The intestinal microflora in allergic Estonian and Swedish 2-year-old children

BACKGROUND: The prevalence of allergic diseases seems to have increased particularly over the past 35-40 years. Furthermore, allergic disease is less common among children in the formerly socialist countries of central and Eastern Europe as compared with Western Europe. It has been suggested that a reduced microbial stimulation during infancy and early childhood would result in a slower postnatal maturation of the immune system and development of an optimal balance between TH1- and TH2-like immunity. AIMS: To test the hypothesis that allergic disease among children may be associated with differences in their intestinal microflora in two countries with a low (Estonia) and a high (Sweden) prevalence of allergy. METHODS: From a prospective study of the development of allergy in relation to environmental factors, 29 Estonian and 33 Swedish 2-year-old children were selected. They were either nonallergic (n = 36) or had a confirmed diagnosis of allergy (n = 27) as verified by typical history and at least one positive skin prick test to egg or cow's milk. Weighed samples of faeces were serially diluted (10-2-10-9) and grown under anaerobic conditions. The counts of the various genera and species were calculated for each child. In addition, the relative amounts of the particular microbes were expressed as a proportion of the total count. RESULTS: The allergic children in Estonia and Sweden were less often colonized with lactobacilli (P < 0.01), as compared with the nonallergic children in the two countries. In contrast, the allergic children harboured higher counts of aerobic micro-organisms (P < 0. 05), particularly coliforms (P < 0.01) and Staphylococcus aureus (P < 0.05). The proportions of aerobic bacteria of the intestinal flora were also higher in the allergic children (P < 0.05), while the opposite was true for anaerobes (P < 0.05). Similarly, in the allergic children the proportions of coliforms were higher (P < 0. 05) and bacteroides lower (P < 0.05) than in the nonallergic children. CONCLUSIONS: Differences in the indigenous intestinal flora might affect the development and priming of the immune system in early childhood, similar to what has been shown in rodents. The role of intestinal microflora in relation to the development of infant immunity and the possible consequences for allergic diseases later in life requires further study, particularly as it would be readily available for intervention as a means for primary prevention of allergy by the administration of probiotic bacteria.     

Increased intestinal permeability in bronchial asthma

T lymphocytes are a major component of bronchial inflammatory processes in asthma. Because lymphocytes have the ability to migrate from one mucosal site to another, we initiated this prospective study to demonstrate mucosal abnormalities of the digestive barrier in asthma. To establish this we studied intestinal permeability in a group of 37 patients with asthma (21 allergic and 16 nonallergic) by measuring chromium 51–labeled ethylenediaminetetraacetatic acid (CrEDTA) urinary recovery. The results were compared with those obtained in a group of 13 nonasthmatic patients with chronic obstructive pulmonary disease and 26 healthy control subjects. Urinary recovery of CrEDTA was significantly higher in patients with asthma (2.5% ± 1.95%) than in patients with chronic obstructive pulmonary disease (1.16% ± 0.48%) and healthy control subjects (1.36% ± 0.14%). There was no significant difference in intestinal permeability between patients with allergic asthma (2.94% ± 2.4%) and those with nonallergic asthma (1.92% ± 0.9%). Intestinal permeability was not correlated with the severity of asthma as measured by FEV₁. Similarly, intestinal permeability did not significantly vary according to Aas score or steroid treatment. Serum IgE values and eosinophil blood count were not correlated with intestinal permeability. Intestinal permeability was evaluated sequentially in seven patients with asthma (4 allergic and 3 nonallergic) with a mean interval of 7.6 months (range, 2 to 13 months) and did not significantly change. Our results support the hypothesis that a general defect of the whole mucosal system is present as a cause or a consequence of bronchial asthma. (J ALLERGY CLIN IMMUNOL 1996;97:1173-8.)     

The relationship of rhinitis and asthma, sinusitis, food allergy, and eczema

Epidemiologic, genetic, immunologic, and clinical studies show a close relationship between allergic rhinitis and asthma, food allergy, and atopic dermatitis. Rhinitis and sinusitis often coexist and are commonly referred to with the term rhinosinusitis. These conditions are also linked in the so-called atopic march, which is the sequential appearance of atopic manifestations starting with atopic dermatitis and later followed by food allergy, allergic rhinitis, and asthma. Allergic rhinitis and asthma are now increasingly being approached diagnostically and therapeutically as the one-airway concept.     

