Early postnatal and concurrent exposure to metals and neurobehavioral outcomes at 5 years: Associations with individual environmental exposures and mixtures.

BACKGROUND: Little is known about the effect of postnatal exposure to heavy metals on children's behavior problems. This study aimed to investigate the association between metal exposure during different stages of postnatal life and neurobehavioral outcomes in preschool children. METHODS: Urinary concentrations of six metals (arsenic, cadmium, chromium, lead, manganese, and vanadium) were measured using inductively coupled plasma mass spectrometry in 220 participants at two time points: before 1 year and at 5 years of age. Mothers completed the Child Behavior Checklist when the children were 5 years old. Multivariable linear and logistic regression analyses were used to evaluate the association between metal concentrations and behavioral outcomes. We employed Bayesian kernel machine regression (BKMR) to assess possible joint effects and potential interactions between metal mixtures and behavioral outcomes. RESULTS: Concentrations of urinary arsenic (As) in infants were associated with higher scores for anxious/shy behavior problems (ß ranging from 0.03 to 0.23). Further analyses showed that As exposure increased the odds of scores falling into the borderline or clinical range on anxious/depressed, affective, and pervasive developmental problems (ORs: 2.45-3.40). Stratification by sex indicated significance in girls but not in boys. BKMR analysis showed that, among the metal mixtures, As displayed a major effect on behavior scores. Concentrations of urinary cadmium in infants were also associated with higher behavioral scores but did not increase the risk of clinical problems. A cross-sectional survey in 5-year-olds did not show a significant association between concurrent metal exposure and behavioral outcome. CONCLUSION: Our results showed that exposure to As and Cd during infancy was associated with emotional problems in children. The effect of arsenic exposure was more pronounced among female infants. We suggest reducing exposure to toxic metals during early postnatal life to prevent behavioral problems in children."

MAP3K8 is a potential therapeutic target in airway epithelial inflammation.

BACKGROUND: We have previously discovered clusters of sequentially negative and positive modulators of acute inflammation during cytokine stimulation in epithelial cells and identified potential targets for therapy within these clusters. MAP3K8 is a druggable kinase that we found to be a hub of a principal interaction network. We describe here the results of MAP3K8 knockdown in the A549 lung cancer cell line, the BEAS-2B epithelial cell line and normal human bronchial epithelial (NHBE) cells following IL-1ß stimulation. We analysed signalling transduction and global gene expression after IL-1ß stimulation with and without MAP3K8 knockdown, quantifying levels of the inflammatory cytokines IL-6, IL-8 and RANTES levels by qPCRs and/or by ELISAs. We also examined potential small molecule inhibitors for MAP3K8 in the same models. RESULTS: IL-1ß significantly and consistently increased MAP3K8 expression after 2 h in A549, BEAS-2B and NHBE cells. Phosphorylation of MAP3K8 occurred at 20 min after IL-1ß stimulation and MAP3K8 protein was degraded at 30 min. MAP3K8 knockdown significantly reduced IL-6, IL-8 levels after IL-1ß stimulation and yielded a 10-fold enhancement of the anti-inflammatory effects of dexamethasone. Phosphorylation of ERK1/2 (P-ERK1/2) and phosphorylation of SAPK/JNK (P-SAPK/JNK) decreased at 30 min after IL-1ß stimulation with MAP3K8 knockdown. The combination of dexamethasone and MAP3K8 knockdown resulted in greater inhibition of phosphorylated ERK1/2 and SAPK/JNK. Nineteen genes including MMP1, MMP3, MMP10, ITGB8, LAMC2 and PLAT (P corrected < 0.01 respectively) demonstrated a distinct altered temporal response to IL-1ß following suppression of MAP3K8. However, putative MAP3K8 inhibitors including Tpl2-1, Tpl2-2 and GSK2222867A only showed inhibition of IL-6 and IL-8 production at a high dose. CONCLUSIONS: These results confirm that MAP3K8 is a key mediator of the early inflammatory response and that it is a potential target in inflammatory diseases. However, current tool compounds do not effectively inhibit its effects.

T-cell receptor diversity and allergen sensitivity in childhood asthma and atopic dermatitis.

