Reduced Th22 cell proportion and prevention of atopic dermatitis in infants following maternal probiotic supplementation.

BACKGROUND: In the randomized, controlled study Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT), maternal probiotic supplementation reduced the incidence of atopic dermatitis (AD) in the offspring. In the current study, we hypothesized that the effect was mediated by a shift in the T helper (Th) cells in the children. OBJECTIVE: To examine whether Th cell proportions were affected by maternal probiotic supplementation and thus could mediate the preventive effect of probiotics on AD. METHODS: A total of 415 pregnant women were randomized to ingest a combination of Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis subsp. lactis Bb-12 (Bb-12) and Lactobacillus acidophilus La-5 (La-5) or placebo, and their offspring were assessed for AD during the first 2 years of life. Peripheral blood collected at 3 months of age was analysed for regulatory T cells (n=140) and Th subsets (n=77) including Th1, Th2, Th9, Th17 and Th22. RESULTS: The proportion of Th22 cells was reduced in children in the probiotic group compared to the placebo group (median 0.038% vs 0.064%, P=.009). The difference between the probiotic and placebo groups was also observed in the children who did not develop AD during the 2-year follow-up. The proportion of Th22 cells was increased in children who developed AD compared to the children who did not develop AD (0.090% vs 0.044%, P<.001). Mediation analysis indicated that the preventive effect of probiotics was partially mediated through the reduction in Th22 cells. CONCLUSION: Perinatal maternal probiotic supplementation with a combination of LGG, Bb-12 and La-5 reduced the proportion of Th22 cells in 3-month-old children. This may partially explain the preventive effect of probiotics on AD.

Transition from infant- to adult-like gut microbiota.

Transition from an infant to an adult associated gut microbiota with age through establishment of strict anaerobic bacteria remains one of the key unresolved questions in gut microbial ecology. Here a comprehensive comparative analysis of stool microbiota in a large cohort of mothers and their children sampled longitudinally up until 2 years of age using sequencing analysis tool was presented that allows realistic microbial diversity estimates. In this work, evidence for the switch from children to adult associated microbial profile between 1 and 2 years of age was provided, suggestively driven by Bifidobacterium breve. An Operational Taxonomic Unit (OTU) belonging to B. breve was highly prevalent in the population throughout the first year of life, and was negatively associated with detection of a range of adult-like OTUs. Although an adult profile was not fully established by 2 years of age, it was demonstrated that with regards to the most prevalent OTUs, their prevalence in the child population by then already resembled that of the adult population. Taken together, it was proposed that late-colonizing OTUs were recruited at a later stage and were not acquired at birth with the recruitment being controlled by gatekeeping OTUs until the age of 1 year.

Bifidobacterial succession and correlation networks in a large unselected cohort of mothers and their children.

Bifidobacteria are a major microbial component of infant gut microbiota, which is believed to promote health benefits for the host and stimulate maturation of the immune system. Despite their perceived importance, very little is known about the natural development of and possible correlations between bifidobacteria in human populations. To address this knowledge gap, we analyzed stool samples from a randomly selected healthy cohort of 87 infants and their mothers with >90% of vaginal delivery and nearly 100% breast-feeding at 4 months. Fecal material was sampled during pregnancy, at 3 and 10 days, at 4 months, and at 1 and 2 years after birth. Stool samples were predicted to be rich in the species Bifidobacterium adolescentis, B. bifidum, B. dentium, B. breve, and B. longum. Due to high variation, we did not identify a clear age-related structure at the individual level. Within the population as a whole, however, there were clear age-related successions. Negative correlations between the B. longum group and B. adolescentis were detected in adults and in 1- and 2-year-old children, whereas negative correlations between B. longum and B. breve were characteristic for newborns and 4-month-old infants. The highly structured age-related development of and correlation networks between bifidobacterial species during the first 2 years of life mirrors their different or competing nutritional requirements, which in turn may be associated with specific biological functions in the development of healthy gut.

Modelling bacterial transmission in human allergen-specific IgE sensitization.

AIMS: The impact of bacterial transmission from mother to child on human allergy development is poorly understood. The aim of the present work was therefore to use a temporal collected dataset of 117 mothers and their children to model the potential effect of mother-to-child bacterial transmission on allergy (IgE) sensitization. METHODS AND RESULTS: We have recently shown a negative IgE correlation to high Escherichia coli levels until the age of 1 year, with a shift to positive correlation to high Bacteroides fragilis levels at the age of 2. In the present work, we used the previous published data to model the persistence and interaction effects of E. coli and B. fragilis with respect to IgE sensitization. Temporal modelling was made by first defining a stochastic model for sensitization state based on Markov chains and regression tree analyses. Subsequent simulations were used to determine the impact of mother-to-infant bacterial transmission. The regression tree analyses showed that E. coli colonization within 4 days was negatively correlated to sensitization, while lack of E. coli colonization at day 4 combined with B. fragilis colonization after 4 months was positively correlated. With Markov chain analyses, we found that E. coli was highly persistent in infants until the age of 4 months, while the persistence of B. fragilis increased with age. CONCLUSIONS: Simulations showed that the mother's bacterial composition correlated significantly to the child's IgE sensitization state at the age of 2 years. High E. coli and low B. fragilis levels in the mother were negatively correlated, while low E. coli and high B. fragilis were positively correlated to IgE. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results support that allergy could partly be communicable, being transferred from mother to infant through the gut microbiota.

