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The gut microbiome is shaped through infancy and impacts the maturation of the immune system, thus protecting against chronic disease later in life. Phages, or viruses that infect bacteria, modulate bacterial growth by lysis and lysogeny, with the latter being especially prominent in the infant gut. Viral metagenomes (viromes) are difficult to analyse because they span uncharted viral diversity, lacking marker genes and standardized detection methods. Here we systematically resolved the viral diversity in faecal viromes from 647 1-year-olds belonging to Copenhagen Prospective Studies on Asthma in Childhood 2010, an unselected Danish cohort of healthy mother–child pairs. By assembly and curation we uncovered 10,000 viral species from 248 virus family-level clades (VFCs). Most (232 VFCs) were previously unknown, belonging to the Caudoviricetes viral class. Hosts were determined for 79% of phage using clustered regularly interspaced short palindromic repeat spacers within bacterial metagenomes from the same children. Typical Bacteroides-infecting crAssphages were outnumbered by undescribed phage families infecting Clostridiales and Bifidobacterium. Phage lifestyles were conserved at the viral family level, with 33 virulent and 118 temperate phage families. Virulent phages were more abundant, while temperate ones were more prevalent and diverse. Together, the viral families found in this study expand existing phage taxonomy and provide a resource aiding future infant gut virome research.

SummaryLarge cohort studies have contributed significantly to our understanding of the factors that influence the development of the bacterial component of the gut microbiome (GM) during the first years of life. However, the factors that shape the colonization by other important GM members such as the viral fraction remain more elusive. Most gut viruses are bacteriophages (phages), i.e., viruses attacking bacteria in a host specific manner, and to a lesser extent, but also widely present, eukaryotic viruses, including viruses attacking human cells. Here, we utilize the deeply phenotyped COPSAC2010 birth cohort consisting of 700 infants to investigate how social, pre-, peri- and postnatal factors may influence the gut virome composition at one year of age, where fecal virome data was available from 645 infants.Among the different exposures studied, having older siblings and living in an urban vs. rural area had the strongest impact on gut virome composition. Differential abundance analysis from a total of 16,118 viral operational taxonomic units (vOTUs) (mainly phages, but also 6.1% eukaryotic viruses) identified 2,105 vOTUs varying with environmental exposures, of which 5.9% were eukaryotic viruses and the rest was phages. Bacterial hosts for these phages were mainly predicted to be within theBacteroidaceae, Prevotellaceae, andRuminococcaceaefamilies, as determined by CRISPR spacer matches. Spearman correlation coefficients indicated strong co-abundance trends of vOTUs and their targeted bacterial host, which underlined the predicted phage-host connections. Further, our findings show that some gut viruses encode important metabolic functions and how the abundance of genes encoding these functions is influenced by environmental exposures. Genes that were significantly associated with early life exposures were found in a total of 42 vOTUs. 18 of these vOTUs had their life styles predicted, with 17 of them having a temperate lifestyle. These 42 vOTUs carried genes coding for enzymes involved in alanine, aspartate and glutamate metabolism, glycolysis-gluconeogenesis, as well as fatty acid biosynthesis. The latter implies that these phages could be involved in the utilization and degradation of major dietary components and affect infant health by influencing the metabolic capacity of their bacterial host.Given the importance of the GM in early life for maturation of the immune system and maintenance of metabolic health, these findings provide a valuable source of information for understanding early life factors that predispose for autoimmune and metabolic disorders.