BACKGROUND: Childhood allergies of asthma and atopic dermatitis (AD) involve an overactive T-cell immune response triggered by allergens. However, the impact of T-cell receptor (TCR) repertoires on allergen sensitization and their role in mediating different phenotypes of asthma and AD in early childhood remains unclear. METHODS: A total of 78 children, comprising 26 with asthma alone, 26 with AD alone, and 26 healthy controls (HC), were enrolled. TCR repertoire profiles were determined using a unique molecular identifier system for next-generation sequencing. Integrative analyses of their associations with allergen-specific IgE levels and allergies were performed. RESULTS: The diversity in TCR alpha variable region (TRAV) genes of TCR repertoires and complementarity determining region 3 (CDR3) clonality in TRAV/TRBV (beta) genes were significantly higher in children with AD compared with those with asthma and HC (p < .05). Compared with HC, the expression of TRAV13-1 and TRAV4 genes was significantly higher in both asthma and AD (p < .05), with a significant positive correlation with mite-specific IgE levels (p < .01). In contrast, TRBV7-9 gene expression was significantly lower in both asthma and AD (p < .01), with this gene showing a significant negative correlation with mite-specific IgE levels (p < .01). Furthermore, significantly higher TRAV8-3 gene expression, positively correlated with food-specific IgE levels, was found in children with AD compared with those with asthma (p < .05). CONCLUSION: Integrated TCR repertoires analysis provides clinical insights into the diverse TCR genes linked to antigen specificity, offering potential for precision immunotherapy in childhood allergies.

Metabolomic profiling of maternal plasma identifies inverse associations of acetate and urea with anti-SARS-CoV-2 antibody titers following COVID-19 vaccination during pregnancy.

We conducted a comprehensive metabolomic analysis of plasma samples obtained from pregnant women who displayed varying post-vaccination antibody titers after receiving mRNA-1273-SARS-CoV-2 vaccines. The study involved 62 pregnant women, all of whom had been vaccinated after reaching 24 weeks of gestation. To quantify post-vaccination plasma antibody titers, we employed binding antibody units (BAU) in accordance with the World Health Organization International Standard. Subsequently, we classified the study participants into three distinct BAU/mL categories: those with high titers (above 2000), medium titers (ranging from 1000 to 2000), and low titers (below 1000). Plasma metabolomic profiling was conducted using 1H nuclear magnetic resonance spectroscopy, and the obtained data were correlated with the categorized antibody titers. Notably, in pregnant women exhibiting elevated anti-SARS-CoV-2 antibody titers, reduced plasma concentrations of acetate and urea were observed. A significant negative correlation between these compounds and antibody titers was also evident. An analysis of metabolomics pathways revealed significant inverse associations between antibody titers and four distinct amino acid metabolic pathways: (1) biosynthesis of phenylalanine, tyrosine, and tryptophan; (2) biosynthesis of valine, leucine, and isoleucine; (3) phenylalanine metabolism; and (4) degradation of valine, leucine, and isoleucine. Additionally, an association between the synthesis and degradation pathways of ketone bodies was evident. In conclusion, we identified different metabolic pathways that underlie the diverse humoral responses triggered by COVID-19 mRNA vaccines during pregnancy. Our data hold significant implications for refining COVID-19 vaccination approaches in expectant mothers. KEY MESSAGES : Anti-SARS-CoV-2 antibody titers decline as the number of days since COVID-19 vaccination increases. Anti-SARS-CoV-2 antibody titers are inversely associated with acetate, a microbial-derived metabolite, and urea. Amino acid metabolism is significantly associated with SARS-CoV-2 antibody titers.

Vitamin D level is inversely related to allergen sensitization for risking atopic dermatitis in early childhood.

