Immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during recent decades in westernized countries. The rate of ...cesarean delivery has also increased in this period and has been associated with the development of some of these diseases.
Mature children born by cesarean delivery were analyzed for risk of hospital contact for chronic immune diseases recorded in the Danish national registries in the 35-year period 1977-2012. Two million term children participated in the primary analysis. We studied childhood diseases with a suspected relation to a deviant immune-maturation and a debut at young age. The effect of cesarean delivery on childhood disease incidences were estimated by means of confounder-adjusted incidence rate ratios with 95% confidence intervals obtained in Poisson regression analyses.
Children delivered by cesarean delivery had significantly increased risk of asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel disease, immune deficiencies, and leukemia. No associations were found between cesarean delivery and type 1 diabetes, psoriasis, or celiac disease.
Cesarean delivery exemplifies a shared environmental risk factor in early life associating with several chronic immune diseases. Understanding commonalities in the underlying mechanisms behind chronic diseases may give novel insight into their origin and allow prevention.
Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with ...n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring.
We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood
(COPSAC
) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval CI, 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization.
Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).
Despite the accelerating number of uncultivated virus sequences discovered in metagenomics and their apparent importance for health and disease, the human gut virome and its interactions with ...bacteria in the gastrointestinal tract are not well understood. This is partly due to a paucity of whole-virome datasets and limitations in current approaches for identifying viral sequences in metagenomics data. Here, combining a deep-learning based metagenomics binning algorithm with paired metagenome and metavirome datasets, we develop Phages from Metagenomics Binning (PHAMB), an approach that allows the binning of thousands of viral genomes directly from bulk metagenomics data, while simultaneously enabling clustering of viral genomes into accurate taxonomic viral populations. When applied on the Human Microbiome Project 2 (HMP2) dataset, PHAMB recovered 6,077 high-quality genomes from 1,024 viral populations, and identified viral-microbial host interactions. PHAMB can be advantageously applied to existing and future metagenomes to illuminate viral ecological dynamics with other microbiome constituents.
Bacteriophages constitute an important part of the human gut microbiota, but their impact on this community is largely unknown. Here, we cultivate temperate phages produced by 900 E. coli strains ...isolated from 648 fecal samples from 1-year-old children and obtain coliphages directly from the viral fraction of the same fecal samples. We find that 63% of strains hosted phages, while 24% of the viromes contain phages targeting E. coli. 150 of these phages, half recovered from strain supernatants, half from virome (73% temperate and 27% virulent) were tested for their host range on 75 E. coli strains isolated from the same cohort. Temperate phages barely infected the gut strains, whereas virulent phages killed up to 68% of them. We conclude that in fecal samples from children, temperate coliphages dominate, while virulent ones have greater infectivity and broader host range, likely playing a role in gut microbiota dynamics.
The composition of the human gut microbiome matures within the first years of life. It has been hypothesized that microbial compositions in this period can cause immune dysregulations and potentially ...cause asthma. Here we show, by associating gut microbial composition from 16S rRNA gene amplicon sequencing during the first year of life with subsequent risk of asthma in 690 participants, that 1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 years. This association is only apparent among children born to asthmatic mothers, suggesting that lacking microbial stimulation during the first year of life can trigger their inherited asthma risk. Conversely, adequate maturation of the gut microbiome in this period may protect these pre-disposed children.
Asthma is believed to arise through early life aberrant immune development in response to environmental exposures that may influence the airway microbiota. Here, we examine the airway microbiota ...during the first three months of life by 16S rRNA gene amplicon sequencing in the population-based Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC
) cohort consisting of 700 children monitored for the development of asthma since birth. Microbial diversity and the relative abundances of Veillonella and Prevotella in the airways at age one month are associated with asthma by age 6 years, both individually and with additional taxa in a multivariable model. Higher relative abundance of these bacteria is furthermore associated with an airway immune profile dominated by reduced TNF-α and IL-1β and increased CCL2 and CCL17, which itself is an independent predictor for asthma. These findings suggest a mechanism of microbiota-immune interactions in early infancy that predisposes to childhood asthma.
Early-life microbiota has been linked to the development of chronic inflammatory diseases. It has been hypothesized that maternal vaginal microbiota is an important initial seeding source and ...therefore might have lifelong effects on disease risk. To understand maternal vaginal microbiota's role in seeding the child's microbiota and the extent of delivery mode-dependent transmission, we studied 665 mother-child dyads from the COPSAC
cohort. The maternal vaginal microbiota was evaluated twice in the third trimester and compared with the children's fecal (at 1 week, 1 month, and 1 year of age) and airway microbiota (at 1 week, 1 month, and 3 months). Based on the concept of weighted transfer ratios (WTRs), we have identified bacterial orders for which the WTR displays patterns indicate persistent or transient transfer from the maternal vaginal microbiome, as well as orders that are shared at later time points independent of delivery mode, indicating a common reservoir.
