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Introduction: The diagnosis and management of cow's milk allergy (CMA) is a topic of debate and controversy. Our aim was to compare the opinions of expert groups from the Middle East (n = 14) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (n = 13). Methods: These Expert groups voted on statements that were developed by the ESPGHAN group and published in a recent position paper. The voting outcome was compared. Results: Overall, there was consensus amongst both groups of experts. Experts agreed that symptoms of crying, irritability and colic, as single manifestation, are not suggestive of CMA. They agreed that amino-acid based formula (AAF) should be reserved for severe cases (e.g., malnutrition and anaphylaxis) and that there is insufficient evidence to recommend a step-down approach. There was no unanimous consensus on the statement that a cow's milk based extensively hydrolysed formula (eHF) should be the first choice as a diagnostic elimination diet in mild/moderate cases. Although the statements regarding the role for hydrolysed rice formula as a diagnostic and therapeutic elimination diet were accepted, 3/27 disagreed. The votes regarding soy formula highlight the differences in opinion in the role of soy protein in CMA dietary treatment. Generally, soy-based formula is seldom available in the Middle-East region. All ESPGHAN experts agreed that there is insufficient evidence that the addition of probiotics, prebiotics and synbiotics increase the efficacy of elimination diets regarding CMA symptoms (despite other benefits such as decrease of infections and antibiotic intake), whereas 3/14 of the Middle East group thought there was sufficient evidence. Discussion: Differences in voting are related to geographical, cultural and other conditions, such as cost and availability. This emphasizes the need to develop region-specific guidelines considering social and cultural conditions, and to perform further research in this

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Background: The basophil activation test is an emerging clinical tool in the diagnosis of cow's milk allergy (CMA). The aim was to assess the association between the basophil allergen threshold sensitivity to the major milk protein casein (casein-specific CD-sens), the levels of milk- and casein-specific Immunoglobulin E antibodies (IgE-ab), and the severity of allergic reactions at milk challenges. Methods: We enrolled 34 patients aged 5–15 (median 9) years who underwent a double-blind placebo-controlled milk-challenge (DBPCMC) as screening before inclusion in an oral immunotherapy study for CMA. The severity of the allergic reaction at the DBPCMC was graded using Sampson's severity score. Venous blood was drawn before the DBPCMC. Milk- and casein-specific IgE-ab were analyzed. Following in vitro stimulation of basophils with casein, casein-specific CD-sens, was determined. Results: Thirty-three patients completed the DBPCMC. There were strong correlations between casein-specific CD-sens and IgE-ab to milk (rs = 0.682, p <.001), and between casein-specific CD-sens and IgE-ab to casein (rs = 0.823, p <.001). There was a correlation between the severity of the allergic reaction and casein-specific CD-sens level (rs = 0.395, p =.041) and an inverse correlation between casein-specific CD-sens level and the cumulative dose of milk protein to which the patient reacted at the DBPCMC (rs = −0.418, p =.027). Among the 30 patients with an allergic reaction at the DBPCMC, 67% had positive casein-specific CD-sens, 23% had negative casein-specific CD-sens, and 10% were declared non-responders. Conclusion: Two thirds of those reacting at the DBPMC had positive casein-specific CD-sens, but reactions also occurred despite negative casein-specific CD-sens. The association between casein-specific CD-sens and the severity of the allergic reaction and cumulative dose of milk protein, respectively, was moderate.

Human milk, due to its unique composition, is the optimal standard for infant nutrition. Osteopontin (OPN) is abundant in human milk but not bovine milk. The addition of bovine milk osteopontin (bmOPN) to formula may replicate OPN’s concentration and function in human milk. To address safety concerns, we convened an expert panel to assess the adequacy of safety data and physiological roles of dietary bmOPN in infancy. The exposure of breastfed infants to human milk OPN (hmOPN) has been well-characterized and decreases markedly over the first 6 months of lactation. Dietary bmOPN is resistant to gastric and intestinal digestion, absorbed and cleared from circulation within 8–24 h, and represents a small portion (<5%) of total plasma OPN. Label studies on hmOPN suggest that after 3 h, intact or digested OPN is absorbed into carcass (62%), small intestine (23%), stomach (5%), and small intestinal perfusate (4%), with <2% each found in the cecum, liver, brain, heart, and spleen. Although the results are heterogenous with respect to bmOPN’s physiologic impact, no adverse impacts have been reported across growth, gastrointestinal, immune, or brain-related outcomes. Recombinant bovine and human forms demonstrate similar absorption in plasma as bmOPN, as well as effects on cognition and immunity. The panel recommended prioritization of trials measuring a comprehensive set of clinically relevant outcomes on immunity and cognition to confirm the safety of bmOPN over that of further research on its absorption, distribution, metabolism, and excretion. This review offers expert consensus on the adequacy of data available to assess the safety of bmOPN for use in infant formula, aiding evidence-based decisions on the formulation of infant formula.