Background: There are few studies concerning the impact of serum vitamin D status on the risk of allergen sensitization and atopic dermatitis (AD) during early childhood. Method: Children with AD and age-matched healthy controls (HC) were prospectively enrolled at age 0.5, 2, and 4 years. Serum 25-hydroxyvitamin D (25[OH]D) level was measured using Elecsys Vitamin D Total assay. The study utilized the ImmunoCAP assay to analyze specific IgE for food and inhalant allergens, along with total serum IgE levels. It explored the connection between vitamin D levels and allergen sensitization, as well as their influence on AD at different ages. Results: A total of 222 children including 95 (59 AD and 36 HC), 66 (37 AD and 29 HC), and 61 (32 AD and 29 HC) children were classified at age 0.5, 2, and 4 years, respectively. In children with AD, there was a significantly lower vitamin D level at age 2 and 4, but a significantly higher prevalence of food and mite sensitization at all ages in comparison with HC (P < 0.001). Vitamin D level was found to be inversely related to the prevalence of allergen sensitization at age 4 (P < 0.05). However, vitamin D level appeared to have high importance for allergen sensitization at all ages and AD at age 2 and 4 years. Conclusion: Vitamin D deficiency is strongly associated with heightened prevalence of allergen sensitization, potentially increasing the susceptibility to AD in early childhood.

Metabolomic Analysis Reveals the Association of Severe Bronchopulmonary Dysplasia with Gut Microbiota and Oxidative Response in Extremely Preterm Infants.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease mainly affecting premature infants needing ventilation or oxygen for respiratory distress. This study aimed to evaluate the molecular linkages for BPD in very and extremely preterm infants using a metabolomics-based approach. A case-control study of enrolling preterm infants born before 32 weeks gestational age (GA) was prospectively performed. These preterm infants were subsequently stratified into the following two groups for further analysis: no or mild BPD, and moderate or severe BPD based on the 2019 NICHD criteria. Urinary metabolomic profiling was performed using 1H-Nuclear magnetic resonance (NMR) spectroscopy coupled with partial least squares discriminant analysis (PLS-DA) at a corrected age of 6 months. Metabolites significantly differentially related to GA and BPD severity were performed between groups, and their roles in functional metabolic pathways were also assessed. A total of 89 preterm infants born before 32 weeks gestation and 50 infants born at term age (above 37 completed weeks' gestation) served as controls and were enrolled into the study. There were 21 and 24 urinary metabolites identified to be significantly associated with GA and BPD severity, respectively (p < 0.05). Among them, N-phenylacetylglycine, hippurate, acetylsalicylate, gluconate, and indoxyl sulfate were five metabolites that were significantly higher, with the highest importance in both infants with GA < 28 weeks and those with moderate to severe BPD, whereas betaine and N,N-dimethylglycine were significantly lower (p < 0.05). Furthermore, ribose and a gluconate related pentose phosphate pathway were strongly associated with these infants (p < 0.01). In conclusion, urinary metabolomic analysis highlights the crucial role of gut microbiota dysbiosis in the pathogenesis of BPD in preterm infants, accompanied by metabolites related to diminished antioxidative capacity, prompting an aggressive antioxidation response in extremely preterm infants with severe BPD.

Combined Plasma DHA-Containing Phosphatidylcholine PCaa C38:6 and Tetradecanoyl-Carnitine as an Early Biomarker for Assessing the Mortality Risk among Sarcopenic Patients.

The coming of the hyper-aged society in Taiwan prompts us to investigate the relationship between the metabolic status of sarcopenic patients and their most adverse outcome-death. We studied the association between any plasma metabolites and the risk for mortality among older Taiwanese sarcopenic patients. We applied a targeted metabolomic approach to study the plasma metabolites of adults aged ≥65 years, and identified the metabolic signature predictive of the mortality of sarcopenic patients who died within a 5.5-year follow-up period. Thirty-five sarcopenic patients who died within the follow-up period (Dead cohort) had shown a specific plasma metabolic signature, as compared with 54 patients who were alive (Alive cohort). Only 10 of 116 non-sarcopenic individuals died during the same period. After multivariable adjustment, we found that sex, hypertension, tetradecanoyl-carnitine (C14-carnitine), and docosahexaenoic acid (DHA)-containing phosphatidylcholine diacyl (PCaa) C38:6 and C40:6 were important risk factors for the mortality of sarcopenic patients. Low PCaa C38:6 levels and high C14-carnitine levels correlated with an increased mortality risk; this was even the same for those patients with hypertension (HTN). Our findings suggest that plasma PCaa C38:6 and acylcarnitine C14-carnitine, when combined, can be a better early biomarker for evaluating the mortality risk of sarcopenia patients.

The association between human milk fatty acid composition in mothers with an elevated body mass index and infant growth changes.

