Kevin Bobbitt

Gene-environment interactions between CD14 C-260T and endotoxin exposure on Foxp3+ and Foxp3- CD4+ lymphocyte numbers and total serum IgE levels in early childhood

BACKGROUND Innate immune system stimuli, such as endotoxin, seem to affect allergy risk. Previously, we described gene-environment interactions between the endotoxin receptor polymorphism C-260T of the CD14 gene and endotoxin exposure on total serum IgE level; however, the mechanism of this interaction is not known. OBJECTIVE To examine whether this gene-environment interaction affects early CD4(+)Foxp3(-) or CD4(+)Foxp3(+) lymphocyte numbers. METHODS Participating children were part of a birth cohort in the Detroit metropolitan area. Participants were genotyped for the CD14 C-260T polymorphism. Endotoxin exposure was estimated from dust measured in the home when children were 6 months old. Intracellular Foxp3 protein expression, a regulatory T-cell marker, was used to characterize CD4(+) lymphocytes in blood samples collected at the age of 12 months; total serum IgE level was also measured at this time. Because race/ethnicity may confound or modify genetic associations, all analyses were stratified by race/ethnicity. RESULTS We observed a significant gene-environment interaction between CD14 C-260T genotype and endotoxin exposure on CD4(+) lymphocyte numbers, particularly CD4(+)Foxp3(-) lymphocytes. Stratified analyses suggest effect modification by race/ ethnicity on CD4(+)Foxp3(+) lymphocyte numbers, with a significant interaction in African American children but not in white children. The interaction between CD14 C-260T genotype and endotoxin exposure on total IgE levels was opposite that observed for CD4(+) lymphocyte numbers, suggesting reciprocal relationships. CONCLUSIONS A gene-environment interaction between endotoxin and CD14 C-260T genotype on IgE levels may be the result of an upstream, opposing effect on CD4(+)Foxp3(+) and CD4(+)Foxp3(-) lymphocyte numbers. Race/ethnicity may affect which of these cell populations is affected by this gene-environment interaction.

Transforming growth factor beta (TGFβ1) in breast milk and indicators of infant atopy in a birth cohort.

The infant guts ability to suppress immunologic reactions to food proteins could be influenced by levels of TGFβ in breast milk. We hypothesized that lower levels of TGFβ1 in the breast milk (BM) of mothers in the WHEALS birth cohort are associated with atopy at infant age 2–3 yrs.

