Low-Protein Infant Formula Enriched with Alpha-Lactalbumin during Early Infancy May Reduce Insulin Resistance at 12 Months: A Follow-Up of a Randomized Controlled Trial.

High protein intake during infancy results in accelerated early weight gain and potentially later obesity. The aim of this follow-up study at 12 months was to evaluate if modified low-protein formulas fed during early infancy have long-term effects on growth and metabolism. In a double-blinded RCT, the ALFoNS study, 245 healthy-term infants received low-protein formulas with either alpha-lactalbumin-enriched whey (α-lac-EW; 1.75 g protein/100 kcal), casein glycomacropeptide-reduced whey (CGMP-RW; 1.76 g protein/100 kcal), or standard infant formula (SF; 2.2 g protein/100 kcal) between 2 and 6 months of age. Breastfed (BF) infants served as a reference. At 12 months, anthropometrics and dietary intake were assessed, and serum was analyzed for insulin, C-peptide, and insulin-like growth factor 1 (IGF-1). Weight gain between 6 and 12 months and BMI at 12 months were higher in the SF than in the BF infants (p = 0.019; p < 0.001, respectively), but were not significantly different between the low-protein formula groups and the BF group. S-insulin and C-peptide were higher in the SF than in the BF group (p < 0.001; p = 0.003, respectively), but more alike in the low-protein formula groups and the BF group. Serum IGF-1 at 12 months was similar in all study groups. Conclusion: Feeding modified low-protein formula during early infancy seems to reduce insulin resistance, resulting in more similar growth, serum insulin, and C-peptide concentrations to BF infants at 6-months post intervention. Feeding modified low-protein formula during early infancy results in more similar growth, serum insulin, and C-peptide concentrations to BF infants 6-months post intervention, probably due to reduced insulin resistance in the low-protein groups.

Effects of bile salt-stimulated lipase on blood cells and associations with disease activity in human inflammatory joint disorders.

The bile salt-stimulated lipase (BSSL) was originally recognized as a lipolytic enzyme expressed by the exocrine pancreas and in some species, notably humans, the lactating mammary gland, being secreted into the duodenum and with the mother's milk, respectively. However, BSSL is also present in the blood and has been assigned additional functions, even beyond the gastrointestinal tract. Conventional BSSL knockout mice are protected from developing disease in animal models of arthritis, and antibodies directed towards BSSL prevent or mitigate disease in similar models. The aim of this study was to investigate the role of BSSL as a newly discovered player in inflammation and specifically in inflammatory joint disorders. As part of mechanism of action, we here show that BSSL is secreted by neutrophils, interacts with monocytes and stimulates their migration in vitro. An anti-BSSL antibody that blocks the human BSSL-monocyte interaction was shown to simultaneously prevent the signaling pathway by which BSSL induce cell migration. Moreover, in this cohort study we show that BSSL levels are significantly higher in blood samples from patients with rheumatoid arthritis and psoriatic arthritis compared to healthy controls. The BSSL levels in patients' blood also correlated with disease activity scores and established inflammatory markers. Hence, although the mode of action is not yet fully clarified, we conclude that BSSL could be considered a proinflammatory component in the innate immune system and thus a possible novel target for treatment of chronic inflammation.

A randomized, controlled trial of a Nordic, protein-reduced complementary diet in infants: effects on body composition, growth, biomarkers, and dietary intake at 12 and 18 months.

BACKGROUND: High intake of protein and low intake of plant-based foods during complementary feeding can contribute to negative long-term health effects. OBJECTIVES: To investigate the effects of a protein-reduced, Nordic complementary diet on body composition, growth, biomarkers, and dietary intake, compared with current Swedish dietary recommendations for infants at 12 and 18 mo. METHODS: Healthy, term infants (n = 250) were randomly allocated to either a Nordic group (NG) or a conventional group (CG). From 4 to 6 mo, NG participants received repeated exposures of Nordic taste portions. From 6 to 18 mo, NG was supplied with Nordic homemade baby food recipes, protein-reduced baby food products, and parental support. CG followed the current Swedish dietary recommendations. Measurements of body composition, anthropometry, biomarkers, and dietary intake were collected from baseline and at 12 and 18 mo. RESULTS: Of the 250 infants, 82% (n = 206) completed the study. There were no group differences in body composition or growth. In NG, protein intake, blood urea nitrogen and plasma IGF-1 were lower compared to CG at 12 and 18 mo. Infants in NG consumed 42% to 45% more fruits and vegetables compared to CG at 12 and 18 mo, which was reflected in a higher plasma folate at 12 and 18 mo. There were no between-group differences in EI or iron status. CONCLUSIONS: Introduction of a predominantly plant-based, protein-reduced diet as part of complementary feeding is feasible and can increase fruit and vegetable intake. This trial was registered at clinicaltrials.gov as NCT02634749.