Even in the absence of antibiotic exposure, the gut microbiome of infants has been shown to contain numerous antibiotic resistance genes (ARGs), but the mechanism for this remains unclear. In environmental bacteria, the selective advantage of ARGs can be increased through co-localization with genes such as other ARGs, biocide resistance genes, metal resistance genes, and virulence genes. However, this phenomenon is unknown from the human gut microbiome during early life despite frequent exposures to biocides and metals from an early age. Here, we conducted a comprehensive analysis of genetic co-localization of resistance genes in a cohort of 662 Danish children and examined the association between such co-localization and environmental factors as well as gut microbial maturation. Our study showed that co-localization of ARGs with other resistance and virulence genes is common in the early gut microbiome and is associated with gut bacteria that are indicative of low maturity, especiallyE. coli. The most common forms of co-localization involved tetracycline and fluoroquinolone resistance genes located near other ARGs, and, on plasmids, co-localization predominantly occurred in the form of class 1 integrons. Antibiotic use caused a short-term increase in mobile ARGs, while non-mobile ARGs showed no significant change. Finally, we found that a high abundance of virulence genes was associated with low gut microbial maturity and that virulence genes showed even higher potential for mobility than ARGs. Our study highlights important constraints that need to be considered when developing strategies to combat ARG dissemination.

RATIONALE Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. OBJECTIVE To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. METHODS Oropharyngeal swabs, from the Unbiased BIOmarkers for the Prediction of REspiratory Disease outcomes pediatric asthma/wheezing cohort, were characterized by 16S rRNA gene sequencing and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores (ESs) of the MSigDB Hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessing the frequency of exacerbations. MEASUREMENTS AND MAIN RESULTS Oropharyngeal samples of 241 children (age range: 1-17 years, 40% female) revealed 4 taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia and Haemophilus, respectively. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1 % predicted post-salbutamol, and the annual asthma exacerbation frequency during follow-up. The Veillonella-cluster was the most allergic and included highest percentage of children with ≥2 exacerbations/year during follow-up. The oropharyngeal clusters were different in the ESs of transforming growth factor β (highest in Veillonella-cluster) and Wnt/β-Catenin signaling (highest in Haemophilus-cluster) transcriptomic pathways in blood (all q-values < 0.05). CONCLUSION The analysis of the oropharyngeal microbiota of children with asthma/wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with exacerbations' risk and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiological insights and potentially new treatment approaches.

SUMMARY Background Prolonged systemic antibiotic treatment is often a part of management of hidradenitis suppurativa (HS). Although biologic therapies are now available, the patient’s treatment journey leading to biologic therapy is unclear. Objectives To examine treatment patterns and duration of systemic treatment use in patients with HS preceding biologic therapy. Methods We identified all patients with HS receiving treatment with biologics in the Danish National Patient Registry from 2010 to 2018 and extracted their entire prescription history of specific systemic treatments from the Danish National Prescription Registry since its inception in 1995. The patients’ treatment journeys are graphically displayed through Sankey diagrams and box plots generated to show temporal distributions. Descriptive patient characteristics were presented as frequencies with percentages for categorical variables and as means with SDs or medians with interquartile ranges (IQRs) for continuous variables. Results A total of 225 patients with HS were included. Patients had most frequently been treated with penicillin (n = 214; 95·1%), dicloxacillin (n = 194; 86·2%), tetracycline (n = 145; 64·4%) and rifampicin/clindamycin (n = 111; 49·3%), as well as the retinoids isotretinoin and acitretin, and dapsone. Prior to biologic therapy, patients received a mean of 4·0 (SD 1·3) different systemic therapies, across a mean of 16·9 (SD 11·3) different treatment series. The mean time from first systemic therapy until biologic therapy was initiated was 15·3 (SD 5·1) years [8·2 (SD 5·9) years when excluding penicillin and dicloxacillin]. Conclusions Patients with HS who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS. Delay in the initiation of biologic therapy may represent a missed opportunity to prevent disease progression. What is already known about this topic? The treatment journey leading to biologic therapy in patients with HS has not previously been investigated. What does this study add? Our data from 225 patients with HS illustrate that patients who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS.