The effects of climate change on respiratory allergy and asthma induced by pollen and mold allergens

The impact of climate change on the environment, biosphere, and biodiversity has become more evident in the recent years. Human activities have increased atmospheric concentrations of carbon dioxide (CO₂) and other greenhouse gases. Change in climate and the correlated global warming affects the quantity, intensity, and frequency of precipitation type as well as the frequency of extreme events such as heat waves, droughts, thunderstorms, floods, and hurricanes. Respiratory health can be particularly affected by climate change, which contributes to the development of allergic respiratory diseases and asthma. Pollen and mold allergens are able to trigger the release of pro-inflammatory and immunomodulatory mediators that accelerate the onset the IgE-mediated sensitization and of allergy. Allergy to pollen and pollen season at its beginning, in duration and intensity are altered by climate change. Studies showed that plants exhibit enhanced photosynthesis and reproductive effects and produce more pollen as a response to high atmospheric levels of carbon dioxide (CO₂). Mold proliferation is increased by floods and rainy storms are responsible for severe asthma. Pollen and mold allergy is generally used to evaluate the interrelation between air pollution and allergic respiratory diseases, such as rhinitis and asthma. Thunderstorms during pollen seasons can cause exacerbation of respiratory allergy and asthma in patients with hay fever. A similar phenomenon is observed for molds. Measures to reduce greenhouse gas emissions can have positive health benefits.     

GA2LEN (Global Allergy and Asthma European Network) addresses the allergy and asthma 'epidemic'

Allergic diseases represent a major health problem in Europe. They are increasing in prevalence, severity and costs. The Global Allergy and Asthma European Network (GA²LEN), a Sixth EU Framework Program for Research and Technological Development (FP6) Network of Excellence, was created in 2005 as a vehicle to ensure excellence in research bringing together research and clinical institutions to combat fragmentation in the European research area and to tackle Allergy in its globality. The Global Allergy and Asthma European Network has benefited greatly from the voluntary efforts of researchers who are strongly committed to this model of pan-European collaboration. The network was organized in order to increase networking for scientific projects in allergy and asthma around Europe and to make GA²LEN the world leader in the field. Besides these activities, research has also been carried out and the first papers are being published. Achievements of the Global Allergy and Asthma European Network can be grouped as follows: (i) those for a durable infrastructure built up during the project phase, (ii) those which are project-related and based on these novel infrastructures, and (iii) the development and implementation of guidelines. The major achievements of GA²LEN are reported in this paper.     

Integrin beta 3 genotype influences asthma and allergy phenotypes in the first 6 years of life

BACKGROUND: The integrin beta3 gene (ITGB3) encodes a subunit of the platelet and monocyte-specific fibrinogen receptor and the widely expressed vitronectin receptor, which have diverse roles in cell migration, adhesion, and signaling. Previous work from our laboratory reported associations between single nucleotide polymorphisms (SNPs) in ITGB3 and asthma and allergic sensitization in 4 populations. OBJECTIVE: To examine whether SNPs in ITGB3 are associated with the development of asthma and allergic phenotypes in early life. METHODS: We typed 13 SNPs in 206 children participating in a birth cohort study and tested for associations with asthma and allergy phenotypes in the first 6 years of life. RESULTS: Our study revealed significant associations between SNPs in ITGB3 and asthma, wheezing, and IgE levels, suggesting an early role for this gene in the development of asthma and allergy. In particular, SNPs at the 3' end of the gene were significantly associated with IgE levels beginning at 1 year of age, whereas a SNP in intron 1 showed significant interaction effects with viral respiratory illness in infancy on asthma susceptibility. CONCLUSION: Our results suggest that genetic variation in ITGB3 contributes to asthma susceptibility and allergic sensitization, and that the effects of this gene begin early in life. Similar to our earlier study, different SNPs in the gene are associated with asthma and IgE. CLINICAL IMPLICATIONS: ITGB3 may play an important role in the development of asthma and allergy and may represent a potential therapeutic target for the treatment of these disorders.     