Low-Protein Formulas with Alpha-Lactalbumin-Enriched or Glycomacropeptide-Reduced Whey: Effects on Growth, Nutrient Intake and Protein Metabolism during Early Infancy: A Randomized, Double-Blinded Controlled Trial.

Protein intake is higher in formula-fed than in breast-fed infants during infancy, which may lead to an increased risk of being overweight. Applying alpha-lactalbumin (α-lac)-enriched whey or casein glycomacropeptide (CGMP)-reduced whey to infant formula may enable further reduction of formula protein by improving the amino acid profile. Growth, nutrient intake, and protein metabolites were evaluated in a randomized, prospective, double-blinded intervention trial where term infants received standard formula (SF:2.2 g protein/100 kcal; n = 83) or low-protein formulas with α-lac-enriched whey (α-lac-EW;1.75 g protein/100 kcal; n = 82) or CGMP-reduced whey (CGMP-RW;1.76 g protein/100 kcal; n = 80) from 2 to 6 months. Breast-fed infants (BF; n = 83) served as reference. Except between 4 and 6 months, when weight gain did not differ between α-lac-EW and BF (p = 0.16), weight gain was higher in all formula groups compared to BF. Blood urea nitrogen did not differ between low-protein formula groups and BF during intervention, but was lower than in SF. Essential amino acids were similar or higher in α-lac-EW and CGMP-RW compared to BF. Conclusion: Low-protein formulas enriched with α-lac-enriched or CGMP-reduced whey supports adequate growth, with more similar weight gain in α-lac-enriched formula group and BF, and with metabolic profiles closer to that of BF infants.

Targeting the gut-lung axis by synbiotic feeding to infants in a randomized controlled trial.

BACKGROUND: Formula-fed infants are at increased risk of infections. Due to the cross-talk between the mucosal systems of the gastrointestinal and respiratory tracts, adding synbiotics (prebiotics and probiotics) to infant formula may prevent infections even at distant sites. Infants that were born full term and weaned from breast milk were randomized to prebiotic formula (fructo- and galactooligosaccharides) or the same prebiotic formula with Lactobacillus paracasei ssp. paracasei F19 (synbiotics) from 1 to 6 months of age. The objective was to examine the synbiotic effects on gut microbiota development. RESULTS: Fecal samples collected at ages 1, 4, 6, and 12 months were analyzed using 16S rRNA gene sequencing and a combination of untargeted gas chromatography-mass spectrometry/liquid chromatography-mass spectrometry. These analyses revealed that the synbiotic group had a lower abundance of Klebsiella, a higher abundance of Bifidobacterium breve compared to the prebiotic group, and increases in the anti-microbial metabolite d-3-phenyllactic acid. We also analyzed the fecal metagenome and antibiotic resistome in the 11 infants that had been diagnosed with lower respiratory tract infection (cases) and 11 matched controls using deep metagenomic sequencing. Cases with lower respiratory tract infection had a higher abundance of Klebsiella species and antimicrobial resistance genes related to Klebsiella pneumoniae, compared to controls. The results obtained using 16S rRNA gene amplicon and metagenomic sequencing were confirmed in silico by successful recovery of the metagenome-assembled genomes of the bacteria of interest. CONCLUSIONS: This study demonstrates the additional benefit of feeding specific synbiotics to formula-fed infants over prebiotics only. Synbiotic feeding led to the underrepresentation of Klebsiella, enrichment of bifidobacteria, and increases in microbial degradation metabolites implicated in immune signaling and in the gut-lung and gut-skin axes. Our findings support future clinical evaluation of synbiotic formula in the prevention of infections and associated antibiotic treatment as a primary outcome when breastfeeding is not feasible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01625273 . Retrospectively registered on 21 June 2012.