Daratumumab is an integral part of the treatment of multiple myeloma (MM) but its real-world efficacy has only been described in small cohorts. MAMMOTH is the only large multi-center study that reported the outcomes of CD38-refractory MM. The present study includes a complete, Danish, nation-wide cohort of 635 MM patients who initiated treatment a daratumumab-containing index regimen (IR) prior to 1.1.2019, and describes the outcomes of 472 patients who discontinued their IR until 1.1.2021. Patients received a median of 3 lines of therapy (LOT) prior to the IR. The median time from diagnosis to discontinuation of the IR (T 0) was 4 years. At T 0, 73% of patients were quadruple drug class exposed (CE). The median overall survival (mOS) after T 0 was 12.2 months in the entire cohort, 15.3 months in double CE, 22.5 months in triple CE, 12.6 months in quadruple CE and 8.3 months in alkylator-bortezomib-carfilzomib-daratumumab-lenalidomide-pomalidomide-exposed patients. After T 0, 79%, 48%, 29%, 17%, 10% and 6% of patients received 1, 2, 3, 4, 5, 6 additional LOT, respectively, achieving overall response rates ranging from 44% to 11% and median time to next treatment (TNT) from 138 to 54 days. In the first subsequent LOT after T 0, 51% of patients were retreated with daratumumab. Despite the lack of benefit in terms response and TNT, daratumumab retreatment was associated with superior OS on multivariate analysis adjusting for age, previous transplantation, IR, drug class exposure at T 0, treating site, time from diagnosis to T 0 and presence of cytogenetic high-risk markers. Median OS was 24.6 months in patients retreated with and 11.3 months in patients treated without daratumumab (p Legends to Figure: A: Overall survival after T 0; B: Overall survival after T 0 by cytogenetic risk; C: Overall survival after T 0 by IR; D: Overall survival after T 0 by prior exposure. Abbreviations: T 0=time of discontinuation of the first daratumumab-containing line of therapy; IR=index regimen; high-risk=t(4;14), t(14;16) or del17p by FISH; D-mono=daratumumab monotherapy; D-bor=daratumumab-bortezomib-dexamethasone; D-len=daratumumab-lenalidomide-dexamethasone; D-other=daratumumab in other combinations; Double_CE=exposed to daratumumab and another class of drugs; Triple_CE=exposed to daratumumab and two other classes of drugs; Quadruple_CE=exposed to daratumumab and three other classes of drugs; ABCDLP-exposed=exposed to daratumumab, bortezomib, carfilzomib, lenalidomide and pomalidomide Figure 1 Figure 1. Disclosures Szabo: Takeda: Consultancy; Sanofi: Consultancy; Janssen: Consultancy.

Maternal dietary interventions during pregnancy with fish oil and high dose vitamin D have been shown to reduce the incidence of asthma and wheeze in offspring, potentially through microbial effects in pregnancy or early childhood. Here we analyze the bacterial compositions in longitudinal samples from 695 pregnant women and their children according to intervention group in a nested, factorial, double-blind, placebo-controlled, randomized trial of n-3 long-chain fatty acids and vitamin D supplementation. The dietary interventions affect the infant airways, but not the infant fecal or maternal vaginal microbiota. Changes in overall beta diversity are observed, which in turn associates with a change in immune mediator profile. In addition, airway microbial maturation and the relative abundance of specific bacterial genera are altered. Furthermore, mediation analysis reveals the changed airway microbiota to be a minor and non-significant mediator of the protective effect of the dietary interventions on risk of asthma. Our results demonstrate the potential of prenatal dietary supplements as manipulators of the early airway bacterial colonization., Here, the authors present the results of a mother–child cohort randomized clinical trial of n-3 LCPUFA and vitamin D maternal supplementation, finding an association between supplement-induced microbiota changes in infant airways at age 1-month but not the infant fecal or maternal vaginal microbiome.