BACKGROUND & AIMS: Few studies have investigated alternations in human milk polyunsaturated fatty acid (PUFA) composition in the context of maternal obesity and its effects on infant growth trajectories. This study explored whether maternal weight status and breastfeeding type influence human milk FA composition and infant anthropometry during the first six months of life. METHODS: Mother-infant dyads were enrolled from the Prediction of Allergies in Taiwanese Children birth cohort study. Data concerning maternal pre-pregnancy weight, infants' breastfeeding practices, and anthropometric data were obtained regularly. We identified and compared between the composition of 30 FAs in the colostrum and 2-month milk, respectively, in obese/overweight (OB/OW) and normal-weight (NW) mothers. Multiple linear regression analyses were performed to determine the association between PUFA composition at different lactation stages and infant anthropometric parameter changes and to identify the independent variables for body mass index (BMI) z-scores by six months of age. RESULTS: We included 338 mother-infant dyads (OB/OW mothers, 16.9 %). OB/OW mothers exhibited lower total n-3 PUFAs (P = 0.035), higher ratios of arachidonic acid (C20:4n-6)/eicosapentaenoic acid (C20:5n-3) + docosahexaenoic acid (C22:6n-3), and n-6/n-3 PUFA in colostrum (P = 0.037 and 0.011, respectively), and their offspring had higher body weight and BMI z-scores. Nevertheless, no PUFA composition or n-6/n-3 PUFA ratios in colostrum and 2-month milk were associated with anthropometric parameter changes by age 6 months. Infant birth weight z-scores were independently associated with BMI outcomes at age 6 months (adjusted ß = 0.16, 95 % confidence interval (0.05-0.35), P = 0.010) CONCLUSION: Neither n-3 nor n-6 PUFA profiles nor n-6/n-3 PUFA ratios at different lactation stages were found to be associated with anthropometric changes by age 6 months, suggesting that human milk PUFA composition may not be an important determinant of early infant growth trajectories.

Longitudinal analysis of the impact of smoking exposure on atopic indices and allergies in early childhood.

Background: Exposure to smoking is recognized as a health hazard; however, a longitudinal analysis of the impact of smoking exposure in families on the allergic reactions related to childhood atopic diseases has not been well addressed. Methods: Children who completed a three-year follow-up period from the birth cohort were included in this study. The history of smoking exposure was recorded, and the urine cotinine levels were measured at 1 and 6 months, and 1, 2, and 3 years of age. Specific IgE levels against food and mite allergens were measured at age 6 months, and 1, 2, and 3 years. Their relevance to family smoking exposure and the subsequent development of atopic diseases was also analyzed. This study was approved by the Ethics Committee of Chang Gung Memorial Hospital (No. 102-1842C). Results: A total of 198 infants were enrolled in this study. The prevalence of passive smoking exposure among these children was as high as 45%. The urine cotinine levels were significantly higher in children with history of smoking exposure (P < 0.001). At 6 months of age, the food-specific IgE levels and the prevalence of eczema were significantly higher in children with smoking exposure than in those without smoking exposure (P < 0.05). By contrast, the urine cotinine levels were significantly higher in children with IgE sensitization (>100 kU/L, P < 0.05) at 3 years of age, which was also significantly associated with a higher prevalence of allergic rhinitis and development of asthma (P < 0.01). Conclusion: Family smoking exposure appears to be strongly associated with food sensitization in infancy and with IgE production in later childhood. This could potentially increase the susceptibility of developing infantile eczema and subsequent childhood airway allergies.

Metabolomics Analysis Reveals Molecular Signatures of Metabolic Complexity in Children with Hypercholesterolemia.