Metabolic Phenotype and Microbiome of Infants Fed Formula Containing Lactobacillus paracasei Strain F-19.

Early childhood nutrition drives the development of the gut microbiota. In contrast to breastfeeding, feeding infant formula has been shown to impact both the gut microbiota and the serum metabolome toward a more unfavorable state. It is thought that probiotics may alter the gut microbiota and hence create a more favorable metabolic outcome. To investigate the impact of supplementation with Lactobacillus paracasei spp. paracasei strain F-19 on the intestinal microbiota and the serum metabolome, infants were fed a formula containing L. paracasei F19 (F19) and compared to a cohort of infants fed the same standard formula without the probiotic (SF) and a breast-fed reference group (BF). The microbiome, as well as serum metabolome, were compared amongst groups. Consumption of L. paracasei F19 resulted in lower community diversity of the gut microbiome relative to the SF group that made it more similar to the BF group at the end of the intervention (4 months). It also significantly increased lactobacilli and tended to increase bifidobacteria, also making it more similar to the BF group. The dominant genus in the microbiome of all infants was Bifidobacterium throughout the intervention, which was maintained at 12 months. Although the serum metabolome of the F19 group was more similar to the group receiving the SF than the BF group, increases in serum TCA cycle intermediates and decreases in several amino acids in the metabolome of the F19 group were observed, which resulted in a metabolome that trended toward the BF group. Overall, L. paracasei F19 supplementation did not override the impact of formula-feeding but did impact the microbiome and the serum metabolome in a way that may mitigate some unfavorable metabolic impacts of formula-feeding.

Assessing the safety of bioactive ingredients in infant formula that affect the immune system: recommendations from an expert panel.

Bioactive ingredients for infant formula have been sought to reduce disparities in health outcomes between breastfed and formula-fed infants. Traditional food safety methodologies have limited ability to assess some bioactive ingredients. It is difficult to assess the effects of nutrition on the infant immune system because of coincident developmental adaptations to birth, establishment of the microbiome and introduction to solid foods, and perinatal environmental factors. An expert panel was convened to review information on immune system development published since the 2004 Institute of Medicine report on evaluating the safety of new infant formula ingredients and to recommend measurements that demonstrate the safety of bioactive ingredients intended for that use. Panel members participated in a 2-d virtual symposium in November 2020 and in follow-up discussions throughout early 2021. Key topics included identification of immune system endpoints from nutritional intervention studies, effects of human milk feeding and human milk substances on infant health outcomes, ontologic development of the infant immune system, and microbial influences on tolerance. The panel explored how "nonnormal" conditions such as preterm birth, allergy, and genetic disorders could help define developmental immune markers for healthy term infants. With consideration of breastfed infants as a reference, ensuring proper control groups, and attention to numerous potential confounders, the panel recommended a set of standard clinical endpoints including growth, response to vaccination, infection and other adverse effects related to inflammation, and allergy and atopic diseases. It compiled a set of candidate markers to characterize stereotypical patterns of immune system development during infancy, but absence of reference ranges, variability in methods and populations, and unreliability of individual markers to predict disease prevented the panel from including many markers as safety endpoints. The panel's findings and recommendations are applicable for industry, regulatory, and academic settings, and will inform safety assessments for immunomodulatory ingredients in foods besides infant formula.

Immunological Effects of Adding Bovine Lactoferrin and Reducing Iron in Infant Formula: A Randomized Controlled Trial.

