Low Concentration of Fecal Valeric Acid at 1 Year of Age Is Linked with Eczema and Food Allergy at 13 Years of Age: Findings from a Swedish Birth Cohort.

BACKGROUND: Short-chain fatty acids (SCFAs) are abundant bacterial metabolites in the gut, with immunomodulatory properties. Hence, they may influence allergy development. Previous studies have linked fecal SCFA pattern during infancy with allergy. However, the association of SCFAs to allergic outcomes in adolescence is not well established. Here, we examined how the fecal SCFA pattern at 1 year of age related to allergy at 13 years of age. METHODS: Levels of 8 SCFAs in fecal samples collected at 1 year of age from 110 children were quantified using gas chromatography. The same individuals were evaluated at 13 years of age for allergic symptoms, allergy diagnosis and allergy medication by questionnaire, and for sensitization using skin prick test against egg, milk, fish, wheat and soy, cat, dog, horse, birch, and timothy grass. RESULTS: The concentration of fecal valeric acid at 1 year of age was inversely associated with eczema at 13 years of age (OR 0.6, 95% CI: 0.4-1.0, p = 0.049) and showed a trend for inverse association with food allergy at 13 years of age (OR 0.6, 95% CI: 0.4-1.0, p = 0.057). In a sub-group analysis of children with eczema at 1 year of age, a higher concentration of fecal valeric acid was linked with reduced risk of their eczema remaining at 13 years of age (OR 0.2, 95% CI: 0.0-1.5), although this latter analysis did not reach statistical significance (p = 0.12). CONCLUSIONS: Our findings lend further support to the notion of early childhood as a critical period when allergy may be programmed via the gut microbiota. Higher levels of fecal valeric acid may be characteristic of a protective gut microbiota and/or actively contribute to protection from eczema and food allergy.

Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development.

BACKGROUND: Although a reduced gut microbiota diversity and low mucosal total IgA levels in infancy have been associated with allergy development, IgA responses to the gut microbiota have not yet been studied. OBJECTIVE: We sought to determine the proportions of IgA coating together with the characterization of the dominant bacteria, bound to IgA or not, in infant stool samples in relation to allergy development. METHODS: A combination of flow cytometric cell sorting and deep sequencing of the 16S rDNA gene was used to characterize the bacterial recognition patterns by IgA in stool samples collected at 1 and 12 months of age from children staying healthy or having allergic symptoms up to 7 years of age. RESULTS: The children with allergic manifestations, particularly asthma, during childhood had a lower proportion of IgA bound to fecal bacteria at 12 months of age compared with healthy children. These alterations cannot be attributed to differences in IgA levels or bacterial load between the 2 groups. Moreover, the bacterial targets of early IgA responses (including coating of the Bacteroides genus), as well as IgA recognition patterns, differed between healthy children and children with allergic manifestations. Altered IgA recognition patterns in children with allergy were observed already at 1 month of age, when the IgA antibodies are predominantly maternally derived in breast-fed children. CONCLUSION: An aberrant IgA responsiveness to the gut microbiota during infancy precedes asthma and allergy development, possibly indicating an impaired mucosal barrier function in allergic children.

Probiotic administration among free-living older adults: a double blinded, randomized, placebo-controlled clinical trial.

BACKGROUND: Diseases of the digestive system have been found to contribute to a higher symptom burden in older adults. Thus, therapeutic strategies able to treat gastrointestinal discomfort might impact the overall health status and help older adults to increase their overall health status and optimal functionality. OBJECTIVE: The aim of this double-blinded, randomized, placebo-controlled clinical trial was to evaluate the effect of the probiotic strain Lactobacillus reuteri on digestive health and wellbeing in older adults. METHODS: The study enrolled general older adults (>65 years). After eligibility screening qualified subjects (n = 290) participated in a 2-arm study design, with each arm consisting of 12 weeks of intervention of either active or placebo product. Primary outcome measure was set to changes in gastrointestinal symptoms and secondary outcome measures were changes in level of wellbeing, anxiety and stress. Follow up was performed at 8 and 12 weeks. RESULTS: No persistent significant effects were observed on the primary or secondary outcome parameters of the study. A modest effect was observed in the probiotic arm, were levels of stress decreased at week 8 and 12. Similarly, we found that subjects suffering from indigestion and abdominal pain, respectively, showed a significant decrease of anxiety at week 8 after probiotic treatment, but not at week 12. CONCLUSION: The RCT failed to show any improvement in digestive health after daily intake of a probiotic supplement containing L. reuteri. Neither was any significant improvement in wellbeing, stress or anxiety observed. Even though the RCT had a negative outcome, the study highlights issues important to take into consideration when designing trials among older adults. TRIAL REGISTRATION: Clinicaltrials.gov/ NCT01837940 .

