Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial ...changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children.
Fatty acids are a vital component of human milk. They influence infant neurodevelopment and immune function, and they provide ∼50% of milk–s energy content.
The objectives of this study were to ...characterize the composition of human milk fatty acids in a large Canadian birth cohort and identify factors influencing their variability.
In a subset of the CHILD cohort (n = 1094), we analyzed milk fatty acids at 3–4 mo postpartum using GLC. Individual and total SFAs, MUFAs, and n–3 and n–6 PUFAs were analyzed using SD scores and principal component analysis (PCA). Maternal diet, sociodemographic, health, and environmental factors were self-reported. Single-nucleotide polymorphisms were assessed in the fatty acid desaturase 1 (FADS1-rs174556) and 2 (FADS2-rs174575) genes.
Fatty acid profiles were variable, with individual fatty acid proportions varying from 2- to >30-fold between women. Using PCA, we identified 4 milk fatty acid patterns: “MUFA and low SFA,” “high n–6 PUFA,” “high n–3 PUFA,” and “high medium-chain fatty acids.” In multivariable-adjusted analyses, fish oil supplementation and fatty cold water fish intake were positively associated with DHA and the “high n–3 PUFA” pattern. Mothers carrying the minor allele of FADS1-rs174556 had lower proportions of arachidonic acid (ARA; 20:4n–6). Independent of selected dietary variables and genetic variants, Asian ethnicity was associated with higher linoleic acid (18:2n–6) and total n–3 PUFAs. Ethnic differences in ARA were explained by FADS1 genotype. Maternal obesity was independently associated with higher total SFAs, the “high medium-chain fatty acid” pattern, and lower total MUFAs. Lactation stage, season, study site, and maternal education were also independently associated with some milk fatty acids. No associations were observed for maternal age, parity, delivery mode, or infant sex.
This study provides unique insights about the “normal” variation in the composition of human milk fatty acids and the contributing dietary, genetic, sociodemographic, health, and environmental factors. Further research is required to assess implications for infant health.
Abstract
Allergic diseases affect millions of people worldwide. An increase in their prevalence has been associated with alterations in the gut microbiome, i.e., the microorganisms and their genes ...within the gastrointestinal tract. Maturation of the infant immune system and gut microbiota occur in parallel; thus, the conformation of the microbiome may determine if tolerant immune programming arises within the infant. Here we show, using deeply phenotyped participants in the CHILD birth cohort (
n
= 1115), that there are early-life influences and microbiome features which are uniformly associated with four distinct allergic diagnoses at 5 years: atopic dermatitis (AD,
n
= 367), asthma (As,
n
= 165), food allergy (FA,
n
= 136), and allergic rhinitis (AR,
n
= 187). In a subset with shotgun metagenomic and metabolomic profiling (
n
= 589), we discover that impaired 1-year microbiota maturation may be universal to pediatric allergies (AD
p
= 0.000014; As
p
= 0.0073; FA
p
= 0.00083; and AR
p
= 0.0021). Extending this, we find a core set of functional and metabolic imbalances characterized by compromised mucous integrity, elevated oxidative activity, decreased secondary fermentation, and elevated trace amines, to be a significant mediator between microbiota maturation at age 1 year and allergic diagnoses at age 5 years (β
indirect
= −2.28;
p
= 0.0020). Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease.
Multiple studies have demonstrated that early-life exposure to pets or siblings affords protection against allergic disease; these associations are commonly attributed to the "hygiene hypothesis". ...Recently, low diversity of the infant gut microbiota has also been linked to allergic disease. In this study, we characterize the infant gut microbiota in relation to pets and siblings.
The study population comprised a small sub-sample of 24 healthy, full term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mothers reported on household pets and siblings. Fecal samples were collected at 4 months of age, and microbiota composition was characterized by high-throughput signature gene sequencing.
Microbiota richness and diversity tended to be increased in infants living with pets, whereas these measures were decreased in infants with older siblings. Infants living with pets exhibited under-representation of Bifidobacteriaceae and over-representation of Peptostreptococcaceae; infants with older siblings exhibited under-representation of Peptostreptococcaceae.
This study provides new evidence that exposure to pets and siblings may influence the early development of the gut microbiota, with potential implications for allergic disease. These two traditionally protective "hygiene hypothesis" factors appear to differentially impact gut microbiota composition and diversity, calling into question the clinical significance of these measures. Further research is required to confirm and expand these findings.
