Long-Term Effects and Potential Impact of Early Nutrition with Breast Milk or Infant Formula on Glucose Homeostasis Control in Healthy Children at 6 Years Old: A Follow-Up from the COGNIS Study.

There is scarce evidence about early nutrition programming of dynamic aspects of glucose homeostasis. We analyzed the long-term effects of early nutrition on glycemic variability in healthy children. A total of 92 children participating in the COGNIS study were considered for this analysis, who were fed with: a standard infant formula (SF, n = 32), an experimental formula (EF, n = 32), supplemented with milk fat globule membrane (MFGM) components, long-chain polyunsaturated fatty acids (LC-PUFAs), and synbiotics, or were breastfed (BF, n = 28). At 6 years old, BF children had lower mean glucose levels and higher multiscale sample entropy (MSE) compared to those fed with SF. No differences in MSE were found between EF and BF groups. Normal and slow weight gain velocity during the first 6 months of life were associated with higher MSE at 6 years, suggesting an early programming effect against later metabolic disorders, thus similarly to what we observed in breastfed children. Conclusion: According to our results, BF and normal/slow weight gain velocity during early life seem to protect against glucose homeostasis dysregulation at 6 years old. EF shows functional similarities to BF regarding children's glucose variability. The detection of glucose dysregulation in healthy children would help to develop strategies to prevent the onset of metabolic disorders in adulthood.

Association study between hypothalamic functional connectivity, early nutrition, and glucose levels in healthy children aged 6 years: The COGNIS study follow-up.

Breastfeeding (BF) is the gold standard in infant nutrition; knowing how it influences brain connectivity would help understand the mechanisms involved, which would help close the nutritional gap between infant formulas and breast milk. We analyzed potential long-term differences depending on the diet with an experimental infant formula (EF), compared to a standard infant formula (SF) or breastfeeding (BF) during the first 18 months of life on children's hypothalamic functional connectivity (FC) assessed at 6 years old. A total of 62 children participating in the COGNIS randomized clinical trial (Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02094547) were included in this study. They were randomized to receive an SF (n = 22) or a bioactive nutrient-enriched EF (n = 20). BF children were also included as a control study group (BF: n = 20). Brain function was evaluated using functional magnetic resonance imaging (fMRI) and mean glucose levels were collected through a 24-h continuous glucose monitoring (CGM) device at 6 years old. Furthermore, nutrient intake was also analyzed during the first 18 months of life and at 6 years old through 3-day dietary intake records. Groups fed with EF and BF showed lower FC between the medial hypothalamus (MH) and the anterior cingulate cortex (ACC) in comparison with SF-fed children. Moreover, the BF children group showed lower FC between the MH and the left putamen extending to the middle insula, and higher FC between the MH and the inferior frontal gyrus (IFG) compared to the EF-fed children group. These areas are key regions within the salience network, which is involved in processing salience stimuli, eating motivation, and hedonic-driven desire to consume food. Indeed, current higher connectivity found on the MH-IFG network in the BF group was associated with lower simple sugars acceptable macronutrient distribution ranges (AMDRs) at 6 months of age. Regarding linoleic acid intake at 12 months old, a negative association with this network (MH-IFG) only in the BF group was found. In addition, BF children showed lower mean glucose levels compared to SF-fed children at 6 years old. Our results may point out a possible relationship between diet during the first 18 months of life and inclined proclivity for hedonic eating later in life. Clinical trial registration: https://www.clinicaltrials.gov/, identifier NCT02094547.

A synbiotics, long chain polyunsaturated fatty acids, and milk fat globule membranes supplemented formula modulates microbiota maturation and neurodevelopment.