Human seroreactivity to gut microbiota antigens.

BACKGROUND: Although immune responses directed against antigens from the intestinal microbiota are observed in certain diseases, the normal human adaptive immune response to intestinal microbiota is poorly defined. OBJECTIVE: Our goal was to assess the adaptive immune response to the intestinal microbiota present in 143 healthy adults and compare this response with the response observed in 52 children and their mothers at risk of having allergic disease. METHODS: Human serum was collected from adults and children followed from birth to 7 years of age, and the serum IgG response to a panel of intestinal microbiota antigens was assessed by using a novel protein microarray. RESULTS: Nearly every subject tested, regardless of health status, had serum IgG that recognized a common set of antigens. Seroreactivity to the panel of antigens was significantly lower in atopic adults. Healthy infants expressed the highest level of IgG seroreactivity to intestinal microbiota antigens. This adaptive response developed between 6 and 12 months of age and peaked around 2 years of age. Low IgG responses to certain clusters of microbiota antigens during infancy were associated with allergy development during childhood. CONCLUSIONS: There is an observed perturbation of the adaptive response to antigens from the microbiota in allergic subjects. These perturbations are observable even in childhood, suggesting that optimal stimulation of the adaptive immune system by the microbiota might be needed to prevent certain immune-mediated diseases.

Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section.

OBJECTIVE: The early intestinal microbiota exerts important stimuli for immune development, and a reduced microbial exposure as well as caesarean section (CS) has been associated with the development of allergic disease. Here we address how microbiota development in infants is affected by mode of delivery, and relate differences in colonisation patterns to the maturation of a balanced Th1/Th2 immune response. DESIGN: The postnatal intestinal colonisation pattern was investigated in 24 infants, born vaginally (15) or by CS (nine). The intestinal microbiota were characterised using pyrosequencing of 16S rRNA genes at 1 week and 1, 3, 6, 12 and 24 months after birth. Venous blood levels of Th1- and Th2-associated chemokines were measured at 6, 12 and 24 months. RESULTS: Infants born through CS had lower total microbiota diversity during the first 2 years of life. CS delivered infants also had a lower abundance and diversity of the Bacteroidetes phylum and were less often colonised with the Bacteroidetes phylum. Infants born through CS had significantly lower levels of the Th1-associated chemokines CXCL10 and CXCL11 in blood. CONCLUSIONS: CS was associated with a lower total microbial diversity, delayed colonisation of the Bacteroidetes phylum and reduced Th1 responses during the first 2 years of life.

No effect of probiotics on respiratory allergies: a seven-year follow-up of a randomized controlled trial in infancy.