Vitamin D plays multiple roles in regulation of protective and maladaptive immunity. Although epidemiologic studies link poor in vivo 25(OH)D status to increased viral respiratory infections, we ...poorly understand how vitamin D affects viral pattern recognition receptor (PRR)-driven cytokine production. In this study, we hypothesized that the biologically active metabolite of vitamin D, 1,25(OH)2D3, inhibits human proinflammatory and anti-inflammatory innate cytokine responses stimulated by representative bacterial or viral PRR ligands. Fresh PBMCs or CD14(+) monocytes were stimulated with TLR4, TLR7/8-selective ligands, or respiratory syncytial virus (RSV) ± 1,25(OH)2D3. Proinflammatory and anti-inflammatory responses resulting from TLR4 stimulation were inhibited ∼50% in the presence of 1,25(OH)2D3. Conversely, its usage at physiologic through pharmacologic concentrations inhibited neither proinflammatory nor anti-inflammatory responses evoked by viral PRR ligands or infectious RSV. This differential responsiveness was attributed to the finding that TLR7/8, but not TLR4, stimulation markedly inhibited vitamin D receptor mRNA and protein expression, selectively reducing the sensitivity of viral PRR responses to modulation. 1,25(OH)2D3 also enhanced expression of IkBa, a potent negative regulator of NF-κB and cytokine production, in TLR4-stimulated monocytes while not doing so upon TLR7/8 stimulation. Thus, 1,25(OH)2D3 inhibits both proinflammatory and a broad panel of anti-inflammatory responses elicited by TLR4 stimulation, arguing that the common view of it as an anti-inflammatory immune response modifier is an oversimplification. In viral responses, it consistently fails to modify TLR7/8- or RSV-stimulated innate cytokine production, even at supraphysiologic concentrations. Collectively, the data call into question the rationale for increasingly widespread self-medication with vitamin D supplements.
Gut microbiota and allergic disease in children Bridgman, Sarah L; Kozyrskyj, Anita L; Scott, James A ...
Annals of allergy, asthma, & immunology,
02/2016, Letnik:
116, Številka:
2
Journal Article
The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant ...allergic sensitization enhances subsequent development of these allergic diseases at age 3 years.
Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available.
Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk RR, 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36).
Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.
Recent trials have shown that avoiding peanuts during infancy increases the risk of peanut allergy; however, these studies did not address maternal peanut consumption.
We sought to investigate the ...relationship between maternal peanut consumption while breast-feeding, timing of direct peanut introduction, and peanut sensitization at age 7 years.
Secondary analysis of a nested cohort within the 1995 Canadian Asthma Primary Prevention Study intervention study was performed. Breast-feeding and maternal and infant peanut consumption were captured by repeated questionnaires during infancy. Skin prick testing for peanut sensitization was performed at age 7 years.
Overall, 58.2% of mothers consumed peanuts while breast-feeding and 22.5% directly introduced peanuts to their infant by 12 months. At 7 years, 9.4% of children were sensitized to peanuts. The lowest incidence (1.7%) was observed among children whose mothers consumed peanuts while breast-feeding and directly introduced peanuts before 12 months. Incidence was significantly higher (P < .05) if mothers consumed peanuts while breast-feeding but delayed introducing peanuts to their infant beyond 12 months (15.1%), or if mothers avoided peanuts themselves but directly introduced peanuts by 12 months (17.6%). Interaction analyses controlling for study group and maternal atopy confirmed that maternal peanut consumption while breast-feeding and infant peanut consumption by 12 months were protective in combination, whereas either exposure in isolation was associated with an increased risk of sensitization (P interaction = .003).
In this secondary analysis, maternal peanut consumption while breast-feeding paired with direct introduction of peanuts in the first year of life was associated with the lowest risk of peanut sensitization, compared with all other combinations of maternal and infant peanut consumption.
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Over the past 20 years, the Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many ...national guidelines. However, uptake of existing guidelines is poor. A major revision of the GINA report was published in 2014, and updated in 2015, reflecting an evolving understanding of heterogeneous airways disease, a broader evidence base, increasing interest in targeted treatment, and evidence about effective implementation approaches. During development of the report, the clinical utility of recommendations and strategies for their practical implementation were considered in parallel with the scientific evidence.This article provides a summary of key changes in the GINA report, and their rationale. The changes include a revised asthma definition; tools for assessing symptom control and risk factors for adverse outcomes; expanded indications for inhaled corticosteroid therapy; a framework for targeted treatment based on phenotype, modifiable risk factors, patient preference, and practical issues; optimisation of medication effectiveness by addressing inhaler technique and adherence; revised recommendations about written asthma action plans; diagnosis and initial treatment of the asthma-chronic obstructive pulmonary disease overlap syndrome; diagnosis in wheezing pre-school children; and updated strategies for adaptation and implementation of GINA recommendations.
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