OBJECTIVES: Compared to formula-fed infants, breastfed infants have a lower risk of infections. Two possible reasons for this are the presence of the anti-infective and anti-inflammatory protein lactoferrin and the lower level of iron in breast milk. We explored how adding bovine lactoferrin and reducing the iron concentration in infant formula affect immunology and risk of infections in healthy infants. METHODS: In a double-blind controlled trial, term formula-fed (FF) Swedish infants (n = 180) were randomized to receive, from 6 weeks to 6 months of age, a low-iron formula (2 mg/L) with added bovine lactoferrin (1.0 g/L) (Lf+; n = 72); low-iron formula with no added lactoferrin (Lf-; n = 72); and standard formula at 8 mg/L iron and no added lactoferrin (control formula [CF]; n = 36). Cytokines, infections, and infection related treatments were assessed until 12 months of age. RESULTS: No adverse effects were observed. There were no apparent effects on transforming growth factor beta (TGF-ß)1, TGF-ß2, tumor necrosis factor alfa (TNF-α) or interleukin2 (IL-2) at 4, 6, or 12 months, except of higher TGF-ß2 at 6 months in the CF group in comparison to the low iron groups combined (P = 0.033). No significant differences in otitis, respiratory infections, gastroenteritis, or other monitored infections and treatments were detected for any of the study feeding groups during the first 6 months and only a few and diverging effects were observed between 6 and 12 months. CONCLUSIONS: Adding bovine lactoferrin and reducing iron from 8 to 2 mg/L in infant formula was safe. No clinically relevant effects on cytokines or infection related morbidity were observed in this well-nourished and healthy population.

The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree.

Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in Xenopus laevis oocytes using biophysical and biochemical methods. The mutant failed to transport the specific SGLT1 sugar analog α-methyl-D-glucopyranoside (αMDG). Q457R SGLT1 was synthesized in amounts comparable to the wild-type (WT) transporter. SGLT1 charge measurements and freeze-fracture electron microscopy demonstrated that the mutant protein was inserted into the plasma membrane. Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter. Together with our previous studies on Q457C and Q457E mutants, we established that the positive charge on Q457R prevented the translocation of sugar from the outward-facing to inward-facing conformation. This is contrary to other GGM cases where missense mutations caused defects in trafficking SGLT1 to the plasma membrane. Thirteen GGM patients are now added to the pedigree traced back to the late 17th century. The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden.

Serum cytokine patterns are modulated in infants fed formula with probiotics or milk fat globule membranes: A randomized controlled trial.

BACKGROUND: Proteins and lipids of milk fat globule membrane (MFGM) and probiotics are immunomodulatory. We hypothesized that Lactobacillus paracasei ssp. paracasei strain F19 (F19) would augment vaccine antibody and T helper 1 type immune responses whereas MFGM would produce an immune response closer to that of breastfed (BF) infants. OBJECTIVE: To compare the effects of supplementing formula with F19 or bovine MFGM on serum cytokine and vaccine responses of formula-fed (FF) and BF infants. DESIGN: FF infants were randomized to formula with F19 (n = 195) or MFGM (n = 192), or standard formula (SF) (n = 194) from age 21±7 days until 4 months. A BF group served as reference (n = 208). We analyzed seven cytokines (n = 398) in serum at age 4 months using magnetic bead-based multiplex technology. Using ELISA, we analyzed anti-diphtheria IgG (n = 258) and anti-poliovirus IgG (n = 309) concentrations in serum before and after the second and third immunization, respectively. RESULTS: Compared with SF, the F19 group had greater IL-2 and lower IFN-γ concentrations (p<0.05, average effect size 0.14 and 0.39). Compared with BF, the F19 group had greater IL-2, IL-4 and IL-17A concentrations (p<0.05, average effect size 0.42, 0.34 and 0.26, respectively). The MFGM group had lower IL-2 and IL-17A concentrations compared with SF (p<0.05, average effect size 0.34 and 0.31). Cytokine concentrations were comparable among the MFGM and BF groups. Vaccine responses were comparable among the formula groups. CONCLUSIONS: Contrary to previous studies F19 increased IL-2 and lowered IFN-γ production, suggesting that the response to probiotics differs across populations. The cytokine profile of the MFGM group approached that of BF infants, and may be associated with the previous finding that infectious outcomes for the MFGM group in this cohort were closer to those of BF infants, as opposed to the SF group. These immunomodulatory effects support future clinical evaluation of infant formula with F19 or MFGM.

Neurodevelopment and growth until 6.5 years of infants who consumed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial.