BACKGROUND: Supplementation with the probiotic Lactobacillus reuteri reduced the incidence of IgE-associated allergic disease in infancy. This treatment might therefore also reduce the risk of asthma and allergic rhinoconjunctivitis in school age. OBJECTIVE: To evaluate whether perinatal and infant supplementation with L. reuteri reduced the prevalence of respiratory allergic disease in school age and to explore whether this supplementation was associated with any long-term side effects. METHODS: A randomized, placebo-controlled trial with oral supplementation with L. reuteri ATCC 55730 (1 × 10(8) CFU) during the last month of gestation and through the first year of life comprising 232 families with allergic disease, of whom 184 completed a 7-yr follow-up. The primary outcomes at 7 yr of age were allergic disease and skin prick test reactivity (ClinicalTrials.gov ID NCT01285830). RESULTS: The prevalence of asthma (15% in the probiotic vs. 16% in placebo group), allergic rhinoconjunctivitis (27% vs. 20%), eczema (21% vs. 19%) and skin prick test reactivity (29% vs. 26%) was similar in the probiotic and placebo group. Growth indices and gastrointestinal symptoms were similar in the two groups. No severe adverse events were reported. CONCLUSION: The effect of L. reuteri on sensitization and IgE-associated eczema in infancy did not lead to a lower prevalence of respiratory allergic disease in school age. Thus, the effect of L. reuteri on the immune system seems to be transient. Administration of L. reuteri during the last weeks of gestation and in infancy was not associated with any long-term side effects.

Low diversity of the gut microbiota in infants with atopic eczema.

BACKGROUND: It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing incidence of allergic disease. The advent of powerful, cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts. OBJECTIVE: We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development. METHODS: Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool samples at 1 week, 1 month, and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age (ClinicalTrials.gov ID NCT01285830). RESULTS: Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month (P = .004) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month (P = .02 and P = .01) and the phylum Proteobacteria at 12 months of age (P = .02). The microbiota was less uniform at 1 month than at 12 months of age, with a high interindividual variability. At 12 months, when the microbiota had stabilized, Proteobacteria, comprising gram-negative organisms, were more abundant in infants without allergic manifestation (Empirical Analysis of Digital Gene Expression in R [edgeR] test: P = .008, q = 0.02). CONCLUSION: Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema.

Slow salivary secretory IgA maturation may relate to low microbial pressure and allergic symptoms in sensitized children.

It is unknown why allergic symptoms do not develop in all sensitized children. We analyzed prospectively the postnatal secretory IgA (SIgA) development and whether high SIgA levels would protect sensitized infants from developing allergic symptoms. Salivary total IgA and SIgA levels were determined by ELISA, and allergy development was investigated at 3, 6, and 12 mo and at 2 and 5 y in two birth cohorts in Estonia (n = 110) and Sweden (n = 91), two geographically adjacent countries with different living conditions and allergy incidence. Total and SIgA levels increased with age, reaching adult levels at the age of 5. Virtually, all salivary IgA in Estonian children was in the secretory form, while a major part of IgA in Swedish saliva lacked the secretory component up to 2 y of age. In Sweden, high levels of salivary IgA without secretory component correlated inversely with house dust endotoxin levels. High SIgA levels were associated with less development of allergic symptoms in sensitized Swedish children. In conclusion, postnatal maturation of the salivary SIgA system proceeds markedly slower in Swedish than Estonian children, possibly as a consequence of low microbial pressure. SIgA may limit allergy-mediated tissue damage at mucosal surfaces in sensitized individuals.

High salivary secretory IgA antibody levels are associated with less late-onset wheezing in IgE-sensitized infants.

Low levels of secretory IgA (SIgA) and transient IgA deficiency have been associated with an increased risk for allergy, but data are conflicting. The aim was to assess the relationship between salivary SIgA antibody levels at 1 yr and wheezing at age four in a birth cohort, in particular the possible protective role of salivary SIgA in sensitized children. Saliva samples were obtained from all children (n=67) with a positive skin prick test (SPT) at 1 yr and 212 children with a negative SPT. In all, 200 of these children responded to questionnaires at 4 yrs and 183 were skin prick tested at that age. The levels of salivary SIgA and salivary IgA antibodies to the most common food allergen egg and inhalant allergen cat were analyzed by ELISA. Serum was analyzed for IgE antibodies to egg and cat. Development of late-onset wheezing was associated with low SIgA levels in children with positive SPT to at least one allergen both at 1 and 4 yrs of age (p=0.04), as well as in children with circulating IgE antibodies to egg or cat at 1 yr (p=0.02). None of nine persistently sensitized children with SIgA levels in the upper quartile developed wheezing, when compared to 10/20 children with lower levels (p=0.01). Older siblings, more than three infections during infancy, at least one smoking parent, and male gender, were all associated with SIgA in the upper quartile. In conclusion, high levels of SIgA antibodies in sensitized infants were associated with significantly less late-onset wheezing, supporting a protective role against development of asthmatic symptoms. Recurrent infections and other factors supporting an increased microbial pressure during infancy were associated with high levels of salivary SIgA.