BACKGROUND & AIMS: The critical window of concurrent developmental paths of the nervous system and gut microbiota in infancy provides an opportunity for nutritional interventions with potential health benefits later in life. METHODS: We compared the dynamics of gut microbiota maturation and explored its association with neurodevelopment at 12 months and 4 years of age in 170 full-term healthy infants fed a standard formula (SF) or a new formula (EF) based on standard formula supplemented with synbiotics, long chain polyunsaturated fatty acids (LC-PUFA) and bovine milk fat globule membranes (MFGM), including a breastfed reference group (BF). RESULTS: Using Dirichlet Multinomial Modelling, we characterized three microbial enterotypes (Mixed, anaerobic and aerobic profile; Bact, Bacteroides-dominant; Firm, Firmicutes-enriched) and identified a new enterotype dominated by an unidentified genus within Lachnospiraceae (U_Lach). Enterotypes were associated with age (Mixed with baseline, U_Lach with month 6, Bact and Firm with months 12 and 18). Trajectories or timely enterotype shifts in each infant were not random but strongly associated with type of feeding. Trajectories in SF shifted from initial Mixed to U_Lach, Bact or Firm at month. Microbiota maturation in EF split into a fast trajectory as in SF, and a slow trajectory with Mixed to U_Lach, Bact or Firm transitions at months 12 or 18, as in BF. EF infants with slow trajectories were more often in-home reared and born by vaginal delivery to mothers with pre-pregnancy lean BMI. At 12 months of age, language and expressive language scores were significantly higher in EF infants with fast trajectories than in BF. Neurodevelopmental outcomes were similar between EF infants with slow trajectories and BF at 12 months and 4 years of age. CONCLUSIONS: Feeding a synbiotics, LC-PUFA and MFGM supplemented formula in a specific infant environment promoted probiotic growth and retarded gut microbiota maturation with similar neurodevelopment outcomes to breastfed infants. CLINICAL TRIAL REGISTRY NUMBER: NCT02094547.

Infant Formula Supplemented With Milk Fat Globule Membrane, Long-Chain Polyunsaturated Fatty Acids, and Synbiotics Is Associated With Neurocognitive Function and Brain Structure of Healthy Children Aged 6 Years: The COGNIS Study.

Background: Adequate nutrient intake during the first few months of life plays a critical role on brain structure and function development. Objectives: To analyze the long-term effects of an experimental infant formula (EF) on neurocognitive function and brain structure in healthy children aged 6 years compared to those fed with a standard infant formula or breastfed. Methods: The current study involved 108 healthy children aged 6 years and participating in the COGNIS Study. At 0-2 months, infants were randomized to receive up to 18 months of life a standard infant formula (SF) or EF enriched with milk fat globule membrane (MFGM), long-chain polyunsaturated fatty acids (LC-PUFAs) and synbiotics. Furthermore, a reference group of breastfed (BF) infants were also recruited. Children were assessed using neurocognitive tests and structural Magnetic Resonance Imaging (MRI) at 6 years old. Results: Experimental infant formula (EF) children showed greater volumes in the left orbital cortex, higher vocabulary scores and IQ, and better performance in an attention task than BF children. EF children also presented greater volumes in parietal regions than SF kids. Additionally, greater cortical thickness in the insular, parietal, and temporal areas were found in children from the EF group than those fed with SF or BF groups. Further correlation analyses suggest that higher volumes and cortical thickness of different parietal and frontal regions are associated with better cognitive development in terms of language (verbal comprehension) and executive function (working memory). Finally, arachidonic acid (ARA), adrenic acid (AdA), docosahexaenoic acid (DHA) levels in cheek cell glycerophospholipids, ARA/DHA ratio, and protein, fatty acid, and mineral intake during the first 18 months of life seem to be associated with changes in the brain structures at 6 years old. Conclusions: Supplemented infant formula with MFGM components, LC-PUFAs, and synbiotics seems to be associated to long-term effects on neurocognitive development and brain structure in children at 6 years old. Clinical Trial Registration: https://www.clinicaltrials.gov/, identifier: NCT02094547.

Short- and Long-Term Implications of Human Milk Microbiota on Maternal and Child Health.