Consumption of acidic fruit pouches in infancy may damage the epithelial barrier in the gastrointestinal tract and is suggested to increase allergy risk. We aimed to explore if a high fruit pouch consumption is associated with a higher incidence of early allergic manifestations. We included 2959 parent–child dyads from the Swedish prospective, population-based NorthPop birth cohort study with parentally reported data on frequency of fruit pouch consumption at 9 months of age, as well as parentally reported eczema, wheeze, physician-diagnosed asthma, and food allergy in the first 18 months of life. Immunoglobulin E levels (IgE) in serum (n = 1792), as response to a food mix and an inhalant mix, were determined at age 18 months. Compared with no consumption, daily consumption of one or more pouches at 9 months of age was associated with inhalant sensitization (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.06–4.87, n = 1792) but did not remain significant in the multivariable adjusted model (aOR 2.08, 95% CI 0.95–4.53, n = 1679). There were no associations between fruit pouch consumption and allergic manifestations at this young age. This study suggests that fruit pouch consumption is not associated with allergic phenotypes or IgE sensitization in early childhood.

Rapid urbanisation and global biodiversity loss are changing human microbial ecology, which is accelerated by the progressive loss of protective factors for example, contact with natural environments and animals, and less consumption of traditional foods. Early life represents a critical window both for optimal colonisation and immune system development. The frequency of caesarean section (CS) delivery is high and increasing in many parts of the world, and there is strong evidence that CS delivery has a marked influence on early colonisation, with depletion of strains of commensal bacteria. Colonisation of human ecological niches, particularly the gastrointestinal tract, parallels normal local and systemic immune development. CS delivery has been associated with increased risk of allergic diseases and there is emerging evidence that this is mediated by alterations of the microbiome. Small proof-of-concept studies have demonstrated that transfer of maternal vaginal microbes directly after elective CS delivery partially restores the offspring microbiome but transfer of maternal faecal microbes is needed for restoration of the offspring gut microbiome. Randomised clinical trials (RCTs) using microbiome seeding after CS delivery are underway and are anticipated to unravel if this procedure will impact microbial, immunological and metabolic programming, and decrease allergy risk. RCTs using prebiotics and probiotics for primary prevention of allergic diseases (primarily eczema) have been conducted, but large heterogeneity between studies have hampered meta-analysis and the development of specific practice guidelines. In the first RCT to test the biodiversity hypothesis, exposure to playground sand with added microbially diverse soil, led to shifts in the skin and gut bacterial communities and increases in immunoregulatory biomarkers compared with exposure to microbially poor sand (placebo). Collectively, appropriate health-supporting microbial exposures by optimised nutr

Taste perception is a well-documented driving force in food selection, with variations in, e.g., taste receptor encoding and glucose transporter genes conferring differences in taste sensitivity and food intake. We explored the impact of maternal innate driving forces on sweet taste preference and intake and assessed whether their children differed in their intake of sweet foods or traits related to sweet intake. A total of 133 single nucleotide polymorphisms (SNPs) in genes reported to associate with eating preferences were sequenced from saliva-DNA from 187 mother-and-child pairs. Preference and intake of sweet-, bitter-, sour-, and umami-tasting foods were estimated from questionnaires. A total of 32 SNP variants associated with a preference for sweet taste or intake at a p-value < 0.05 in additive, dominant major, or dominant minor allele models, with two passing corrections for multiple testing (q < 0.05). These were rs7513755 in the TAS1R2 gene and rs34162196 in the OR10G3 gene. Having the T allele of rs34162196 was associated with higher sweet intake in mothers and their children, along with a higher BMI in mothers. Having the G allele of rs7513755 was associated with a higher preference for sweets in the mothers. The rs34162196 might be a candidate for a genetic score for sweet intake to complement self-reported intakes.