Breast milk cytokine and IgA composition differ in Estonian and Swedish mothers-relationship to microbial pressure and infant allergy.

The immune system of the neonate is influenced by maternal immunity during pregnancy and lactation. An altered microbial exposure, possibly underlying the increase of allergic diseases in affluent societies, may affect maternal breast milk immune composition. Secretory IgA (SIgA), IL-4, IL-10, IL-13, IFN-[gamma], TGF-[beta]1, and TGF-[beta]2 were analyzed with ELISA in colostrum and 1-mo mature milk from mothers from Estonia (n = 39) and Sweden (n = 60), the two geographically adjacent countries with different living conditions and allergy incidence. The IL-10 and IFN-[gamma] levels were higher in colostrum from Estonian than Swedish mothers, whereas the opposite was true for TGF-[beta]2. In mature milk, higher SIgA and IFN-[gamma] levels but lower TGF-[beta]1 and TGF-[beta]2 levels were observed in Estonian than Swedish mothers. Interestingly, in Sweden but not Estonia, the TGF-[beta]1 and TGF-[beta]2 levels correlated inversely with environmental endotoxin concentrations, whereas positive correlations to microbial load were observed for IL-4, IL-10, and IFN-[gamma]. High colostral IL-13 levels were associated with allergic sensitization during infancy in Sweden. In conclusion, Estonian mothers have lower breast milk levels of TGF-[beta], particularly TGF-[beta]2, but higher levels of SIgA, IL-10, and IFN-[gamma] than Swedish mothers, possibly because of differences in microbial load.

Antibiotic use in infancy and symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 and 7 years old: International Study of Asthma and Allergies in Childhood Phase III.

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.

Early identification of atopy in the prediction of persistent asthma in children.

The long-term solution to the asthma epidemic is thought to be prevention, and not treatment of established disease. Atopic asthma arises from gene-environment interactions, which mainly take place during a short period in prenatal and postnatal development. These interactions are not completely understood, and hence primary prevention remains an elusive goal. We argue that primary-care physicians, paediatricians, and specialists lack knowledge of the role of atopy in early life in the development of persistent asthma in children. In this review, we discuss how early identification of children at high risk is feasible on the basis of available technology and important for potential benefits to the children. Identification of an asthmatic child's atopic status in early life has practical clinical and prognostic implications, and sets the basis for future preventative strategies.

Probiotic lactobacilli in breast milk and infant stool in relation to oral intake during the first year of life.

OBJECTIVES: This is to identify factors affecting the prevalence of Lactobacillus reuteri in maternal faeces and breast milk and infant faeces after oral supplementation with L reuteri and to assess the influence on microbial ecology, particularly Clostridium difficile and Bifidobacterium colonization. MATERIALS AND METHODS: In this double-blind trial, 232 mothers with a family history of atopic disease were randomized to a daily intake of either L reuteri American-type culture collection (ATCC) 55730 (1 x 10 colony-forming units [CFU]) or placebo for the last 4 weeks of pregnancy. Their babies then continued with the same study product daily from birth until 12 months of age. Bacterial counts and prevalence were assessed in maternal breast milk and faeces and infant faeces, using conventional cultivation methods. RESULTS: The prevalence of L reuteri was higher during the first year of life in the stool samples from infants in the active as compared with the placebo-treated group. The highest prevalence was recorded at 5 to 6 days of age (82% in the treated vs 20% in the placebo group, P < 0.001). Lactobacillus reuteri was isolated from 12% and 2%, respectively, in the colostrum samples (P < 0.05). Breast-feeding seemed to reduce faecal L reuteri counts, although antibiotics did not influence the levels of L reuteri. The administration of L reuteri did not affect bifidobacteria or C difficile colonization. CONCLUSION: Lactobacillus reuteri may be detected in breast milk after oral supplementation to the mother and in almost all infants after oral supplementation during the first year of life, as well as occasionally in many untreated infants.

