Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21.
To ...test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze.
We followed 983 children in rural areas of Europe from birth until age 6 years. Symptoms of wheeze, rhinitis, fever, and environmental exposures were documented with weekly diaries during year 1. Asthma at age 6 was defined as ever having a reported doctor's diagnosis. Single-nucleotide polymorphisms related to ORMDL3 (rs8076131) and GSDMB (rs7216389, rs2290400) at 17q21 were genotyped.
Early wheeze was positively associated with presence of older siblings among carriers of known asthma risk alleles at 17q21 (e.g., rs8076131) (adjusted odds ratio aOR, 1.53; 95% confidence interval CI, 1.16-2.01). Exposure to farm animal sheds was inversely related to wheeze (aOR, 0.44; 95% CI, 0.33-0.60). Both effects were similarly observed in children with transient wheeze up to age 3 years without subsequent development of asthma (aOR, 1.71 95% CI, 1.09-2.67; and aOR, 0.48 95% CI, 0.30-0.76, respectively).
These findings suggest that the chromosome 17q21 locus relates to episodes of acute airway obstruction common to both transient wheeze and asthma. The previously identified asthma risk alleles are the ones susceptible to environmental influences. Thus, this gene-environment interaction reveals two faces of 17q21: The same genotype constitutes genetic risk and allows for environmental protection, thereby providing options for prospective prevention strategies.
Several studies report an important role of CD8+ cytotoxic T-cells in atopy. Farm children show protection against atopy development, partly explained by CD4+ T-cell subtypes. Additional effects of ...CD8+ T-cells are unknown being investigated in this study within the PASTURE/EFRAIM birth cohort in PBMCs from farming and non-farming 6-year-old (N=76) German children. CD3+CD8+CD25+ T-cells were analyzed by flow cytometry. Genotyping of 17q21 locus-SNPs associated with childhood asthma was performed. No differences in CD8+ T-cell subsets were seen between farmers and non-farmers regardless of asthma. Among farm children, asthmatics displayed increased CD3+CD8low(CD25+) T-cells compared to non-asthmatics. Asthmatic farm children exhibited a lower PI-induced stimulatory capacity of CD3+CD8low(CD25+) cells and a lower IFN-γ secretion than non-asthmatic farm children. Among farm children with GSDMB and ORMDL3 risk alleles, asthmatics displayed higher CD3+CD8low cells than non-asthmatics. Our data indicates a specific role of CD8low T-cells in asthmatic farm children.
•Asthmatic farm children exhibit more CD3+CD8low T-cells compared to non-asthmatic farm children.•IFN-γ secretion is decreased in asthmatic compared to non-asthmatic farm-exposed children•Asthmatic farm children with asthma risk alleles have more CD3+CD8low T-cells than non-asthmatic children with risk alleles.•The amount of CD8low T-cells indicates a specific farm-dependent mechanism associated with childhood asthma.
Background
Respiratory tract infections and their symptoms are frequent during early childhood, but their risk factors, including the effect of early immune regulation, are less known. The aim of the ...study was to analyze whether stimulated cord blood cytokine production is associated with the frequency of respiratory tract infection symptoms or infections during the first year of life.
Methods
The study population consisted of children of mothers from farm or non‐farm rural environment from Austria, Finland, Germany, and Switzerland who participated in a prospective birth cohort study (PASTURE: Protection against Allergy—Study in Rural Environments) (N = 550). Cord blood samples were stimulated with the combination of phorbol ester and ionomycin (P/I) for 24 h, and the production of IL‐5, IL‐10, TNF‐α, and IFN‐γ was determined using ELISA. Information about infectious morbidity was collected using weekly diaries.
Results
P/I‐stimulated production of IL‐5 (adjusted risk ratio (aRR) for ≤median production, 0.37; 95% confidence interval (CI), 0.25–0.55, aRR for >median production, 0.41; 95% CI, 0.27–0.61 vs. production <detection limit) and IFN‐γ (aRR for ≤median production, 0.62; 95% CI, 0.40–0.95, aRR for >median production, 0.39; 95% CI, 0.25–0.62 vs. production <detection limit) in cord blood were associated with lower number of weeks with reported middle ear infection. There was a tendency toward positive association with P/I‐stimulated TNF‐α production and middle ear infections.
Conclusion
Our results suggest that increased Th2‐ and Th1‐associated cytokine responses at birth may provide protection from later middle ear infections.
Background Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective We ...sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-γ ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.
Background
Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm‐milk exposure was partially mediated by regulatory T cells (Tregs). ...The aim of this study was to investigate the critical time window of the ‘asthma‐protective’ farm effect via Tregs during childhood immune maturation.
Methods
Tregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12‐myristate 13‐acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+CD25highFOXP3upper20%). mRNA expression of Treg/Th1/Th2/Th17‐associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents.
Results
Treg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm‐milk and animal‐stable exposure was associated with decreased LPS‐stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS‐stimulated‐Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96–132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN‐γ (P = 0.015) and IL‐9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17‐associated cell markers decreased between 4.5 and 6 years (P < 0.001).