Background We hypothesized that insufficient intake of fish oil–derived omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy is a contributing factor to gastroenteritis in early childhood. We examined the effect of n-3 LCPUFA supplementation on gastroenteritis symptoms in the offspring’s first 3 years of life. Methods This was a double-blinded, randomized controlled trial whereby 736 mothers were administered n-3 LCPUFA or control from pregnancy week 24 until 1 week after birth. We measured the number of days with gastroenteritis, number of episodes with gastroenteritis, and the risk of having a gastroenteritis episode in the first 3 years of life. Results A median reduction of 2.5 days with gastroenteritis (P = .018) was shown, corresponding to a 14% reduction in the n-3 LCPUFA group compared with controls in the first 3 years of life (P = .037). A reduction in the number of gastroenteritis episodes (P = .027) and a reduced risk of having an episode (hazard ratio, 0.80 [95% confidence interval, .66–.97]; P = .023) were also shown. Conclusions Fish oil supplementation from the 24th week of pregnancy led to a reduction in the number of days and episodes with gastroenteritis symptoms in the first 3 years of life. The findings suggest n-3 LCPUFA supplementation as a preventive measure against gastrointestinal infections in early childhood. Clinical Trials Registration NCT00798226.

The gut microbiome (GM) is shaped through infancy and plays a major role in determining susceptibility to chronic inflammatory diseases later in life. Bacteriophages (phages) are known to modulate bacterial populations in numerous ecosystems, including the gut. However, virome data is difficult to analyse because it mostly consists of unknown viruses, i.e. viral dark matter. Here, we manually resolved the viral dark matter in the largest human virome study published to date. Fecal viromes from a cohort of 647 infants at 1 year of age were deeply sequenced and analysed through successive rounds of clustering and curation. We uncovered more than ten thousand viral species distributed over 248 viral families falling within 17 viral order-level clades. Most of the defined viral families and orders were novel and belonged to the Caudoviricetes viral class. Bacterial hosts were predicted for 79% of the viral species using CRISPR spacers, including those in metagenomes from the same fecal samples. While Bacteroides-infecting Crassphages were present, novel viral families were more predominant, including phages infecting Clostridiales and Bifidobacterium. Phage lifestyles were determined for more than three thousand caudoviral species. Lifestyles were homogeneous at the family level for 149 Caudoviricetes families, including 32 families that were found to be virulent, while 117 were temperate. Virulent phage families were more abundant but temperate ones were more diverse and widespread. Together, the viral families found in this study represent a major expansion of existing bacteriophage taxonomy.

The gut microbiome (GM) is shaped through infancy and plays a major role in determining susceptibility to chronic inflammatory diseases later in life. Bacteriophages (phages) are known to modulate bacterial populations in numerous ecosystems, including the gut. However, virome data is difficult to analyse because it mostly consists of unknown viruses, i.e. viral dark matter. Here, we manually resolved the viral dark matter in the largest human virome study published to date. Fecal viromes from a cohort of 647 infants at 1 year of age were deeply sequenced and analysed through successive rounds of clustering and curation. We uncovered more than ten thousand viral species distributed over 248 viral families falling within 17 viral order-level clades. Most of the defined viral families and orders were novel and belonged to the Caudoviricetes viral class. Bacterial hosts were predicted for 79% of the viral species using CRISPR spacers, including those in metagenomes from the same fecal samples. While Bacteroides-infecting Crassphages were present, novel viral families were more predominant, including phages infecting Clostridiales and Bifidobacterium. Phage lifestyles were determined for more than three thousand caudoviral species. Lifestyles were homogeneous at the family level for 149 Caudoviricetes families, including 32 families that were found to be virulent, while 117 were temperate. Virulent phage families were more abundant but temperate ones were more diverse and widespread. Together, the viral families found in this study represent a major expansion of existing bacteriophage taxonomy.

AIM The objective of this study was to identify possible pre- and postnatal factors influencing neurodevelopment of the young child. METHODS We used data from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010 ) mother-child cohort, but excluded those with a neurological diagnosis, born 0.05 in all tests). Early age at milestone achievement was associated with male sex (p = 0.05), lower maternal age (p = 0.02), higher gestational age (p

Rationale: Childhood asthma is often preceded by recurrent episodes of asthma-like symptoms, which can be triggered by both viral and bacterial agents. Recent randomized controlled trials have show...