Effects of microflora on the neonatal development of gut mucosal T cells and myeloid cells in the mouse

Colonization with commensal flora in very early life may profoundly influence intestinal lymphoid development and bias later immune responses. We defined gut-homing T cell phenotypes and the influence of flora on intestinal immune development in mice. Intestinal T cells were phenotyped and quantified in conventional (CV), germfree (GF) and conventionalized germfree (GF/CV) neonatal mice by immunohistochemistry. Mucosal adressin cell adhesion molecule 1 (MAdCAM-1) was expressed by mucosal vessels at birth in CV and GF mice and was more prevalent in CV than GF small intestine, but was distributed similarly and did not change with age. Less MAdCAM-1 was expressed in the colon; its distribution became restricted after weaning, with no difference between CV and GF mice. CD3(+)beta(7) (+) cells were present in similar numbers in CV and GF intestine at birth. They were CD62L(-) in CV mice and were accompanied by further CD3(+)beta(7) (+)CD62L(-) T cells as development progressed, but in GF and GF/CV intestine they expressed CD62L and numbers did not change. IEL numbers increased at weaning in CV mice in both small and large intestine, but showed delayed development in GF intestine. Macrophages were present at high levels from birth in GF intestine, but dendritic cells did not develop until day 16. Thus, fetus-derived T cells seed the intestinal lamina propria before birth via beta-MadCAM interactions. Their activation status depends on the microbiological status of the dam, and without a commensal flora they remain naive. We propose that these cells regulate antigen responsiveness of the developing mucosal T cell pool.     

Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe

BACKGROUND: Dietary interventions as a means for atopy prevention attract great interest. Some studies in rural environments claimed an inverse association between consumption of farm-produced dairy products and the prevalence of allergic diseases, but current evidence is controversial. OBJECTIVE: To investigate whether consumption of farm-produced products is associated with a lower prevalence of asthma and allergy when compared with shop-purchased products. METHODS: Cross sectional multi-centre study (PARSIFAL) including 14,893 children aged 5-13 years from five European countries (2823 from farm families and 4606 attending Steiner Schools as well as 5440 farm reference and 2024 Steiner reference children). A detailed questionnaire including a dietary component was completed and allergen-specific IgE was measured in serum. RESULTS: Farm milk consumption ever in life showed a statistically significant inverse association with asthma: covariate adjusted odds ratio (aOR) 0.74 [95% confidence interval (CI) 0.61-0.88], rhinoconjunctivitis: aOR 0.56 (0.43-0.73) and sensitization to pollen and the food mix fx5 (cut-off level of >or=3.5 kU/L): aOR 0.67 (0.47-0.96) and aOR 0.42 (0.19-0.92), respectively, and sensitization to horse dander: aOR 0.50 (95% CI 0.28-0.87). The associations were observed in all four subpopulations and independent of farm-related co-exposures. Other farm-produced products were not independently related to any allergy-related health outcome. CONCLUSION: Our results indicate that consumption of farm milk may offer protection against asthma and allergy. A deepened understanding of the relevant protective components of farm milk and a better insight into the biological mechanisms underlying this association are warranted as a basis for the development of a safe product for prevention.     

双歧杆菌对食物过敏治疗作用的实验研究

目的探讨双歧杆菌对食物过敏的治疗作用。方法 4周龄棕色挪威大鼠(Brown-Norway Rat,BN Rat)构建卵清蛋白(ovalbumin,OVA)致敏动物模型,以OVA 1 mg每天连续灌胃6周,同时分别建立PBS对照组和双歧杆菌治疗组;第6周取血测定血清中OVA特异性IgE(OVA-IgE)水平和IgG(OVA-IgG)水平作为模型评测指标;采用张力换能器测定肠道收缩情况,苏木素-伊红染色(Hematoxylin-Eosin stain,HE)及甲苯胺蓝(Toluidine blue Benzen esulfonic acid,TB)染色观察肠组织病理变化和肠粘膜肥大细胞数目和形态变化。结果第6周时实验组OVA-IgE和OVA-IgG含量显著升高,与对照组相比,OVA-IgE存在显著性差异(P<0.05),OVA-IgG存在极显著差异(P<0.01);经益生菌治疗后,OVA-IgE和OVA-IgG含量显著下降,与实验组相比,存在显著性差异(P<0.05)。双歧杆菌治疗组肠组织收缩较OVA组显著降低,存在显著性差异(P<0.05);HE染色和甲苯胺蓝染色可见双歧杆菌治疗组肠粘膜破坏程度、肠粘膜肥大细胞脱颗粒现象较OVA组缓解。结论 OVA致敏模型和双歧杆菌治疗组模型成功建立,双歧杆菌对食物过敏有较好的治疗作用。     

Relevance of sensitization to occupational allergy and asthma in the detergent industry

