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Background: The infant fecal microbiome is known to impact subsequent asthma risk, but the environmental exposures impacting this association, the role of the maternal microbiome, and how the microbiome impacts different childhood asthma phenotypes are unknown. Methods: Our objective was to identify associations between features of the prenatal and early‐life fecal microbiomes and child asthma phenotypes. We analyzed fecal 16 s rRNA microbiome profiling and fecal metabolomic profiling from stool samples collected from mothers during the third trimester of pregnancy (n = 120) and offspring at ages 3–6 months (n = 265), 1 (n = 436) and 3 years (n = 506) in a total of 657 mother–child pairs participating in the Vitamin D Antenatal Asthma Reduction Trial. We used clinical data from birth to age 6 years to characterize subjects with asthma as having early, transient or active asthma phenotypes. In addition to identifying specific genera that were robustly associated with asthma phenotypes in multiple covariate‐adjusted models, we clustered subjects by their longitudinal microbiome composition and sought associations between fecal metabolites and relevant microbiome and clinical features. Results: Seven maternal and two infant fecal microbial taxa were robustly associated with at least one asthma phenotype, and a longitudinal gut microenvironment profile was associated with early asthma (Fisher exact test p =.03). Though mode of delivery was not directly associated with asthma, we found substantial evidence for a pathway whereby cesarean section reduces fecal Bacteroides and microbial sphingolipids, increasing susceptibility to early asthma. Conclusion: Overall, our results suggest that the early‐life, including prenatal, fecal microbiome modifies risk of asthma, especially asthma with onset by age 3 years. [ABSTRACT FROM AUTHOR]

Background: Intestinal microenvironmental perturbations may increase food allergy risk. We hypothesize that children with clinical food allergy, those with food sensitization, and healthy children can be differentiated by intestinal metabolites in the first years of life. Methods: In this ancillary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we performed untargeted metabolomic profiling in 824 stool samples collected at ages 3–6 months, 1 year and 3 years. Subjects included 23 with clinical food allergy at age 3 and/or 6 years, 151 with food sensitization but no clinical food allergy, and 220 controls. We identified modules of correlated, functionally related metabolites and sought associations of metabolite modules and individual metabolites with food allergy/sensitization using regression models. Results: Several modules of functionally related intestinal metabolites were reduced among subjects with food allergy, including bile acids at ages 3–6 months and 1 year, amino acids at age 3–6 months, steroid hormones at 1 year, and sphingolipids at age 3 years. One module primarily containing diacylglycerols was increased in those with food allergy at age 3–6 months. Fecal caffeine metabolites at age 3–6 months, likely derived from breast milk, were increased in those with food allergy and/or sensitization (beta = 5.9, 95% CI 1.0–10.8, p =.02) and were inversely correlated with fecal bile acids and bilirubin metabolites, though maternal plasma caffeine levels were not associated with food allergy and/or sensitization. Conclusions: Several classes of bioactive fecal metabolites are associated with food allergy and/or sensitization including bile acids, steroid hormones, sphingolipids, and caffeine metabolites. [ABSTRACT FROM AUTHOR]

Maternal infection and stress during the prenatal period have been associated with adverse neurodevelopmental outcomes in offspring, suggesting that biomarkers of increased inflammation in the mothers may associate with poorer developmental outcomes. In 491 mother–child pairs from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we investigated the association between maternal levels of two inflammatory biomarkers; interleukin-8 (IL-8) and C-Reactive Protein (CRP) during early (10–18 wks) and late (32–38 wks) pregnancy with offspring scores in the five domains of the Ages and Stages Questionnaire, a validated screening tool for assessing early life development. We identified a robust association between early pregnancy IL-8 levels and decreased fine-motor (β: −0.919, 95%CI: −1.425, −0.414, p = 3.9 × 10−4) and problem-solving skills at age two (β: −1.221, 95%CI: −1.904, −0.414, p = 4.9 × 10−4). Associations between IL-8 with other domains of development and those for CRP did not survive correction for multiple testing. Similarly, while there was some evidence that the detrimental effects of early pregnancy IL-8 were strongest in boys and in those who were not breastfed, these interactions were not robust to correction for multiple testing. However, further research is required to determine if other maternal inflammatory biomarkers associate with offspring neurodevelopment and work should continue to focus on the management of factors leading to increases in IL-8 levels in pregnant women. [ABSTRACT FROM AUTHOR]