Otitis media with middle ear effusion (MEE) can be treated with ventilation tubes (VT) insertion, and it has been speculated that prolonged MEE in childhood can affect neurological development, which ...in turn may be important for later academic achievements.
To investigate the association between middle ear effusion (MEE), treatment with ventilation tubes (VT) and childhood neurological development.
We examined 663 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) unselected mother-child cohort study. Children were followed by study pediatricians with regular visits from pregnancy until 3 years of age. MEE was diagnosed using tympanometry at age 1, 2 and 3 years. Information regarding VT from age 0-3 years was obtained from national registries. We assessed age at achievement of gross motor milestones from birth, language scores at 1 and 2 years, cognitive score at 2.5 years and general development score at age 3 years using standardized quantitative tests.
Children with MEE had a lower 1-year word production vs. children with no disease: (median 2, IQR 0-6 vs. 4, IQR 1-7; p = 0.017), and a lower 1-year word comprehension (median 36; IQR 21-63 vs. 47, IQR 27-84; p = 0.03). Children with VT had a lower 2-5-year cognitive score vs. children with no disease; estimate -2.34; 95% CI -4.56;-0.12; p = 0.039. No differences were found between children with vs. without middle ear disease regarding age at achievement of gross motor milestones, word production at 2 years or the general developmental score at 3 years.
Our study supports the previous findings of an association between MEE and concurrent early language development, but not later neurological endpoints up to the age of 3. As VT can be a treatment of those with symptoms of delayed development, we cannot conclude whether treatment with VT had positive or negative effects on neurodevelopment.
High sensitivity C-reactive protein (hs-CRP) is a marker of systemic low-grade inflammation and associated with chronic inflammatory diseases. It is unknown whether maternal and infant hs-CRP levels ...are correlated and little is known about risk factors in early childhood. Hs-CRP were measured in mothers during pregnancy week 24 (N = 690), and one-week postpartum (N = 675) and in their children age 6 mo (N = 640) enrolled in the Copenhagen Prospective Studies on Asthma in Childhood
(COPSAC
) cohort. The risk factor analysis included anthropometrics, environmental exposures and CRP-Genetic Risk Score (GRS). Mother's body mass index (BMI), use of antibiotics, smoking, cesarean delivery and season were associated with higher maternal hs-CRP level, whereas higher social circumstances were associated with lower hs-CRP level (p < 0.05). Child's BMI, siblings, bacterial airway colonization, current infection, CRP-genetic risk score and season were associated with higher hs-CRP at age 6 mo (all p < 0.05). Mother's hs-CRP level in pregnancy week 24 was associated with hs-CRP level in the child at 6 mo: β-coefficient = 0.11 95% CI: 0.01-0.20, R
= 0.22, p = 0.03. The association was unchanged adjusted for all significant risk factors. Systemic low-grade inflammation in pregnant mothers and their offspring is correlated independently of BMI, environmental exposures and genetic risk factors.
We recently published two independent randomized controlled trials of vitamin D supplementation during pregnancy, both indicating a >20% reduced risk of asthma/recurrent wheeze in the offspring by 3 ...years of age. However, neither reached statistical significance.
To perform a combined analysis of the two trials and investigate whether maternal 25-hydroxy-vitamin D (25(OH)D) level at trial entry modified the intervention effect.
VDAART (N = 806) and COPSAC2010. (N = 581) randomized pregnant women to daily high-dose vitamin D3 (4,000 IU/d and 2,400 IU/d, respectively) or placebo. All women also received a prenatal vitamin containing 400 IU/d vitamin D3. The primary outcome was asthma/recurrent wheeze from 0-3yrs. Secondary end-points were specific IgE, total IgE, eczema and lower respiratory tract infections (LRTI). We conducted random effects combined analyses of the treatment effect, individual patient data (IPD) meta-analyses, and analyses stratified by 25(OH)D level at study entry.
The analysis showed a 25% reduced risk of asthma/recurrent wheeze at 0-3yrs: adjusted odds ratio (aOR) = 0.74 (95% CI, 0.57-0.96), p = 0.02. The effect was strongest among women with 25(OH)D level ≥30ng/ml at study entry: aOR = 0.54 (0.33-0.88), p = 0.01, whereas no significant effect was observed among women with 25(OH)D level <30ng/ml at study entry: aOR = 0.84 (0.62-1.15), p = 0.25. The IPD meta-analyses showed similar results. There was no effect on the secondary end-points.
This combined analysis shows that vitamin D supplementation during pregnancy results in a significant reduced risk of asthma/recurrent wheeze in the offspring, especially among women with 25(OH)D level ≥ 30 ng/ml at randomization, where the risk was almost halved. Future studies should examine the possibility of raising 25(OH)D levels to at least 30 ng/ml early in pregnancy or using higher doses than used in our studies.
COPSAC2010: ClinicalTrials.gov NCT00856947; VDAART: ClinicalTrials.gov NCT00920621.
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