Despite the importance of hypercholesterolemia in children, it is overlooked, and there are currently few metabolomics-based approaches available to understand its molecular mechanisms. Children from a birth cohort had their cholesterol levels measured with the aim of identifying the metabolites for the molecular biological pathways of childhood hypercholesterolemia. One hundred and twenty-five children were enrolled and stratified into three groups according to cholesterol levels (acceptable, <170 mg/dL, n = 42; borderline, 170-200 mg/dL, n = 52; and high, >200 mg/dL, n = 31). Plasma metabolomic profiles were obtained by using 1H-nuclear magnetic resonance (NMR) spectroscopy, and partial least squares-discriminant analysis (PLS-DA) was applied using the MetaboAnalyst 5.0 platform. Metabolites significantly associated with different cholesterol statuses were identified, and random forest classifier models were used to rank the importance of these metabolites. Their associations with serum lipid profile and functional metabolic pathways related to hypercholesterolemia were also assessed. Cholesterol level was significantly positively correlated with LDL-C and Apo-B level, as well as HDL-C and Apo-A1 level separately, whereas HDL-C was negatively correlated with triglyceride level (p < 0.01). Eight metabolites including tyrosine, glutamic acid, ornithine, lysine, alanine, creatinine, oxoglutaric acid, and creatine were significantly associated with the different statuses of cholesterol level. Among them, glutamic acid and tyrosine had the highest importance for different cholesterol statuses using random forest regression models. Carbohydrate and amino acid metabolisms were significantly associated with different cholesterol statuses, with glutamic acid being involved in all amino acid metabolic pathways (FDR-adjusted p < 0.01). Hypercholesterolemia is a significant health concern among children, with up to 25% having high cholesterol levels. Glutamic acid and tyrosine are crucial amino acids in lipid metabolism, with glutamic-acid-related amino acid metabolism playing a significant role in regulating cholesterol levels.

Introduction of Egg White and Yolk to Infant Diets and Early Childhood Atopic Dermatitis.

This study investigated whether the introduction of allergenic foods in infancy is associated with atopic dermatitis (AD) in early childhood. Information regarding parental allergic histories, the introduction of six possible allergenic foods (fruits, egg white, egg yolk, fish, shellfish, and peanuts), and physician-diagnosed AD was obtained using age-specific questionnaires (0-2 years). Immunoglobulin E, specific to 20 food allergens, was also quantified at 12 months of age. Logistic regression analyses were used to determine the association between individual food introduction and the outcomes of food sensitization and AD. We found AD development by 2 years of age was significantly related to a parental history of allergy (adjusted odds ratio (aOR) = 1.29) and not being introduced to egg white and yolk during infancy (aORs = 2.27 and 1.97, respectively). Stratified analyses revealed that the introduction of both egg white and yolk was negatively associated with AD by 2 years of age, especially for those children where both parents had allergic diseases (aOR = 0.10). In summary, the introduction of egg white and yolk to an infant's diet may be a modifiable factor in reducing the risk of physician-diagnosed AD by 2 years of age, which may be particularly important for infants where both parents have allergies.

Allergic Reactions to Vaccines in Children: From Constituents to Specific Vaccines.

Vaccination is an essential public health measure that helps to reduce the burden of infectious diseases in children. Although vaccines have an excellent safety record and the association of severe allergic reactions is rare, public concerns about vaccine safety can lead to incomplete vaccination coverage in children with or without allergies. Therefore, it is important to understand the mechanisms and implications of allergic reactions to vaccines and define strategies to manage them to provide the safest care for vaccine recipients. In this review, we provide an overview on the types of allergic reactions that can occur after vaccination, including those caused by various vaccine constituents. We also discuss the mechanisms underlying these allergic reactions and the recommended diagnosis and management strategies for children with a history of suspected allergic reactions to vaccines. An improved understanding of allergic reactions to vaccines can aid in the enhancement of the safety and effectiveness of vaccination.

Phenotype-specific signatures of systems-level gut microbiome associated with childhood airway allergies.

BACKGROUND: Perturbation of gut symbiosis has been linked to childhood allergic diseases. However, the underlying host-microbe interaction connected with specific phenotypes is poorly understood. METHODS: To address this, integrative analyses of stool metagenomic and metabolomic profiles associated with IgE reactions in 56 children with mite-sensitized airway allergies (25 with rhinitis and 31 with asthma) and 28 nonallergic healthy controls were conducted. RESULTS: We noted a decrease in the number and abundance of gut microbiome-encoded carbohydrate-active enzyme (CAZyme) genes, accompanied with a reduction in species richness, in the asthmatic gut microflora but not in that from allergic rhinitis. Such loss of CAZymes was consistent with the observation that a CAZyme-linked decrease in fecal butyrate was found in asthmatics and negatively correlated with mite-specific IgE responses. Different from the CAZymes, we demonstrated an increase in α diversity at the virulome levels in asthmatic gut microbiota and identified phenotype-specific variations of gut virulome. Moreover, use of fecal metagenomic and metabolomic signatures resulted in distinct effects on differentiating rhinitis and asthma from nonallergic healthy controls. CONCLUSION: Overall, our integrative analyses reveal several signatures of systems-level gut microbiome in robust associations with fecal metabolites and disease phenotypes, which may be of etiological and diagnostic implications in childhood airway allergies.