Background Alterations in the intestinal microbiome are prospectively associated with the development of asthma; less is known regarding the role of microbiome alterations in food allergy development. Methods Intestinal microbiome samples were collected at age 3-6 months in children participating in the follow-up phase of an interventional trial of high-dose vitamin D given during pregnancy. At age 3, sensitization to foods (milk, egg, peanut, soy, wheat, walnut) was assessed. Food allergy was defined as caretaker report of healthcare provider-diagnosed allergy to the above foods prior to age 3 with evidence of IgE sensitization. Analysis was performed using Phyloseq and DESeq2; P-values were adjusted for multiple comparisons. Results Complete data were available for 225 children; there were 87 cases of food sensitization and 14 cases of food allergy. Microbial diversity measures did not differ between food sensitization and food allergy cases and controls. The genera Haemophilus (log2 fold change −2.15, P=.003), Dialister (log2 fold change −2.22, P=.009), Dorea (log2 fold change −1.65, P=.02), and Clostridium (log2 fold change −1.47, P=.002) were underrepresented among subjects with food sensitization. The genera Citrobacter (log2 fold change −3.41, P=.03), Oscillospira (log2 fold change −2.80, P=.03), Lactococcus (log2 fold change −3.19, P=.05), and Dorea (log2 fold change −3.00, P=.05) were underrepresented among subjects with food allergy. Conclusions The temporal association between bacterial colonization and food sensitization and allergy suggests that the microbiome may have a causal role in the development of food allergy. Our findings have therapeutic implications for the prevention and treatment of food allergy. [ABSTRACT FROM AUTHOR]

• Communication domain of the Ages and Stages Questionnaire represents proxy for autism development. • Children with poor communication skills development more likely to report food allergy and eczema. • Autism; eczema and food allergy may share etiology involving dysregulated tryptophan metabolism. Autism Spectrum Disorders (ASD) are complex and multifactorial. Previous investigations have revealed associations between allergic disease and ASD, which are characterized by impaired communication skills. In this study we observed an association between allergic disease and communication skills development as assessed by the Ages and Stages Questionnaire (ASQ) communication score, as a proxy for ASD, among children who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In particular, we observed significant associations between both a diagnosis of eczema at age 3 years (OR = 1.87; confidence interval [CI]: 0.97–3.47; p = 0.054) and a diagnosis of food allergy at age 6 years (OR = 3.61; 95% CI: 1.18–9.85; p = 0.015) with ASQ communication score. Plasma metabolomics analyses suggest that dysregulated tryptophan metabolism may contribute to the pathogenesis of these co-morbidities. [ABSTRACT FROM AUTHOR]

Background: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. Method s : We performed targeted LC–MS/MS‐based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta‐analyzed together. Results: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p‐value range: 1.863E‐04 to 2.24E‐3], increased ceramide levels were associated with asthma risk factors [meta p‐value range: 7.75E‐5 to.013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. Conclusion: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations. [ABSTRACT FROM AUTHOR]