Breast Milk TGFβ is Associated with Neonatal Gut Microbial Composition

BACKGROUND AND OBJECTIVES Breast milk is a complex bioactive fluid that varies across numerous maternal and environmental conditions. Although breast-feeding is known to affect neonatal gut microbiome, the milk components responsible for this effect are not well-characterized. Given the wide range of immunological activity breast milk cytokines engage in, we investigated 3 essential breast milk cytokines and their association with early life gut microbiota. METHODS A total of 52 maternal-child pairs were drawn from a racially diverse birth cohort based in Detroit, Michigan. Breast milk and neonatal stool specimens were collected at 1-month postpartum. Breast milk transforming growth factor (TGF)β1, TGFβ2, and IL-10 were assayed using enzyme-linked immunosorbent assays, whereas neonatal gut microbiome was profiled using 16S rRNA sequencing. RESULTS Individually, immunomodulators TGFβ1 and TGFβ2 were significantly associated with neonatal gut microbial composition (R = 0.024, P = 0.041; R = 0.026, P = 0.012, respectively) and increased richness, evenness, and diversity, but IL-10 was not. The effects of TGFβ1 and TGFβ2, however, were not independent of one another, and the effect of TGFβ2 was stronger than that of TGFβ1. Higher levels of TGFβ2 were associated with the increased relative abundance of several bacteria, including members of Streptococcaceae and Ruminococcaceae, and lower relative abundance of distinct Staphylococcaceae taxa. CONCLUSIONS Breast milk TGFβ concentration explains a portion of variability in gut bacterial microbiota composition among breast-fed neonates. Whether TGFβ acts in isolation or jointly with other bioactive components to alter bacterial composition requires further investigation. These findings contribute to an increased understanding of how breast-feeding affects the gut microbiome-and potentially immune development-in early life.Background and Objectives: Breast milk is a complex bioactive fluid that varies across numerous maternal and environmental conditions. Although breast-feeding is known to affect neonatal gut microbiome, the milk components responsible for this effect are not well-characterized. Given the wide range of immunological activity breast milk cytokines engage in, we investigated 3 essential breast milk cytokines and their association with early life gut microbiota. Methods: A total of 52 maternal-child pairs were drawn from a racially diverse birth cohort based in Detroit, Michigan. Breast milk and neonatal stool specimens were collected at 1-month postpartum. Breast milk transforming growth factor (TGF)&bgr;1, TGF&bgr;2, and IL-10 were assayed using enzyme-linked immunosorbent assays, whereas neonatal gut microbiome was profiled using 16S rRNA sequencing. Results: Individually, immunomodulators TGF&bgr;1 and TGF&bgr;2 were significantly associated with neonatal gut microbial composition (R2 = 0.024, P = 0.041; R2 = 0.026, P = 0.012, respectively) and increased richness, evenness, and diversity, but IL-10 was not. The effects of TGF&bgr;1 and TGF&bgr;2, however, were not independent of one another, and the effect of TGF&bgr;2 was stronger than that of TGF&bgr;1. Higher levels of TGF&bgr;2 were associated with the increased relative abundance of several bacteria, including members of Streptococcaceae and Ruminococcaceae, and lower relative abundance of distinct Staphylococcaceae taxa. Conclusions: Breast milk TGF&bgr; concentration explains a portion of variability in gut bacterial microbiota composition among breast-fed neonates. Whether TGF&bgr; acts in isolation or jointly with other bioactive components to alter bacterial composition requires further investigation. These findings contribute to an increased understanding of how breast-feeding affects the gut microbiome—and potentially immune development—in early life.

108 The Relationship of Pets, Vitamin D and IGE Concentrations to Upper Respiratory Infections in the First Year of Life.

Background The childhood origins of asthma are highly complex but viral respiratory infections during the first year of life may be associated with wheezing and later asthma risk. Recent studies have shown that both exposure to household pets and higher serum vitamin D concentrations may reduce wheezing illness in children. Methods To investigate potential relationships between household pet exposure, cord blood (CB) vitamin D and IgE concentrations and the number of upper respiratory infections (URIs) in the first year of life, we analyzed information from a geographically-based, prospective, non-high-risk, birth cohort. Household pets were assessed during pregnancy and medical records were abstracted for doctor visits of URIs. Because of large differences in vitamin D concentrations between Blacks and Whites racial stratification was done for some analyses. Results The cohort consisted of 1055 children of whom 62.4% were Black and 49.4% were female. When all children were considered, a one natural log unit increase in CB vitamin D concentration was associated with a greater risk of a URI visit (RR = 1.27, 95% CI, 1.01-1.59, P = 0.037) which remained after adjusting for the season of birth (RR = 1.28, P = 0.033). Individually adjusting for the number of children in the family, CB IgE, child gender, family or maternal smoking and race did not substantially change the association of vitamin D to URIs (all RRs were 1.25-1.27), although the risks only remained statistically significant with CB IgE (P = 0.035) and gender (P = 0.043). When models stratified by race including pets, dogs only, or cats only, and CB IgE were fitted with the other variables, the relationship between CB vitamin D disappeared for whites but did not change in magnitude for blacks (RR = 1.31; 95% CI, 0.89-1.92; P = 0.165). Among Whites the only variable associated with URIs was a relationship with female gender (RR = 0.62, 95% CI, 0.41-0.94; P = 0.025) with being in daycare approaching significance (RR = 1.72, 95% CI, 0.94-3.14; P = 0.08). Conclusions In a large, prospective, non-high-risk birth cohort higher, CB vitamin D concentration, after adjusting for other potential confounding variables, was not associated with a decreased risk of physician diagnosed URIs in the first year of life.