There exists considerable historic experience of the relationship between exposure and both the induction of sensitization and the elicitation of respiratory symptoms from industrial enzymes of bacterial and fungal origin used in a wide variety of detergent products. The detergent industry in particular has substantial experience of how the control of exposure leads to limitation of sensitization with low risk of symptoms. However, the experience also shows that there are substantial gaps in knowledge, even when the potential occupational allergy problem is firmly under control, and also that the relationship between exposure and sensitization can be hard to establish. The latter aspect includes a poor appreciation of how peak exposures and low levels of exposure over time contribute to sensitization. Furthermore, while a minority of workers develop specific IgE, essentially none appear to have symptoms, a situation which appears to contradict the allergy dogma that, once sensitized, an individual will react to much lower levels of exposure. For enzymes, the expression of symptoms occurs at similar or higher levels than those that cause induction. In spite of some knowledge gaps, medical surveillance programs and constant air monitoring provide the tools for successful management of enzymes in the occupational setting. Ultimately, the knowledge gained from the occupational setting facilitates the completion of safety assessments for consumer exposure to detergent enzymes. Such assessments have been proven to be correct by the decades of safe use both occupationally and in consumer products.     

The regulation of allergy and asthma

Summary: Allergic diseases and asthma are caused by exaggerated T‐helper 2 (Th2)‐biased immune responses in genetically susceptible individuals. Tolerance to allergens is a mechanism that normally prevents such responses, but the specific immunological events that mediate tolerance in this setting are poorly understood. A number of recent studies indicate that regulatory T cells (Tregs) play an important role in controlling such Th2‐biased responses. Tregs involved in regulating allergy and asthma consist of a family of related types of T cells, including natural CD25⁺ Tregs as well as inducible forms of antigen‐specific adaptive Tregs. Impaired expansion of natural and/or adaptive Tregs is hypothesized to lead to the development of allergy and asthma, and treatment to induce allergen‐specific Tregs could provide curative therapies for these problems.     

Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease

Since genetically engineered animal models of inflammatory bowel disease (IBD) do not develop colitis under germ-free conditions, the intestinal microflora is thought to be one of the most important environmental factors associated with IBD. To understand the involvement of intestinal microflora in the pathogenesis of IBD, we analyzed the constituents of intestinal microflora in IBD. Faecal samples from 73 patients with ulcerative colitis (UC) and 23 patients with Crohn's disease (CD) were analyzed by quantitative PCR using 16S rRNA gene-targeted group-specific primers for Bacteroides fragilis group, Bifidobacterium, Clostridium coccoides groups, Clostridium leptum subgroup, Atopobium cluster, and seven species of Bacteroides. We analyzed the distribution of the predominant microflora by fluorescence in situ hybridization (FISH) using group-specific probes. We also examined the concentration of faecal organic acids produced by intestinal microflora. Contrary to previous reports, we found that the B. fragilis group was significantly decreased in the faeces of patients with IBD. Moreover, B. vulgatus was the predominant microflora in healthy controls and relatively decreased among IBD patients. Most of the microflora adhering to the colonic mucosa surrounding the mucus layer comprised C. coccoides group and Bifidobacterium. B. fragilis group mainly inhabited the faeces, but did not adhere to or invade the mucosa. The concentrations of propionic and butyric acids in the faeces were significantly decreased in patients with IBD. These findings indicate that IBD is not caused by a specific intestinal bacterial cluster or species and that disordered intestinal microflora could be involved in the pathogenesis of IBD.     

食物过敏后肠道通透性的研究

目的：研究食人过敏原后，不同时相下的肠道黏膜通透性变化。方法：将卵蛋白（OVA）致敏大鼠分成3组，分别以OVA（2mg/mL)经肠道攻击1、6和24h后经口投用β乳球蛋白（BLG）5mg/mL,2h后采血，用ELISA法测定血清中BLG的浓度，并对小肠黏膜浸润炎性细胞计数分类。结果：3组实验大鼠血清BLG浓度与对照组比较均增高，P值有显著差异（P＜0．01）；实验组间血清BLG的质量浓度比较无显著差异（P＞0．05），且实验组大鼠小肠黏膜内浸润的炎性细胞种类因食入后时相不同而有差异。结论：在食物过敏反应中，不论速发型或迟发型变态反应，肠道的通透性均增加，但引起的机制不同。     

EAACI Guidelines on the effective transition of adolescents and young adults with allergy and asthma