Problem: Promotion of a healthy pregnancy is dependent on a coordinated immune response that minimizes inflammation at the maternal–fetal interface. Few studies investigated the effect of fetal sex on proinflammatory biomarkers during pregnancy and whether maternal race could impact this association. We aimed to examine whether fetal sex could, independently of maternal race/ethnicity and the condition of pregnancy (normal vs. complicated), impact inflammatory markers (C‐reactive protein [CRP] and interleukin‐8 [IL‐8] levels) in early and late pregnancy. Methods of study: This study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART, N = 816). Maternal serum CRP and IL‐8 levels were measured in early and late pregnancy (10–18 and 32–38 weeks of gestation, respectively). Five hundred and twenty‐eight out of 816 pregnant women who participated in the trial had available CRP and IL‐8 measurements at both study time points. We examined the association of fetal sex with early and late CRP and IL‐8 levels and their paired sample difference. We further investigated whether maternal race/ethnicity, pregnancy complications (i.e., preeclampsia and gestational diabetes), and early pregnancy body mass index (BMI) could affect the association between these two biomarkers and fetal sex adjusting for potential confounders. For this purpose, we used generalized linear and logistic regression models on log‐normalized early and late CRP and IL‐8 levels as well as their split at median to form high and low groups. Results: Women pregnant with male fetuses (266/528 = 56.5%) had higher CRP levels in early to mid‐pregnancy (β =.18: 95% confidence interval [CI]: CI = 0.03–0.32; p =.02). Twenty‐seven percent (143/528) of the study subjects were Hispanic. Hispanic African American [AA] women and women of races other than White and AA had higher levels of CRP at early to mid‐pregnancy compared with White women (β =.57; 95% CI: 0.17–0.97; p <.01 and β =.27; 95% CI: 0.05–0.48; p =.02, respectively). IL‐8 levels were not associated with fetal sex in early and late pregnancy (p's >.05). Other factors such as gestational diabetes and early pregnancy BMI were associated with higher CRP levels and higher CRP and IL‐8 levels, respectively. Dichotomizing log‐normalized cytokine levels at the median in a sensitivity analysis, women with male fetuses had lower odds of high (above‐median) IL‐8 levels at early pregnancy. Also, women with races other than AA and White carrying male fetuses had higher odds of having high (above‐median) late‐pregnancy CRP and early‐pregnancy IL‐8 levels (adjusted odds ratio [aOR] = 3.80, 95% CI: 0.24–1.23; p =.02 and aOR = 3.57; 95% CI: 0.23–1.03; p =.02, respectively). Of the pregnancy complications, women with gestational diabetes mellitus had a higher paired difference of early and late pregnancy CRP levels (β =.38; 95% CI: 0.09–0.68; p =.01), but no difference in IL‐8 levels (p's >.05). No associations between the inflammatory markers and preeclampsia were found. Conclusion: Fetal sex is associated with CRP in early pregnancy and an association with IL‐8 in early pregnancy is implied. Our study further indicates that maternal race/ethnicity could be a contributing factor in the relationship between fetal sex and inflammatory responses during pregnancy. However, the specificity and level of the contribution might vary by type of cytokine, pregnancy stage, and other confounding factors such as BMI that may impact these associations. [ABSTRACT FROM AUTHOR]

Lead (Pb) is widespread and exposure to this non-essential heavy metal can cause multiple negative health effects; however the mechanisms underlying these effects remain incompletely understood. To identify plasma metabolomic signatures of Pb exposure, as measured in blood and toenails. In a subset of men from the VA Normative Aging Study, mass-spectrometry based plasma metabolomic profiling was performed. Pb levels were measured in blood samples and toenail clippings collected concurrently. Multivariable linear regression models, smoothing splines and Pathway analyses were employed to identify metabolites associated with Pb exposure. In 399 men, 858 metabolites were measured and passed QC, of which 154 (17.9%) were significantly associated with blood Pb (p < 0.05). Eleven of these passed stringent correction for multiple testing, including pro-hydroxy-pro (β(95%CI): 1.52 (0.93,2.12), p = 7.18x10 −7 ), N-acetylglycine (β(95%CI): 1.44 (0.85,2.02), p = 1.12x10 −6 ), tartarate (β(95%CI): 0.68 (0.35,1.00), p = 4.84x10 −5 ), vanillylmandelate (β(95%CI): 1.05 (0.47,1.63), p = 4.44x10 −7 ), and lysine (β(95%CI): 1.88 (−2.8,-0.95), p = 9.10x10 −5 ). A subset of 48 men had a second blood sample collected a mean of 6.1 years after their first. Three of the top eleven metabolites were also significant in this second blood sample. Furthermore, we identified 70 plasma metabolites associated with Pb as measured in toenails. Twenty-three plasma metabolites were significantly associated with both blood and toenail measures, while others appeared to be specific to the biosample in which Pb was measured. For example, benzanoate metabolism appeared to be of importance with the longer-term exposure assessed by toenails. Pb exposure is responsible for 0.6% of the global burden of disease and metabolomics is particularly well-suited to explore its pathogenic mechanisms. In this study, we identified metabolites and metabolomic pathways associated with Pb exposure that suggest that Pb exposure acts through oxidative stress and immune dysfunction. These findings help us to better understand the biology of this important public health burden. • Metabolomics provides novel approach to explore influence of lead (Pb) exposure. • We performed metabolomics on plasma samples from 399 men with measured exposure. • Pb exposures acts largely through oxidative stress and immune dysfunction. • Long versus short term exposure may influence the metabolome differently. [ABSTRACT FROM AUTHOR]