BACKGROUND: We previously reported results from a randomized controlled trial in which we found that Swedish infants consuming an experimental low-energy, low-protein formula (EF) supplemented with bovine milk fat globule membranes (MFGMs) until 6 mo of age had several positive outcomes, including better performance in the cognitive domain of Bayley Scales of Infant and Toddler Development 3rd Edition at 12 mo of age, and higher plasma cholesterol concentrations during the intervention, than infants consuming standard formula (SF). OBJECTIVES: We aimed to evaluate neurodevelopment, growth, and plasma cholesterol status at 6 and 6.5 y of age in the same study population. METHODS: We assessed cognitive and executive functions using the Wechsler Intelligence Scale for Children 4th Edition (WISC-IV), Brown Attention-Deficit Disorder Scales for Children and Adolescents (Brown-ADD), and Quantified Behavior (Qb) tests, and behavior using the Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF), at 6.5 y of age. Anthropometrics and plasma lipids were assessed at 6 y of age. RESULTS: There were no differences between the EF and SF groups in any of the subscales in WISC-IV or Brown-ADD at 6.5 y of age, in the proportion of children with scores outside the normal range in the Qb test, nor in clinical or borderline indications of problems in adaptive functioning from parental and teacher's scoring using the CBCL and TRF. There were no differences between the EF and SF groups in weight, length, or head or abdominal circumferences, nor in plasma concentrations of homocysteine, lipids, insulin, or glucose. CONCLUSIONS: Among children who as infants consumed a low-energy, low-protein formula supplemented with bovine MFGMs, there were no effects on neurodevelopment, growth, or plasma cholesterol status 6-6.5 y later.

Acceptance of a Nordic, Protein-Reduced Diet for Young Children during Complementary Feeding-A Randomized Controlled Trial.

Early life is critical for developing healthy eating patterns. This study aimed to investigate the effects of a Nordic, protein-reduced complementary diet (ND) compared to a diet following the current Swedish dietary guidelines on eating patterns and food acceptance. At 4-6 months (mo) of age infants were randomized to a Nordic group (NG, n = 41) or a Conventional group (CG, n = 40), and followed until 18 mo of age. Daily intake of fruits and vegetables (mean ± sd) at 12 mo was significantly higher in the NG compared to the CG: 341 ± 108 g/day vs. 220 ± 76 g/day (p < 0.001), respectively. From 12 to 18 mo, fruit and vegetable intake decreased, but the NG still consumed 32% more compared to the CG: 254 ± 99 g/day vs. 193 ± 67 g/day (p = 0.004). To assess food acceptance, both groups were tested with home exposure meals at 12 and 18 mo. No group differences in acceptance were found. We find that a ND with parental education initiates healthy eating patterns during infancy, but that the exposure meal used in the present study was insufficient to detect major differences in food acceptance. This is most likely explained by the preparation of the meal. Nordic produce offers high environmental sustainability and favorable taste composition to establish healthy food preferences during this sensitive period of early life.

Milk Fat Globule Membrane as a Modulator of Infant Metabolism and Gut Microbiota: A Formula Supplement Narrowing the Metabolic Differences between Breastfed and Formula-Fed Infants.

SCOPE: Milk fat globule membrane (MFGM) is an important component of milk that has previously been removed in the manufacture of infant formulas, but has recently gained attention owing to its potential to improve immunological, cognitive, and metabolic health. The goal of this study is to determine whether supplementing MFGM in infant formula would drive desirable changes in metabolism and gut microbiota to elicit benefits observed in prior studies. METHODS AND RESULTS: The serum metabolome and fecal microbiota are analyzed using 1 H NMR spectroscopy and 16S rRNA gene sequencing respectively in a cohort of Chinese infants given a standard formula or a formula supplemented with an MFGM-enriched whey protein fraction. Supplementing MFGM suppressed protein degradation pathways and the levels of insulinogenic amino acids that are typically enhanced in formula-fed infants while facilitating fatty acid oxidation and ketogenesis, a feature that may favor brain development. MFGM supplementation did not induce significant compositional changes in the fecal microbiota but suppressed microbial diversity and altered microbiota-associated metabolites. CONCLUSION: Supplementing MFGM in a formula reduced some metabolic gaps between formula-fed and breastfed infants.

