiological correlates, we investigated hippocampal long-term potentiation (LTP). Neonatal access to 3′SL-poor milk resulted in decreased attention, spatial and working memory, and altered LTP compared to the control group. These results support the hypothesis that early-life dietary sialylated HMOs exert a long-lasting role in the development of cognitive functions.

Polar lipids, which are found in human milk, serve essential functions within biological membranes, hence their importance in brain development and cognition. Therefore, we aimed to evaluate the longitudinal effects on brain macrostructural and microstructural development and recognition memory of early-life polar lipid supplementation using the translational pig model. Twenty-eight intact (i.e., not castrated) male pigs were provided either a control diet (n = 14) or the control diet supplemented with polar lipids (n = 14) from postnatal day 2 until postnatal week 4. After postnatal week 4, all animals were provided the same nutritionally-adequate diets until postnatal week 24. Pigs underwent magnetic resonance imaging at 8 longitudinal time-points to model brain macrostructural and microstructural developmental trajectories. The novel object recognition task was implemented at postnatal weeks 4 and 8 to evaluate recognition memory. Subtle differences were observed between groups in hippocampal absolute brain volumes and fractional anisotropy, and no differences in myelin water fraction developmental patterns were noted. Behavioral outcomes did not differ in recognition memory, and only minimal differences were observed in exploratory behaviors. Our findings suggest that early-life dietary supplementation of polar lipids has limited effect on brain developmental patterns, object recognition memory, and exploratory behaviors.

Breastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129- St6gal1 tm2Jxm /J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6′SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6′SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6′SL-deficient milk. To test whether lactational 6′SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6′SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6′SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.

Elucidating relationships between the gut and brain is of intense research focus. Multiple studies have demonstrated that modulation of the intestinal environment via prebiotics or probiotics can induce cognitively beneficial effects, such as improved memory or reduced anxiety. However, the mechanisms by which either act remain largely unknown. We previously demonstrated that different types of oligosaccharides affected short- and long-term memory in distinct ways. Given that the oligosaccharide content of human milk is highly variable, and that formula-fed infants typically do not consume similar amounts or types of oligosaccharides, their potential effects on brain development warrant investigation. Herein, a mediation analysis was performed on existing datasets, including relative abundance of bacterial genera, gene expression, brain volume, and cognition in young pigs. Analyses revealed that numerous bacterial genera in both the colon and feces were related to short- and/or long-term memory. Relationships between genera and memory appeared to differ between diets. Mediating variables frequently included GABAergic and glutamatergic hippocampal gene expression. Other mediating variables included genes related to myelination, transcription factors, brain volume, and exploratory behavior. Overall, this analysis identified multiple pathways between the gut and brain, with a focus on genes related to excitatory/inhibitory neurotransmission.