Faecal short chain fatty acid pattern and allergy in early childhood.

AIM: To investigate whether functional changes of the gut flora over time were related to sensitization and allergic symptoms at four years of age. METHODS: The levels of short chain fatty acids (SCFAs) in faecal samples at one (n = 139) and four (n = 53) years of age were related to the development of positive skin prick tests (SPT) and allergic symptoms during the first four years of life. RESULTS: Faecal acetic (p < 0.01) and propionic (p < 0.01) acids decreased from one to four years of age, while valeric acid (p < 0.001) increased. Low levels of i-butyric (p = 0.01), i-valeric (p = 0.03) and valeric acids (p = 0.02) at one year were associated with questionnaire-reported symptoms of food allergy at four years. Positive SPTs and allergic symptoms at four years were associated with low faecal levels of i-butyric, i-valeric and valeric acids. At one year of age, infants with, as compared to without older siblings had higher median levels of valeric acid. CONCLUSION: A slow functional maturation of the gut microflora, as measured by faecal levels of SCFAs is associated with allergy both at one and four years. The findings lend further support to an association between allergy and the development of microbial diversity.

The role of atopic sensitization in flexural eczema: findings from the International Study of Asthma and Allergies in Childhood Phase Two.

BACKGROUND: The association between allergic sensitization and eczema has been debated for years. OBJECTIVE: We sought to determine and compare the strength of the association between allergen skin sensitization and eczema in both developing and industrialized countries. METHODS: Twenty-eight thousand five hundred ninety-one randomly selected 8- to 12-year-old schoolchildren in 20 countries were physically examined for flexural eczema and received skin prick testing to Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat hair, Alternaria tenuis, mixed tree and grass pollen, and allergens of local relevance. RESULTS: The age- and sex-adjusted odds ratios (ORs) for a positive association between flexural eczema and atopy ranged between 0.74 (95% CI, 0.31-1.81) and 4.53 (95% CI, 1.72-11.93), with a significantly stronger association in affluent compared with nonaffluent countries (combined age- and sex-adjusted OR(affluent) = 2.69 [95% CI, 2.31-3.13] and OR(nonaffluent) = 1.17 [95% CI, 0.81-1.70]). The combined population attributable fraction for atopy in flexural eczema was 27.9% for affluent and 1.2% for nonaffluent-country centers. Correlating gross national per-capita income with either ORs or population attributable fractions for atopy in flexural eczema confirmed a highly significant positive association (P = .006 and P < .001, respectively). CONCLUSIONS: The association between atopy and flexural eczema is weak and more variable than previously suggested, and the strength of this association is positively linked to gross national income.

Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood.

In Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC) time trends in the prevalence of rhinoconjunctivitis symptoms were analysed. Cross-sectional questionnaire surveys with identical protocols and questionnaires were completed a mean of 7 yr apart in two age groups comprising 498,083 children. In the 13- to 14-yr age group 106 centres in 56 countries participated, and in the 6- to 7-yr age group 66 centres in 37 countries participated. A slight worldwide increase in rhinoconjunctivitis prevalence was observed, but the variations were large among the centres and there was no consistent regional pattern. Prevalence increases in the older children exceeding 1% per year were recorded in 13 centres, including 3 of 9 centres in Africa, 2 of 15 in Asia-Pacific, 1 of 8 in India, 3 of 15 in Latin America, 3 of 9 in Eastern Europe and 1 of 34 in Western and Northern Europe. Decreasing rhinoconjunctivititis prevalence of similar magnitude was only seen in four centres. The changes were less pronounced in the 6- to 7-yr-old children and only in one centre did any change exceed 1% per year. The decrease in highest prevalence rates in ISAAC Phase I suggests that the prevalence has peaked in those regions. An increase was recorded in several centres, mostly in low and mid-income countries. The increases were more pronounced in the older age group, suggesting that environmental influences on the development of allergy may not be limited to early childhood.