Reducing Iron Content in Infant Formula from 8 to 2 mg/L Does Not Increase the Risk of Iron Deficiency at 4 or 6 Months of Age: A Randomized Controlled Trial.

Many infant formulas are fortified with iron at 8-14 mg/L whereas breast milk contains about 0.3 mg/L. Another major difference between breast milk and infant formula is its high concentration of lactoferrin, a bioactive iron-binding protein. The aim of the present study was to investigate how reducing the iron content and adding bovine lactoferrin to infant formula affects iron status, health and development. Swedish healthy full-term formula-fed infants (n = 180) were randomized in a double-blind controlled trial. From 6 weeks to 6 months of age, 72 infants received low-iron formula (2 mg/L) fortified with bovine lactoferrin (1.0 g/L) (Lf+), 72 received low-iron formula un-fortified with lactoferrin (Lf-) and 36 received standard formula with 8 mg of iron/L and no lactoferrin fortification as controls (CF). Iron status and prevalence of iron deficiency (ID) were assessed at 4 and 6 months. All iron status indicators were unaffected by lactoferrin. At 4 and 6 months, the geometric means of ferritin for the combined low-iron groups compared to the CF-group were 67.7 vs. 88.7 and 39.5 vs. 50.9 µg/L, respectively (p = 0.054 and p = 0.056). No significant differences were found for other iron status indicators. In the low-iron group only one infant (0.7%) at 4 months and none at 6 months developed ID. Conclusion: Iron fortification of 2 mg/L is an adequate level during the first half of infancy for healthy term infants in a well-nourished population. Adding lactoferrin does not affect iron status.

Digestion of human milk fat in healthy infants.

Lipid digestion is critical for infant development, and yet, the interconnection between lipid digestion and the microbiota is largely understudied. This review focuses on digestion of the human milk fat globule and summarizes the current understanding of the mechanisms underlying this process in infants. We first discuss the partial hydrolysis of milk fat in the stomach, which leads to rearrangement of lipid droplets, creating a lipid-water interface necessary for duodenal lipolysis. In the first few months of life, secretion of pancreatic triglyceride lipase, phospholipase A2, and bile salts is immature. The dominant lipases aiding fat digestion in the newborn small intestine are therefore pancreatic lipase-related protein 2 and bile salt-stimulated lipase from both the exocrine pancreas and milk. We summarize the interaction between ionic fatty acids and cations to form insoluble fatty acid soaps and how it is influenced by various factors, including cation availability, pH, and bile salt concentration, as well as saturation and chain length of fatty acids. We further argue that the formation of the soap complex does not contribute to lipid bioavailability. Next, the possible roles that the gut microbiota plays in lipid digestion and absorption are discussed. Finally, we provide a perspective on how the manufacturing process of infant formula and dairy products may alter the physical properties and structure of lipid droplets, thereby altering the rate of lipolysis.

Vitamin D status and cardiometabolic risk markers in young Swedish children: a double-blind randomized clinical trial comparing different doses of vitamin D supplements.

BACKGROUND: Observational studies have linked low vitamin D status to unfavorable cardiometabolic risk markers, but double-blinded vitamin D intervention studies in children are scarce. OBJECTIVES: The aim was to evaluate the effect of different doses of a vitamin D supplement on cardiometabolic risk markers in young healthy Swedish children with fair and dark skin. METHODS: Cardiometabolic risk markers were analyzed as secondary outcomes of a double-blind, randomized, milk-based vitamin D intervention trial conducted during late fall and winter in 2 areas of Sweden (latitude 63°N and 55°N, respectively) in both fair- and dark-skinned 5- to 7-y-old children. During the 3-mo intervention, 206 children were randomly assigned to a daily milk-based vitamin D3 supplement of either 10 or 25 µg or placebo (2 µg; only at 55°N). Anthropometric measures, blood pressure, serum 25-hydroxyvitamin D [25(OH)D], total cholesterol, HDL cholesterol, apoA-I, apoB, and C-reactive protein (CRP) were analyzed and non-HDL cholesterol calculated at baseline and after the intervention. RESULTS: At baseline, serum 25(OH)D was negatively associated with systolic and diastolic blood pressure (ß = -0.194; 95% CI: -0.153, -0.013; and ß = -0.187; 95% CI: -0.150, -0.011, respectively). At follow-up, there was no statistically significant difference in any of the cardiometabolic markers between groups. CONCLUSIONS: We could not confirm any effect of vitamin D supplementation on serum lipids, blood pressure, or CRP in healthy 5- to 7-y-old children. The study was registered at clinicaltrials.gov (NCT01741324).