Human milk (HM) is considered the most complete food for infants as its nutritional composition is specifically designed to meet infant nutritional requirements during early life. HM also provides numerous biologically active components, such as polyunsaturated fatty acids, milk fat globules, IgA, gangliosides or polyamines, among others; in addition, HM has a "bifidogenic effect", a prebiotic effect, as a result of the low concentration of proteins and phosphates, as well as the presence of lactoferrin, lactose, nucleotides and oligosaccharides. Recently, has been a growing interest in HM as a potential source of probiotics and commensal bacteria to the infant gut, which might, in turn, influence both the gut colonization and maturation of infant immune system. Our review aims to address practical approaches to the detection of microbial communities in human breast milk samples, delving into their origin, composition and functions. Furthermore, we will summarize the current knowledge of how HM microbiota dysbiosis acts as a short- and long-term predictor of maternal and infant health. Finally, we also provide a critical view of the role of breast milk-related bacteria as a novel probiotic strategy in the prevention and treatment of maternal and offspring diseases.

Growth patterns and breast milk/infant formula energetic efficiency in healthy infants up to 18 months of life: the COGNIS study.

Type of feeding during early life influences growth trajectory and metabolic risk at later ages. Modifications in infant formula composition have led to evaluate their effects on growth and energetic efficiency (EE) compared with breast-feeding. Main goal was to analyse type of feeding potential effects during first months of life, plus its EE, on growth patterns in healthy formula fed (standard infant formula (SF) vs. experimental infant formula enriched with bioactive nutrients (EF)) and breastfed (BF) infants participating in the COGNIS RCT (http://www.ClinicalTrials.gov, Identifier: NCT02094547) up to 18 months of age. Infants follow-up to 18 months of age (n 141) fed with a SF (n 48), EF(n 56), or BF (n 37), were assessed for growth parameters using WHO standards. Growth velocity (GV) and catch-up were calculated to identify growth patterns. EE of breast milk/infant formula was also estimated. Infants' growth at 6 months showed higher length and lower head circumference gains in SF and EF infants than BF infants. Both weight-for-length and weight-for-age catch-up growth showed significant differences in formula fed groups compared with the BF. No significant differences in GV or catch-up were found at 6-12 and 12-18 months. Regarding EE, infant formula groups showed significantly lower weight and length gains/g of milk protein, and higher weight and length gains/g of milk lipids, than the BF infants. GV during first 6 months, which may be influenced by feeding, seems to be the main predictor of subsequent growth trajectory. Breast-feeding may have positive effects on growth programming due to its nutrients' EE.

The Effects of an Infant Formula Enriched with Milk Fat Globule Membrane, Long-Chain Polyunsaturated Fatty Acids and Synbiotics on Child Behavior up to 2.5 Years Old: The COGNIS Study.

Although early life nutrition influences brain development and mental health, the long-term effects of supplemented infant formula on children´s behavior remain unclear. We analyzed the effects of a bioactive nutrients-enriched-infant formula on children's behavior up to 2.5 years, compared to a standard infant formula or breastfeeding. Current analysis involved 70 children who were fed a standard infant formula (SF, n = 29) or a bioactive compounds enriched-infant formula (EF, n = 41), during their first 18 months of life, and 33 breastfed (BF) children (reference group) participating in the COGNIS study. Behavioral problems were evaluated using the Child Behavior Checklist at 18 months and 2.5 years. Different statistical analyses were performed using SPSS. EF children aged 2.5 years presented fewer pathological affective problems than SF children. Besides, SF children were classified more frequently as bordering on internalizing problems than BF children. Rates of externalizing problems were increased in SF infants compared to EF and BF infants. Higher maternal IQ was found to have beneficial effects on internalizing and total problem rate in their offspring at 18 months of life; finally, higher maternal educational level was related with fewer ADHD problems in children at 18 months, as well as internalizing, externalizing, total and anxiety problems in children aged 2.5 years. Our analysis suggests that enriched infant formula fed infants seem to show fewer behavioral problems up to 2.5 years compared to a standard infant formula-fed infants. In addition to type of early feeding, maternal IQ and educational level seem to play a key role on children behavioral development.

Influence of a Functional Nutrients-Enriched Infant Formula on Language Development in Healthy Children at Four Years Old.