Longitudinal investigation of pathogenic bacterial colonization in early childhood: Emphasis on the determinants of Moraxella catarrhalis colonization.

BACKGROUND: Moraxella catarrhalis is a common, potential pathogen colonizing the respiratory tract in children. However, there is little information regarding the determinants of M. catarrhalis colonization and disease development. METHODS: A population-based cohort study was conducted to collect nasopharyngeal swabs from children aged 1, 2, 4, 6, 12, 18, 24, 36, and 60 months for the detection of four common respiratory tract pathogens, including Staphylococcus aureus, M. catarrhalis, Streptococcus pneumoniae, and Haemophilus influenzae. Questionnaires on breastfeeding status were administered during each visit. RESULTS: A total of 921 children were enrolled between 2012 and 2018. S.aureus was the most common pathogen, although the rates declined during the initial 18 months of life; in contrast, the other three pathogens increased during the first 5 years of life. M. catarrhalis was the second most common colonizing pathogen in all age groups, with prevalence ranging from 0.8% (7/842) at one month to 20.4% (33/162) at 60 months of age. Breastfed children (odds ratio [OR]: 0.56; 95% confidence interval [CI]: 0.35-0.92; P = 0.02) had a lower potential for M. catarrhalis carriage; however, infants with a longer duration of exclusive breastfeeding (OR: 1.12; 95% CI: 1.01-1.25; P = 0.04), especially >12 months of age, had a higher rate of M. catarrhalis carriage. CONCLUSION: Breastfeeding should be promoted because it may be correlated with a lower risk of M. catarrhalis carriage. However, an extended period of exclusive breastfeeding may be positively associated with M. catarrhalis colonization.

Increased fecal human beta-defensin-2 expression in preterm infants is associated with allergic disease development in early childhood.

Background: This study aimed to investigate whether fecal human beta-defensins (HBD)-2 and eosinophil cationic protein (ECP) expression in preterm infants are associated with allergic disease development by age 2 years. Methods: Preterm infants' stool samples were collected at the age of 6 and 12 months postnatally. Information regarding medication exposure histories (antibiotics, antipyretics, probiotics) and physician-diagnosed allergic diseases was obtained using age-specific questionnaires and medical records. We compared the 6-month and 12-month fecal HBD-2 and ECP concentrations between the medication exposure and non-exposure group, respectively, and between children who developed allergic diseases and those who did not by 2 years of age. Univariate and multivariable logistic regression analyses were performed to investigate independent variables related to physician-diagnosed allergic diseases by 2 years of age. Results: Seventy-four preterm infants (gestational age, 31-36 weeks) were included. Fecal HBD-2 levels were significantly increased at 12 months of age among children who developed allergic diseases compared to those who did not (37.18 ± 11.80 ng/g vs. 8.56 ± 4.33 ng/g, P = 0.011). This association was more apparent among allergic children given antibiotics (50.23 ± 16.15 ng/g vs. 9.75 ± 7.16 ng/g, P = 0.008) or antipyretics (46.12 ± 14.22 ng/g vs. 10.82 ± 6.81 ng/g, P = 0.018) during the first year, whereas among allergic children who were previously not exposed to antibiotics or antipyretics, the differences were not significant. Results of the multivariable logistic regression analysis indicated that HBD-2 concentration in 12-month stools was an independent indicator associated with physician-diagnosed allergic diseases by 2 years of age (adjusted odds ratio: 1.03 [95% confidence interval: 1.00-1.05], P = 0.036). Our data revealed a lack of association between fecal ECP and allergic diseases. Conclusions: We found that preterm infants who expressed high fecal HBD-2 at 12 months of age were associated with physician-diagnosed allergic diseases by the age of 2 years. Further studies are needed to determine the role of fecal HBD-2 in the development of allergic diseases.

