This review describes the recent literature on microbial exposures and protective effects for asthma and atopy. Certain microorganism-associated molecular patterns have been identified as agents that ...might influence the development of the immune system, which in turn leads to protective effects for asthma and atopy. Endotoxins from gram-negative bacteria were the first agents associated with a reduced risk for asthma and atopy. In later studies, β(1→3)glucans, extracellular polysaccharides, and muramic acid from, respectively, molds and gram-positive bacteria were associated with a reduced risk of allergy and asthma separately in rural and urban populations. These results already suggested that not just one but several independent microbial signals from gram-negative and gram-positive bacteria, as well as molds, might play a role in explaining the protective effects. Recently, the diversity of microbial exposure has been associated with such a reduced risk in farmers’ children. Surprisingly, the diversity of both fungal and bacterial exposure seemed to have protective effects. These results open new areas of research and create complex challenges. Methodological issues, such as environmental exposure characterization and assessment and elucidation of potential underlying mechanisms, are discussed because these aspects have a major influence on how microbial diversity can be studied in future studies in relation to protective effects for asthma and atopy.
Several studies have suggested an association between the increasing prevalence of allergic diseases and dietary factors.
To prospectively explore the association between changes in body mass index ...(BMI) and symptoms of asthma, rhinitis, rhinoconjunctivitis, and atopic dermatitis to find out whether an increase in BMI increases the risk of developing atopic diseases in adolescence.
Comprehensive questionnaires and anthropometric measurements were applied in a random subsample of the International Study of Asthma and Allergies in Childhood phase II (1995-1996, 9 to 11 years of age) in Germany. Of these participants, 1,794 could be followed up in 2002 to 2003 in the Study on Occupational Allergy Risks (16 to 18 years of age). The associations between changes of BMI from baseline to follow-up and incident and persistent respiratory diseases and atopic dermatitis were assessed.
In logistic regression analyses, weight change in either direction was not statistically significantly associated with the incidence or persistence of any of the diseases of interest except for rhinitis. An increase in BMI was linked to an increased risk of incident rhinitis (odds ratio 1.9, 95% confidence interval 1.2-2.9).
These results indicate a nonsignificant trend between increased body weight and risk of atopic diseases. Aside from limitations owing to a small subgroup of obese participants and questionnaire-based asthma diagnosis, reasons might be related to an interaction between BMI and hormonal influences, age, and duration and severity of overweight. The results underline that BMI does not necessarily play a decisive role in the course of atopic diseases in all populations.
Background Patients with asthma and healthy controls differ in bacterial colonization of the respiratory tract. The upper airways have been shown to reflect colonization of the lower airways, the ...actual site of inflammation in asthma, which is hardly accessible in population studies. Objective We sought to characterize the bacterial communities at 2 sites of the upper respiratory tract obtained from children from a rural area and to relate these to asthma. Methods The microbiota of 327 throat and 68 nasal samples from school-age farm and nonfarm children were analyzed by 454-pyrosequencing of the bacterial 16S ribosomal RNA gene. Results Alterations in nasal microbiota but not of throat microbiota were associated with asthma. Children with asthma had lower α- and β-diversity of the nasal microbiota as compared with healthy control children. Furthermore, asthma presence was positively associated with a specific operational taxonomic unit from the genus Moraxella in children not exposed to farming, whereas in farm children Moraxella colonization was unrelated to asthma. In nonfarm children, Moraxella colonization explained the association between bacterial diversity and asthma to a large extent. Conclusions Asthma was mainly associated with an altered nasal microbiota characterized by lower diversity and Moraxella abundance. Children living on farms might not be susceptible to the disadvantageous effect of Moraxella . Prospective studies may clarify whether Moraxella outgrowth is a cause or a consequence of loss in diversity.
Background Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental ...condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development. Objective This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. Methods Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in TH 1- and TH 2-relevant genes of CD4+ T cells. Results Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-γ dependent. Furthermore, the IFNG promoter of CD4+ T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-γ expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding TH 2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic TH 2 regulatory region conserved noncoding sequence 1 (CNS1). Conclusion These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection.
Background Studies on the association of farm environments with asthma and atopy have repeatedly observed a protective effect of farming. However, no single specific farm-related exposure explaining ...this protective farm effect has consistently been identified. Objective We sought to determine distinct farm exposures that account for the protective effect of farming on asthma and atopy. Methods In rural regions of Austria, Germany, and Switzerland, 79,888 school-aged children answered a recruiting questionnaire (phase I). In phase II a stratified random subsample of 8,419 children answered a detailed questionnaire on farming environment. Blood samples and specific IgE levels were available for 7,682 of these children. A broad asthma definition was used, comprising symptoms, diagnosis, or treatment ever. Results Children living on a farm were at significantly reduced risk of asthma (adjusted odds ratio aOR, 0.68; 95% CI, 0.59-0.78; P < .001), hay fever (aOR, 0.43; 95% CI, 0.36-0.52; P < .001), atopic dermatitis (aOR, 0.80; 95% CI, 0.69-0.93; P = .004), and atopic sensitization (aOR, 0.54; 95% CI, 0.48-0.61; P < .001) compared with nonfarm children. Whereas this overall farm effect could be explained by specific exposures to cows, straw, and farm milk for asthma and exposure to fodder storage rooms and manure for atopic dermatitis, the farm effect on hay fever and atopic sensitization could not be completely explained by the questionnaire items themselves or their diversity. Conclusion A specific type of farm typical for traditional farming (ie, with cows and cultivation) was protective against asthma, hay fever, and atopy. However, whereas the farm effect on asthma could be explained by specific farm characteristics, there is a link still missing for hay fever and atopy.
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.
Background European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still ...not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells. Objective We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant. Methods From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4+ CD25+ forkhead box protein 3 (FOXP3)+ (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctor's diagnosis. Results Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4+ CD25+ , FOXP3+ T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells. Conclusions Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases.
Background Phase III of the International Study of Asthma and Allergies in Childhood measured the global prevalence of symptoms of asthma, rhinoconjunctivitis, and eczema in children. Objective To ...investigate the associations between the use of antibiotics in the first year of life and symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 and 7 years old. Methods Parents or guardians of children 6 and 7 years old completed written questionnaires on current symptoms and possible risk factors. Prevalence odds ratios (ORs) were estimated by using logistic regression. Results A total of 193,412 children from 71 centers in 29 countries participated. Reported use of antibiotics in the first year of life was associated with an increased risk of current asthma symptoms (wheezing in the previous 12 months) with an OR (adjusted for sex, region of the world, language, and per capita gross national income) of 1.96 (95% CI, 1.85-2.07); this fell to 1.70 (1.60-1.80) when adjusted for other risk factors for asthma. Similar associations were observed for severe asthma symptoms (OR, 1.82; 95% CI, 1.67-1.98), and asthma ever (OR, 1.94; 95% CI, 1.83-2.06). Use of antibiotics in the first year of life was also associated, but less strongly, with increased risks of current symptoms of rhinoconjunctivitis (OR, 1.56; 95% CI, 1.46-1.66) and eczema (OR, 1.58; 95% CI, 1.33-1.51). Conclusion There is an association between antibiotic use in the first year of life and current symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 and 7 years old. Further research is required to determine whether the observed associations are causal or are a result of confounding by indication or reverse causation.
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