Mother-to-child transmission of and multiple-strain colonization by Bacteroides fragilis in a cohort of mothers and their children.

Bacteroides fragilis represents an early infant colonizer with important host interactions. Our knowledge about the diversity, transmission, and persistence of this bacterium, however, is limited. Here, we addressed these questions using a combination of multilocus sequence typing (MLST) and variable-number tandem repeat (VNTR) sequence analyses. We used both culture-dependent and -independent typing. We genotyped B. fragilis in fecal samples from a cohort of 93 mothers and their children, with samples taken from the mothers and from the children at the ages 1 to 10 days, 4 months, 1 year, and 2 years. By MLST we found two main B. fragilis groups, which we denoted clades A and B. Direct typing of stool samples using the icd gene revealed seven sequence types, five within clade A and two within clade B. A single clade A sequence type, however, represented 79% of all the sequences. This sequence type was further subtyped using VNTR. VNTR subtyping revealed 16 different VNTR types. Based on the distribution patterns of these, we show mother-to-child transmission and multiple-strain colonization. We argue that negative host selection promotes the coexistence of multiple strains. The significance of our findings is that we have started unraveling the transmission and persistence patterns of one of the most important human gut colonizers.

Temporal variations in early gut microbial colonization are associated with allergen-specific immunoglobulin E but not atopic eczema at 2 years of age.

BACKGROUND: Intestinal microbiota undergoes substantial development during the first 2 years of life, important for intestinal immunologic development and maturation influencing systemic immune responses. OBJECTIVE: We aimed to investigate, using a prospective study design, whether allergen-specific IgE (sIgE) and atopic eczema are associated with variations in gut microbial colonization patterns in an unselected population during the first 2 years of life. METHODS: Faeces from 94 infants were repeatedly sampled from 10 days, 4 months, 1 and 2 years postnatal and analysed for 12 different bacterial species by quantitative real-time PCR. Venous blood samples from the infants were collected at 2 years of age and were analysed for sIgE for 12 specific allergens. The temporal gut colonization patterns for 42 sIgE-positive (sIgE≥0.35 kU/L) and 52 sIgE-negative children (sIgE<0.1 kU/L) were then compared. The association between colonization pattern and phenotype as atopic eczema according to UK Working Party (UKWP) criteria were also described. RESULTS: Subjects with atopic sensitization had lower levels of Escherichia coli at 4 months and 1 year, higher levels of Bifidobacterium longum at 1 year and lower levels of Bacteroides fragilis at 2 years. For E. coli and B. longum, the differences were only transient and had disappeared by 2 years of age. For other species, there were no differences in colonization patterns, and we found no association between colonization pattern and atopic eczema. CONCLUSIONS AND CLINICAL RELEVANCE: We found temporal and transient variations in gut microbial colonization patterns associated with differences in sIgE sensitization at 2 years of age. A full understanding of the principles and mechanisms that underlie intestinal microbial colonization and diversity and host-microbiota relationships will be pivotal for the development of therapeutic approaches that manipulate the intestinal microbiota to maintain human health. [ REGISTRATION NUMBER: ISRCTN28090297].

Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial.

BACKGROUND: Previous reports have suggested that certain probiotics given to mothers and children at risk of atopy halves the incidence of atopic dermatitis (AD) at 2 years of age. OBJECTIVES: To examine if probiotics given to pregnant women in a nonselected population could prevent atopic sensitization or allergic diseases during the child's first 2 years. METHODS: In a randomized, double-blind trial of children from a nonselected maternal population (ClinicalTrials.gov identifier: NCT00159523), women received probiotic milk or placebo from 36 weeks of gestation to 3 months postnatally during breastfeeding. The probiotic milk contained Lactobacillus rhamnosus GG, L. acidophilus La-5 and Bifidobacterium animalis subsp. lactis Bb-12. Children with an itchy rash for more than 4 weeks were assessed for AD. At 2 years of age, all children were assessed for atopic sensitization, AD, asthma and allergic rhinoconjunctivitis. The intention-to-treat (ITT) analysis was enabled by multiple imputations. RESULTS: Four hundred and fifteen pregnant women were computer randomized. At 2 years, 138 and 140 children in the probiotic and the placebo groups, respectively, were assessed. In the ITT analysis, the odds ratio (OR) for the cumulative incidence of AD was 0·51 in the probiotic group compared with the placebo [95% confidence interval (CI) 0·30-0·87; P=0·013]. There were no significant effects on asthma (OR 0·68, 95% CI 0·26-1·80; P=0·437) or atopic sensitization (OR 1·52, 95% CI 0·74-3·14; P=0·254). CONCLUSIONS: Probiotics given to nonselected mothers reduced the cumulative incidence of AD, but had no effect on atopic sensitization.