Metabolomics analysis reveals molecular linkages for the impact of vitamin D on childhood allergic airway diseases.

BACKGROUND: Several studies have reported the relevance between serum vitamin D and allergic immunoglobulin E (IgE) responses and atopic diseases. However, a metabolomics-based approach to the impacts of vitamin D on allergic reactions remains unclear. METHODS: A total of 111 children completed a 3-year follow-up were enrolled and classified based on longitudinal vitamin D status (≥ 30 ng/ml, n = 54; 20-29.9 ng/ml, n = 41; <20 ng/ml, n = 16). Urinary metabolomic profiling was performed using 1 H-Nuclear magnetic resonance (NMR) spectroscopy at age 3. Integrative analyses of their associations related to vitamin D levels, atopic indices, and allergies were performed, and their roles in functional metabolic pathways were also assessed. RESULTS: Six and five metabolites were identified to be significantly associated with vitamin D status and atopic diseases, respectively (FDR-adjusted p-value <.05). A further correlation analysis revealed that vitamin D-associated 3-hydroxyisobutyric acid and glutamine were positively correlated with atopic disease-associated succinic acid and alanine, respectively. Furthermore, hippuric acid was negatively correlated with atopic disease-associated formic acid, which was positively correlated with vitamin D level (p < .01). Absolute eosinophil count (AEC) was positively correlated with serum D. pteronyssinus- and D. farinae-specific IgE level (p < .01) but negatively correlated with vitamin D level (p < .05). Amino acid metabolisms were significantly associated with vitamin D related to childhood allergies. CONCLUSION: Integrative metabolomic analysis provides the link of vitamin D-associated metabolites with the gut microbiome and immunoallergic reactions related to childhood allergies.

Nasopharyngeal microbial profiles associated with the risk of airway allergies in early childhood.

BACKGROUND: Airway microbiota may play an important role in regulating the immune response related to allergic respiratory diseases. A molecular-based approach was used to analyze the association between nasopharyngeal microbiota, serum immunoglobin (Ig)E levels, and childhood respiratory allergies. METHODS: Nasopharyngeal swabs were collected from children aged 36 months with three phenotypes, including allergic respiratory diseases plus atopy, atopy alone, and healthy controls for microbiome analysis using Illumina-based 16S rRNA gene sequencing. RESULTS: In total, 87 children were enrolled, including 36 with allergic respiratory diseases plus atopy, 21 with atopy alone, and 30 healthy controls. Proteobacteria (45.7%), Firmicutes (29.3%), and Actinobacteria (15.3%) were the most prevalent phyla in the study population. Compared with healthy controls, a lower Chao1 index was found in children with allergies (P < 0.035), indicating that bacterial richness was inversely associated with airway allergies. Additionally, in comparison with healthy controls, the genera Acinetobacter, Moraxella, Asaia, and Rhodococcus were more abundant and positively correlated with total serum IgE levels in children with allergies (P < 0.01), whereas the genera Enterococcus and Rickettsia were inversely correlated with total IgE levels, and also appeared to be negatively associated with airway allergies (P < 0.01). CONCLUSIONS: The composition of the nasopharyngeal microbiota alteration may have an influence on childhood respiratory allergies. The inverse association between bacterial richness and allergies postulated that children living in a microbially hygienic environment may increase their risk of developing respiratory allergies.

Longitudinal Metabolomic Analysis Reveals Gut Microbial-Derived Metabolites Related to Formula Feeding and Milk Sensitization Development in Infancy.