BackgroundHarmful effects of prenatal tobacco exposure and possible interaction with 17q12-21 genetic variants have been shown for some asthma outcomes in childhood, whereas findings related to allergy outcomes are more inconsistent. This study aimed to examine the effect of prenatal tobacco exposure and relation to 17q12-21 genotype on a wide array of asthma and allergy-related outcomes in early childhood.MethodsPrenatal tobacco exposure was determined by maternal smoking during the third trimester (yes/no) in 411 children from the phenotyped Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort with clinical follow-up to age 7 years. The rs7216389 single nucleotide polymorphism was used as main representative of the 17q12-21 locus. Asthma end-points included asthma diagnosis, exacerbations, episodes with troublesome lung symptoms and lower respiratory tract infections, spirometry, plethysmography, bronchial responsiveness to methacholine, exercise and cold dry air. Allergy-related endpoints included aeroallergen sensitisation, allergic rhinitis, fractional exhaled nitric oxide, blood eosinophil count and urine eosinophil protein X levels. Statistical analyses were done using Cox regression, linear regression, logistic regression and quasi-Poisson regression.ResultsPrenatal tobacco exposure increased the risk of asthma (adjusted hazard ratio (aHR) 2.05, 95% CI 1.13–3.73; p=0.02), exacerbations (aHR 3.76, 95% CI 2.05–6.91; p1) adjusted mean difference (aMD) −0.07 L, 95% CI −0.13– −0.005 L, p=0.03; maximal mid-expiratory flow aMD −0.19 L·s−1, −0.34– −0.04 L·s−1, p=0.01) and increased bronchial responsiveness to methacholine (provocative dose of methacholine causing a 20% drop in FEV1 adjusted geometric mean ratio 0.55, 95% CI 0.31–0.96; p=0.04). In contrast, there was no association with any allergy-related end-points. The effect on asthma depended on 17q12-21 genotype with an increased risk only among children without risk alleles.ConclusionPrenatal tobacco exposure was associated with asthma dependent on 17q12-21 genotype and with exacerbations, lung function and bronchial responsiveness, but not with any allergy-related outcomes. This suggests that tobacco exposure in utero leads to adverse lung developmental/structural effects rather than susceptibility to develop allergy and type 2 inflammation.

A double-blind randomized controlled trial of n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation or matching placebo during third trimester of pregnancy was conducted within the COPSAC2010 mother-child cohort consisting of 736 women and their children. The objective was to determine if maternal n-3 LCPUFA pregnancy supplementation affects offspring neurodevelopment until 6 years. Neurodevelopment was evaluated in 654 children assessing age of motor milestone achievement, language development, cognitive development, general neurodevelopment, and emotional and behavioral problems. Maternal n-3 LCPUFA supplementation during pregnancy improved early language development and reduced the impact of emotional and behavioral problems. The n-3 LCPUFA supplementation was in boys associated with the earlier achievement of gross motor milestones, improved cognitive development, and a reduced impact of emotional and behavioral problems.

Contains fulltext : 231681.pdf (Publisher’s version ) (Closed access) To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

Antimicrobial resistance (AMR) is an accelerating global threat to modern medicine, yet the nature of AMR in the gut microbiome and how AMR is acquired during early life remain largely unknown. In a cohort of 662 Danish children, we characterized the antibiotic resistance genes (ARGs) acquired during the first year of life and assessed the impacts of diverse environmental exposures on ARG load. Our study reveals a clear bimodal distribution of ARG abundance that is driven by the composition of the gut microbiome, especially E. coli. ARG profiles were significantly affected by various environmental factors. Among these factors, the importance of antibiotics diminished with time since treatment. Finally, ARG load and ARG clusters were also associated with the maturity of the gut microbiome and an asthma-associated bacterial composition. These findings broaden our understanding of AMR in the early life, and have critical implications for efforts to mitigate its spread.