Milk Fat Globule Membranes: Effects on Microbiome, Metabolome, and Infections in Infants and Children.

Dietary supplementation with bovine milk fat globule membrane (MFGM) concentrates has recently emerged as a possible means to improve the health of infants and young children, or defense against infections. We identified 5 double-blind, randomized, controlled trials (DBRCT) exploring the effects of supplementing the diet of infants and children with bovine MFGM concentrates on infections. We reviewed 3 studies which found a protective effect against infections at different ages during infancy and early childhood. Two of them have reported effects on the metabolome, and 1 study also on the microbiome and lipidome. MFGM supplementation had moderate, albeit interesting, effects on the oral and fecal microbiome, fecal and serum/plasma metabolome, and serum and erythrocyte membrane lipidome, which also are reviewed. We conclude that studies on MFGM supplementation during infancy and childhood indicate positive effects on the defense against infections and other outcomes, but more high-quality DBRCTs with well-defined MFGM fractions and outcome measures are needed before firm conclusions can be drawn.

Should formula for infants provide arachidonic acid along with DHA? A position paper of the European Academy of Paediatrics and the Child Health Foundation.

Recently adopted regulatory standards on infant and follow-on formula for the European Union stipulate that from February 2020 onwards, all such products marketed in the European Union must contain 20-50 mg omega-3 DHA (22:6n-3) per 100 kcal, which is equivalent to about 0.5-1% of fatty acids (FAs) and thus higher than typically found in human milk and current infant formula products, without the need to also include ω-6 arachidonic acid (AA; 20:4n-6). This novel concept of infant formula composition has given rise to concern and controversy because there is no accountable evidence on its suitability and safety in healthy infants. Therefore, international experts in the field of infant nutrition were invited to review the state of scientific research on DHA and AA, and to discuss the questions arising from the new European regulatory standards. Based on the available information, we recommend that infant and follow-on formula should provide both DHA and AA. The DHA should equal at least the mean content in human milk globally (0.3% of FAs) but preferably reach 0.5% of FAs. Although optimal AA intake amounts remain to be defined, we strongly recommend that AA should be provided along with DHA. At amounts of DHA in infant formula up to ∼0.64%, AA contents should at least equal the DHA contents. Further well-designed clinical studies should evaluate the optimal intakes of DHA and AA in infants at different ages based on relevant outcomes.

Effectiveness of vitamin D supplementation in Swedish children may be negatively impacted by BMI and serum fructose.

In regions where sunlight exposure is limited, dietary vitamin D intake becomes important for maintaining status. However, Swedish children have been shown to have deficient or marginal status during the winter months even if the recommended dietary intake is met. Since low vitamin D status has been associated with several disease states, this study investigated the metabolic changes associated with improved vitamin D status due to supplementation. During the 3 winter months, 5-7-year-old children (n=170) in northern (Umeå, 63° N) and southern (Malmö, 55° N) Sweden were supplemented daily with 2 (placebo), 10 or 25 µg of vitamin D. BMI-for-age z-scores (BAZ), S-25(OH)D concentrations, insulin concentrations and the serum metabolome were assessed at baseline and follow-up. S-25(OH)D concentrations increased significantly in both supplementation groups (P<.001). Only arginine and isopropanol concentrations exhibited significant associations with improvements in S-25(OH)D. Furthermore, the extent to which S-25(OH)D increased was correlated with a combination of baseline BAZ and the change in serum fructose concentrations from baseline to follow up (P=.012). In particular, the change in S-25(OH)D concentrations was negatively correlated (P=.030) with the change in fructose concentrations for subjects with BAZ ≥0 and consuming at least 20 µg vitamin D daily. These results suggest that although the metabolic changes associated with improved vitamin D status are small, the effectiveness of dietary supplementation may be influenced by serum fructose concentrations.