Early exposure to formula milk increases the likelihood of cow's milk sensitization and food allergies in the later childhood. However, the underlying mechanisms are multifactorial and unclear. Fifty-five children from a follow-up birth cohort study were grouped into exclusive breastfeeding (EBF, n = 33) and formula feeding (EFF, n = 22) in the first six months of life. Urinary metabolites were longitudinally assessed and analyzed at 6 months, 1, and 2 years of age using 1H-nuclear magnetic resonance (NMR) spectroscopy. Integrated analysis of metabolic profiling associated with formula feeding and milk sensitization related to IgE reactions was also investigated. Twenty-two metabolites were significantly obtained in the EFF set at age 0.5, whereas nine metabolites were predominantly obtained in the milk sensitization set at age 1. A subsequent analysis of metabolic change from 6 months to age 1 identified eight metabolites, including 3-methyl-2-oxovaleric acid, glutarate, lysine, N-phenylacetylglycine, N,N-dimethylglycine, 3-indoxysulfate, 2-oxoglutaric acid, and pantothenate associated with formula feeding and milk sensitization with same trend variation. Among them, 3-indoxysulfate, N-phenylacetylglycine, and N,N-dimethylglycine were gut microbial-derived without IgE association. By contrast, 3-methyl-2-oxovaleric acid, glutarate, and lysine were IgE related associated with formula feeding contributing to milk sensitization (p < 0.05). Longitudinal urinary metabolomic analysis provides molecular insight into the mechanism of formula feeding associated with milk sensitization. Gut microbial-derived metabolites associated with formula feeding and IgE associated metabolites related to branched-chain amino acid metabolism play roles in developing sensitization and allergic symptoms in response to formula feeding.

Longitudinal changes in body mass index Z-scores during infancy and risk of childhood allergies.

BACKGROUND: Few studies address the dynamic changes of body mass index (BMI) Z-scores during infancy with breastfeeding and their impact on childhood atopic diseases. METHODS: A total of 183 children from a birth cohort regularly followed-up for 4 years were enrolled in this study. Time series data of BMI Z-scores from 1 month to 2 years of age was clustered using K-means method in R software. Breastfeeding status during the first 6 months of life was recorded and classified. The total serum and specific immunoglobulin E (IgE) levels to food and inhalant allergens were measured at age 0.5, 1, 1.5, and 2 years. RESULTS: Using K-means clustering, the dynamic changes in BMI Z-scores were classified into three clusters (cluster A, increasing, n = 62; cluster B; decreasing, n = 62; cluster C, constant low, n = 59). Despite having no statistical association with atopic diseases, a decreasing trend in infantile BMI Z-scores was significantly associated with a higher prevalence of IgE sensitization at age 1 which increased the risk of rhinitis development at age 4 (P = 0.007). No difference in BMI Z-scores was determined between different breastfeeding patterns. However, exclusive formula feeding ≥6 months was found to be significantly associated with mite sensitization at age 1.5 years which risks asthma development at age 4 (P = 0.001). CONCLUSIONS: A decreasing trend of BMI Z-scores during infancy is determined to be inversely associated with IgE and allergen sensitization, which may potentially increase the risk of allergies in early childhood.

Cord blood soluble Fas ligand linked to allergic rhinitis and lung function in seven-year-old children.

BACKGROUND: Serum or cord blood soluble Fas ligand (FasL) has been related to asthma, allergic rhinitis, and atopic dermatitis in cross-sectional and short-term follow-up studies. However, the association of cord blood soluble FasL with long-term allergic outcomes has seldom been investigated. METHODS: The Prediction of Allergies in Taiwanese Children birth cohort study recruited healthy newborns upon delivery. At birth, blood was collected from the umbilical cords of these children, and the cord blood soluble Fas ligand levels were measured. At the age of seven years, the allergic outcome of each child was diagnosed by pediatric allergists and pulmonologists. Tests were conducted to measure the specific immunoglobulin E, fractional exhaled nitric oxide (FeNO), and pulmonary function levels of each child. RESULTS: Cord blood soluble FasL levels were higher in seven-year-old children with allergic rhinitis (Odds ratio [OR] = 2.41, p = 0.012) and expiratory airway obstruction (the highest forced expiratory volume in 1 second/forced vital capacity < 90%, OR = 2.11, p = 0.022). The FeNO and Dermatophagoides pteronyssinus-specific immunoglobulin E levels of seven-year-old children were positively correlated with cord blood soluble FasL levels (p = 0.006 and 0.02, respectively). CONCLUSION: In this birth cohort, the cord blood soluble FasL levels were associated with allergic rhinitis, obstructive-type lung function, FeNO, and house dust mite sensitization in 7-year-old children. The cord blood soluble FasL level might be used as a predictor for allergic diseases in children who are 7 years old.