Nutrition during early life is essential for brain development and establishes the basis for cognitive and language skills development. It is well established that breastfeeding, compared to formula feeding, has been traditionally associated with increased neurodevelopmental scores up to early adulthood. We analyzed the long-term effects of a new infant formula enriched with bioactive compounds on healthy children's language development at four years old. In a randomized double-blind COGNIS study, 122 children attended the follow-up call at four years. From them, 89 children were fed a standard infant formula (SF, n = 46) or an experimental infant formula enriched with functional nutrients (EF, n = 43) during their first 18 months of life. As a reference group, 33 exclusively breastfed (BF) were included. Language development was assessed using the Oral Language Task of Navarra-Revised (PLON-R). ANCOVA, chi-square test, and logistic regression models were performed. EF children seemed to show higher scores in use of language and oral spontaneous expression than SF children, and both SF and EF groups did not differ from the BF group. Moreover, it seems that SF children were more frequently categorized into "need to improve and delayed" in the use of language than EF children, and might more frequently present "need to improve and delayed" in the PLON-R total score than BF children. Finally, the results suggest that SF children presented a higher risk of suffering language development than BF children. Secondary analysis also showed a slight trend between low socioeconomic status and poorer language skills. The functional compound-enriched infant formula seems to be associated with beneficial long-term effects in the development of child's language at four years old in a similar way to breastfed infants.

Impact of gut microbiota on neurogenesis and neurological diseases during infancy.

The first years of life constitute a crucial period for neurodevelopment and a window of opportunity to develop new strategies to prevent neurological and mental diseases. Different studies have shown the influence of gut bacteria in neurogenesis and a functional relationship between gut microbiota and the brain, known as 'gut-brain axis', in which the intestinal microbiota is proposed to play a key role in neurophysiological processes. It has been observed that certain microbiome metabolites could be related to the development of neurological disorders through mechanisms still unknown. Then, more studies are needed to broaden the knowledge regarding the relationship between the Central Nervous System and the gastrointestinal tract, which could help to develop new preventive and treatment protocols.

Infant growth, neurodevelopment and gut microbiota during infancy: which nutrients are crucial?

PURPOSE OF REVIEW: To update the role of specific nutrients during infant development. RECENT FINDINGS: Several bioactive nutrients such as long-chain polyunsaturated fatty acids (LC-PUFAs), iron, vitamins, proteins, or carbohydrates have been identified to exert an important role during the first 1000 days of life on infant growth, neurodevelopment, and gut microbiota establishment and maturation. LC-PUFAs are structural constituents of the central nervous system (CNS), being essential in retinal development or hippocampal plasticity. Recently, components of the milk fat globule membrane (MFG) are being added to infant formulas because of their key role in infant's development. A high intake of proteins induces a faster weight gain during infancy which correlates with later obesity. Digestible carbohydrates provide glucose, crucial for an adequate functioning of CNS; nondigestible carbohydrates [e.g. human milk oligosaccharides (HMOs)] are the main carbon source for gut bacteria. Iron-deficiency anemia during infancy has been associated with alterations of mental and psychomotor development. Folate metabolism, closely related to vitamins B6 and B12, controls epigenetic changes, whereas inadequate status of vitamin D affects bone development, but may also increase intestinal permeability and alter gut microbiota composition. SUMMARY: LC-PUFAs, proteins, carbohydrates, iron, and vitamins during early life are critical for infant's growth, neurodevelopment, and the establishment and functioning of gut microbiota.

Cortical Visual Evoked Potentials and Growth in Infants Fed with Bioactive Compounds-Enriched Infant Formula: Results from COGNIS Randomized Clinical Trial.

Postnatal nutrition is essential for growth and neurodevelopment. We analyzed the influence of a new enriched-infant formula with bioactive compounds on growth, neurodevelopment, and visual function (VF) in healthy infants during their first 18 months of life. A total of 170 infants were randomized in the COGNIS randomized clinical trial (RCT) to receive a standard infant formula (SF = 85) or a new experimental infant formula supplemented with functional nutrients (EF = 85). As a control, 50 breastfed infants (BF) were enrolled. Growth patterns were evaluated up to 18 months of life; neurodevelopment was assessed by general movements at 2, 3, and 4 months; VF was measured by cortical visual evoked potentials at 3 and 12 months. No differences in growth and neurodevelopment were found between groups. Regarding VF, SF and EF infants presented prolonged latencies and lower amplitudes in the P100 wave than BF infants. In the EF group, a higher percentage of infants presented response at 7½'of arc at 12 months compared to 3 months of age; a similar proportion of BF and EF infants presented responses at 7½'of arc at 12 months of age. Early nutritional intervention with bioactive compounds could narrow the gap in growth and neurodevelopment between breastfed and formula-fed infants.