Background: Early life antibiotic treatment is one likely exposure influencing allergy risk. The objective was to investigate associations between pre- and postnatal antibiotic exposures and the development of allergic manifestations until age 18 months. Methods: We included 1387 mother–child dyads from the prospective, population-based NorthPop birth cohort study. Data on antibiotic exposures in pregnancy and childhood were collected by web-based questionnaires. Until the child turned 18 months old, parents (n = 1219) reported symptoms of wheeze, eczema, and physician-diagnosed asthma; parents (n = 1025) reported physician-diagnosed food allergy. At age 18 months, serum immunoglobulin E levels to inhalant (Phadiatop) and food (Food mix fx5) allergens were determined. Associations were estimated using bivariable and multivariable logistic regressions. Results: Prenatal antibiotic exposure was positively associated with food sensitization in the crude (OR 1.82, 95% CI 1.01–3.26) but not in the adjusted analyses (aOR 1.58, 0.82–3.05). A borderline significant association was found between prenatal exposure and wheeze (aOR 1.56, 0.95–2.57). Postnatal antibiotics were positively associated with wheeze (aOR 2.14, 1.47–3.11), asthma (aOR 2.35, 1.32–4.19), and eczema (aOR 1.49, 1.07–2.06). Postnatal antibiotics were negatively associated with food sensitization (aOR 0.46, 95% CI 0.25–0.83) but not with food allergy nor sensitization to inhalants. Conclusion: Pre- and postnatal antibiotic exposure demonstrated positive associations with allergic manifestations and the former also with food sensitization. In contrast, there was a negative association between postnatal antibiotics and food sensitization. Food sensitization is often transient but may precede respiratory allergies. Future studies should investigate the relationship between antibiotic exposure and food sensitization later in childhood.

BACKGROUND: We aimed to characterize breast milk microbiota and define associations with saliva and fecal microbiota and selected diseases in preschool children. METHODS: In a longitudinal cohort study, the microbiotas from breast milk, mouth, and fecal samples were characterized by 16S rRNA gene sequencing. Questionnaires and medical records provided information on demographics, medical, and dental data. RESULTS: The phylogeny in breast milk, saliva swabs, and feces differed at all levels (p < 0.0003), though all harbored species in Streptococcus, Veillonella, and Haemophilus. Species richness was highest in breast milk with increasing resemblance with the oral swab microbiota by increasing age. Caries-affected children at age 5 had been fed breast milk with tenfold higher abundance of caries-associated bacteria, e.g., Streptococcus mutans, than caries-free children (p < 0.002). At that age, taxa, e.g., Neisseria sicca were overrepresented in saliva swabs of children with otitis media (LDA score >2, p < 0.05). Gut symbionts, e.g., Bacteroides, were underrepresented in 3-month fecal samples in children later diagnosed with allergic disease (LDA score >2, p < 0.05). CONCLUSIONS: Distinct microbiotas for the three sources were confirmed, though resemblance between milk and oral swab microbiota increased by age. Future studies should evaluate if the observed associations with disease outcomes are causal. IMPACT: Few studies have studied the association between breast milk microbiota and gastrointestinal microbiota beyond early infancy. The present study confirms distinct microbiota profiles in breast milk, saliva swabs, and feces in infancy and indicates increasing resemblance between breast milk and the oral microbiota by increasing age. The fecal microbiota at 3 months was associated with later allergic disease; the saliva microbiota by age 5 differed between children with and without otitis media at the same age; and children with caries by age 5 h

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 f

Concerns have been raised that an overconsumption of baby food fruit pouches among toddlers might increase the risk of childhood obesity. This study aimed to quantify the consumption of fruit pouches and other fruit containing food products and to explore potential correlations between the consumption of these products and body-mass index z-score (BMIz) at 18 months, taking other predictive factors into consideration. The study was based on 1499 children and one-month-recall food frequency questionnaires from the Swedish population-based birth cohort NorthPop. Anthropometric outcome data were retrieved from child health care records. BMIz at 18 months of age was correlated to maternal BMI and gestational weight gain and inversely correlated to fruit juice consumption and breastfeeding. BMIz at 18 months of age was not correlated to consumption of fruit pouches, sugar-sweetened beverages, whole fruit or milk cereal drink. Overweight at 18 months of age was correlated to maternal BMI and inversely correlated to breastfeeding duration. To our knowledge, this is the first study that investigates possible associations between baby food fruit pouch consumption and overweight in toddlers. We found that moderate fruit pouch consumption is not associated with excess weight at 18 months of age.