Conclusions
Tregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical ‘time window’ for Treg‐mediated asthma protection via environmental exposure before age 6 years.
Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today
. The asthma-protective effect of farms appears to be ...associated with rich home dust microbiota
, which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts
that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children
and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.
Summary
Background
Gut microbiota and intestinal inflammation regulate the development of immune‐mediated diseases, such as allergies. Fecal calprotectin is a biomarker of intestinal inflammation.
...Objective
We evaluated the association of early‐age fecal calprotectin levels to the later development of allergic diseases in children from farming and non‐farming environments and further studied the effect of gut microbiota on the fecal calprotectin levels.
Methods
Fecal calprotectin was measured from 758 infants participating in the PASTURE study at the age of 2 months using the ELISA method. Serum‐specific IgE levels were measured at 6 years of age. Data of environmental factors, doctor‐diagnosed atopic dermatitis (AD) and asthma were collected by questionnaire. Multivariate logistic regression models were used for analysis. The composition of fecal microbiota was analysed in a subgroup of 120 infants with 16S rRNA pyrosequencing. The effect of Escherichia coli lipopolysaccharide (LPS) on in vitro monocyte IL‐10 secretion was studied by flow cytometry.
Results
The infants with high fecal calprotectin levels at 2 months, that is above the 90th percentile, had an increased risk of developing AD and asthma/asthmatic bronchitis by the age of 6 years (aOR 2.02 (1.06–3.85) and 2.41 (1.25–4.64), respectively). High fecal calprotectin levels correlated negatively with fecal Escherichia. LPS from E. coli stimulated production of IL‐10 in monocytes.
Conclusion and Clinical Relevance
High degree intestinal inflammation at 2 months of age, detected as high fecal calprotectin, predicted asthma and AD by the age of 6 years and was linked to low abundance of fecal Escherichia. Impaired IL‐10 activation due to the lack of colonization with E. coli could explain the intestinal inflammation associated high fecal calprotectin and later risk of asthma and AD. Our results have implications for the design of probiotic treatments and suggest that early intestinal colonization has long‐term health effects.
Background
The highly consistent association of growing up on a farm with a reduced asthma risk has so far been attributed to direct farm exposure. In contrast, geographic determinants of the larger ...environment have never been assessed. In this study, the effects of proximity to farms and environmental variables in relation to the residential address on asthma and atopy were assessed.
Methods
Addresses of 2265 children of the Bavarian arm of the GABRIELA study were converted into geocodes. Proximity to the nearest cow farm was calculated, and environmental characteristics were derived from satellite data or terrestrial monitoring. Bacterial diversity in mattress dust samples was assessed in 501 children by sequencing of the 16S rRNA amplicons. Logistic regression models were used to calculate associations between outcomes and exposure variables.
Results
Asthma and atopy were inversely associated with the presence of a farm within a radius of maximum 100 m. The environmental variables greenness, tree cover, soil sealing, altitude, air pollution differed not only between farm and non‐farm children but also between farm children with and without another farm nearby. The latter distinction revealed strong associations with characteristics of traditional farms including a broader diversity of microbial exposure, which mainly contributed to the protective effect on asthma. In non‐farm children, the protective effect of a farm nearby was completely explained by consumption of farm milk.
Conclusions
Clustering of farms within a neighborhood of 100 m is strongly associated with the protective effect on asthma and may represent a more traditional style of farming with broader microbial exposure.
Background Farm milk consumption has been identified as an exposure that might contribute to the protective effect of farm life on childhood asthma and allergies. The mechanism of action and the role ...of particular constituents of farm milk, however, are not yet clear. Objective We sought to investigate the farm milk effect and determine responsible milk constituents. Methods In rural regions of Germany, Austria, and Switzerland, a comprehensive questionnaire about farm milk consumption and other farm-related exposures was completed by parents of 8334 school-aged children, and 7606 of them provided serum samples to assess specific IgE levels. In 800 cow's milk samples collected at the participants' homes, viable bacterial counts, whey protein levels, and total fat content were analyzed. Asthma, atopy, and hay fever were associated to reported milk consumption and for the first time to objectively measured milk constituents by using multiple regression analyses. Results Reported raw milk consumption was inversely associated to asthma (adjusted odds ratio aOR, 0.59; 95% CI, 0.46-0.74), atopy (aOR, 0.74; 95% CI, 0.61-0.90), and hay fever (aOR, 0.51; 95% CI, 0.37-0.69) independent of other farm exposures. Boiled farm milk did not show a protective effect. Total viable bacterial counts and total fat content of milk were not significantly related to asthma or atopy. Increased levels of the whey proteins BSA (aOR for highest vs lowest levels and asthma, 0.53; 95% CI, 0.30-0.97), α-lactalbumin (aOR for interquartile range and asthma, 0.71; 95% CI, 0.52-0.97), and β-lactoglobulin (aOR for interquartile range and asthma, 0.62; 95% CI, 0.39-0.97), however, were inversely associated with asthma but not with atopy. Conclusions The findings suggest that the protective effect of raw milk consumption on asthma might be associated with the whey protein fraction of milk.
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