Early nutrition and gut microbiome: interrelationship between bacterial metabolism, immune system, brain structure, and neurodevelopment.

Disturbances of diet during pregnancy and early postnatal life may impact colonization of gut microbiota during early life, which could influence infant health, leading to potential long-lasting consequences later in life. This is a nonsystematic review that explores the recent scientific literature to provide a general perspective of this broad topic. Several studies have shown that gut microbiota composition is related to changes in metabolism, energy balance, and immune system disturbances through interaction between microbiota metabolites and host receptors by the gut-brain axis. Moreover, recent clinical studies suggest that an intestinal dysbiosis in gut microbiota may result in cognitive disorders and behavioral problems. Furthermore, recent research in the field of brain imaging focused on the study of the relationship between gut microbial ecology and large-scale brain networks, which will help to decipher the influence of the microbiome on brain function and potentially will serve to identify multiple mediators of the gut-brain axis. Thus, knowledge about optimal nutrition by modulating gut microbiota-brain axis activity will allow a better understanding of the molecular mechanisms involved in the crosstalk between gut microbiota and the developing brain during critical windows. In addition, this knowledge will open new avenues for developing novel microbiota-modulating based diet interventions during pregnancy and early life to prevent metabolic disorders, as well as neurodevelopmental deficits and brain functional disorders.

The Effect of an Infant Formula Supplemented with AA and DHA on Fatty Acid Levels of Infants with Different FADS Genotypes: The COGNIS Study.

Polymorphisms in the fatty acid desaturase (FADS) genes influence the arachidonic (AA) and docosahexaenoic (DHA) acid concentrations (crucial in early life). Infants with specific genotypes may require different amounts of these fatty acids (FAs) to maintain an adequate status. The aim of this study was to determine the effect of an infant formula supplemented with AA and DHA on FAs of infants with different FADS genotypes. In total, 176 infants from the COGNIS study were randomly allocated to the Standard Formula (SF; n = 61) or the Experimental Formula (EF; n = 70) group, the latter supplemented with AA and DHA. Breastfed infants were added as a reference group (BF; n = 45). FAs and FADS polymorphisms were analyzed from cheek cells collected at 3 months of age. FADS minor allele carriership in formula fed infants, especially those supplemented, was associated with a declined desaturase activity and lower AA and DHA levels. Breastfed infants were not affected, possibly to the high content of AA and DHA in breast milk. The supplementation increased AA and DHA levels, but mostly in major allele carriers. In conclusion, infant FADS genotype could contribute to narrow the gap of AA and DHA concentrations between breastfed and formula fed infants.

Complementary Feeding in Developed Countries: The 3 Ws (When, What, and Why?).

While a wide knowledge exists on the effects of breast milk or infant formula on growth and infant development, less attention has been paid to the importance of complementary feeding (CF). This review focuses on current recommendations for optimal introduction of CF in healthy full-term European infants and discusses the potential impact of this type of feeding on health outcomes. Overall, exclusive breastfeeding is recommended at least for 4 months and preferable for 6 months, followed by the introduction of CF alongside breast milk; infants' nutrient requirements must meet the differences between nutrients provided by breast milk and the estimated total needs. There is growing evidence that healthy feeding practices during the CF period have positive short- and long-term effects on optimal growth, body composition, neurodevelopment, healthy food preferences, and gut microbiota composition and function; adequate and healthy CF may also diminish the risk of infections, allergies, type 1 diabetes mellitus, as well as celiac and non-communicable diseases. Following the expert recommendations, the design of nutritional strategies must encourage parents to provide a healthy lifestyle for their offspring. Future research should aim to optimize timing, content, and methods of CF; furthermore, it is necessary to explore future CF-targeted health-promoting strategies in early life (appetite regulation, eating patterns, eating behavior, gut dysbiosis, etc.) to prevent growth/obesity outcomes, immune system related-diseases or non-communicable diseases in later life.