Adolescent and young adult (AYA) patients need additional support, while they experience the challenges associated with their age. They need specific training to learn the knowledge and skills required to confidently self-manage their allergies and/or asthma. Transitional care is a complex process, which should address the psychological, medical, educational and vocational needs of AYA in the developmentally appropriate way. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline to provide evidence-based recommendations for healthcare professionals to support the transitional care of AYA with allergy and/or asthma. This guideline was developed by a multidisciplinary working panel of experts and patient representatives based on two recent systematic reviews. It sets out a series of general recommendations on operating a clinical service for AYA, which include the following: (a) starting transition early (11-13 years), (b) using a structured, multidisciplinary approach, (c) ensuring AYA fully understand their condition and have resources they can access, (d) active monitoring of adherence and (e) discussing any implications for further education and work. Specific allergy and asthma transition recommendations include (a) simplifying medication regimes and using reminders; (b) focusing on areas where AYA are not confident and involving peers in training AYA patients; (c) identifying and managing psychological and socio-economic issues impacting disease control and quality of life; (d) enrolling the family in assisting AYA to undertake self-management; and (e) encouraging AYA to let their friends know about their allergies and asthma. These recommendations may need to be adapted to fit into national healthcare systems.     

Mast cells in allergic asthma and beyond

Mast cells have been regarded for a long time as effector cells in IgE mediated type I reactions and in host defence against parasites. However, they are resident in all environmental exposed tissues and express a wide variety of receptors, suggesting that these cells can also function as sentinels in innate immune responses. Indeed, studies have demonstrated an important role of mast cells during the induction of life-saving antibacterial responses. Furthermore, recent findings have shown that mast cells promote and modulate the development of adaptive immune responses, making them an important hinge of innate and acquired immunity. In addition, mast cells and several mast cell-produced mediators have been shown to be important during the development of allergic airway diseases. In the present review, we will summarize findings on the role of mast cells during the development of adaptive immune responses and highlight their function, especially during the development of allergic asthma.     

The relationship between serum 25 hydroxy vitamin d levels and asthma in children

Purpose

Asthma and other allergic disorders have increased over the past decades in nearly all nations. Many studies have suggested the role of vitamin D deficiency in both T-helper1 and T-helper2 diseases; however, the association between vitamin D, allergy, and asthma remains uncertain. In this study, the associations of 25-hydroxy vitamin D3 levels with asthma and with the severity of asthma were evaluated.

Methods

This cross-sectional study was conducted on 50 asthmatic children and 50 healthy controls aged 6-18 years. Serum 25-hydroxy vitamin D3 levels were determined and compared between the two groups. The relationship between serum vitamin D levels and pulmonary function test outcomes and eosinophil counts were examined in asthmatic patients.

Results

Univariate analysis of the relationship between asthma and vitamin D showed that decreased vitamin D levels were associated with significantly increased odds of asthmatic state (P=0.002). In a multivariate analysis after adjustment for age, body mass index, and sex, the relationship between vitamin D and asthma increased. In asthmatic patients, 25-hydroxy vitamin D levels had direct and significant correlations with both predicted FEV1 (R²=0.318; P=0.024) and FEV1/FVC (R²=0.315; P=0.026). There were no associations between vitamin D level and eosinophil counts, duration of disease, and the number of hospitalization or unscheduled visits in the previous year (P>0.05).

Conclusions

These results showed that serum 25-hydroxy vitamin D levels were inversely associated with asthma, and there was a direct and significant relationship between vitamin D levels and pulmonary function test outcomes in asthmatic children. An interventional study in asthmatic patients with low serum vitamin D concentration may establish a causal relationship between asthma and vitamin D.     

Effect of contamination of germfree guinea pigs by individual members of the intestinal microflora on antibody and complement levels

On the 3rd day after birth germfree guinea pigs were contaminated by one of the following representatives of the normal intestinal microflora:Bacillus mesentericus,Bacillus subtilis,Staphylococous albus, andStreptococcus faecalis. The levels of antibodies against the microorganisms used for monocontamination and also againstEscherichia coli 055, which is pathogenic for guinea pigs, and the serum complement levels were studied in the animals at the age of 2 weeks. Contamination of the guinea pigs byB. mesentericus andB. subtilis did not significantly change the antibody levels against these microorganisms, whereasS. albus andS. faecalis appreciably stimulated antibody formation. Similar results were obtained with respect toE. coli 055. The complement level was significantly increased by the spore-bearing aerobes and byS. albus.Research Laboratory of Experimental Biological Models, Academy of Medical Sciences of the USSR, Moscow Region. (Presented by Academician of the Academy of Medical Sciences of the USSR A. M. Chernukh.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 9, pp. 1100–1102, September, 1976.