OBJECTIVES: To investigate changes in vaginal microbiota during pregnancy, and the association between vaginal dysbiosis and reproductive outcomes.METHODS: A total of 730 (week 24) and 666 (week 36) vaginal samples from 738 unselected pregnant women were studied by microscopy (Nugent score) and characterized by 16S rRNA gene sequencing. A novel continuous vaginal dysbiosis score was developed based on these methods using a supervised partial least squares model.RESULTS: Among women with bacterial vaginosis in week 24 (n = 53), 47% (n = 25) also had bacterial vaginosis in week 36. In contrast, among women without bacterial vaginosis in week 24, only 3% (n = 18) developed bacterial vaginosis in week 36. Vaginal samples dominated by Lactobacillus crispatus (OR 0.35, 95% CI 0.20-0.60) and Lactobacillus iners (OR 0.40, 95% CI 0.23-0.68) in week 24 were significantly more stable by week 36 when compared with other vaginal community state types. Vaginal dysbiosis score at week 24 was associated with a significant increased risk of emergency, but not elective, caesarean section (OR 1.37, 955 CI 1.15-1.64, p < 0.001), suggesting a 37% increased risk per standard deviation increase in vaginal dysbiosis score.CONCLUSIONS: Changes in vaginal microbiota from week 24 to week 36 of pregnancy correlated with bacterial vaginosis status and vaginal community state type. A novel vaginal dysbiosis score was associated with a significantly increased risk of emergency, but not elective, caesarean section. This was not found for bacterial vaginosis or any vaginal community state type and could point to the importance of investigating vaginal dysbiosis as a nuanced continuum instead of crude clusters.

Presentation with severe acute kidney injury due to cast nephropathy (CN) is a medical emergency in multiple myeloma (MM), with high risk of dialysis-dependent renal failure and death. Accrual of patients with CN into interventional studies is difficult, while phase III trials exclude patients with severe renal insufficiency. Real-world data are warranted. We assessed 2252 patients from the population-based Danish Multiple Myeloma Registry (DMMR) who were diagnosed between 2013 and 2017. We identified 204 patients with clinically-suspected CN, defined as serum creatinine concentration >177 μmol/L and serum free light chain (sFLC) concentration >1000 mg/L at the time of diagnosis. The median age was 72 years. Thirty-one percent of patients presented with dialysis-dependent renal failure. Kidney biopsies were performed in 19% of patients and showed CN in 74% of cases. Despite prompt initiation of bortezomib-based therapy in 94% of patients, 33% of patients died in the first year after diagnosis. Compared with the rest of the patients in the DMMR with symptomatic MM, patients with clinically-suspected CN had worse overall survival (OS) irrespective of transplant eligibility. Achievement of renal recovery was associated with deep reductions of involved sFLC. Achievement of very good partial response or better in the first line of therapy and/or deep reduction of involved sFLC at 3 months after initiation of therapy were associated with superior OS. In conclusion, MM patients presenting with clinically-suspected CN have an alarmingly high one-year mortality when treated with current standards of care. Early and deep hematologic response is crucial for survival.

Background Urbanization is linked with an increased burden of asthma and atopic traits. A putative mechanism is insufficient exposure to beneficial microbes early in life, leading to immune dysregulation, as was previously shown for indoor microbial exposures. Objective Our aim was to investigate whether urbanization is associated with the microbiota composition in the infants’ body and early immune function, and whether these contribute to the later risk of asthma and atopic traits. Methods We studied the prospective Copenhagen Prospective Studies on Asthma in Childhood 20102010 mother-child cohort of 700 children growing up in areas with different degrees of urbanization. During their first year of life, airway and gut microbiotas, as well as immune marker concentrations, were defined. When the children were 6 years of age, asthma and atopic traits were diagnosed by pediatricians. Results In adjusted analyses, the risk of asthma and aeroallergen sensitization were increased in urban infants. The composition of especially airway but also gut microbiotas differed between urban and rural infants. The living environment–related structure of the airway microbiota was already associated with immune mediator concentrations at 1 month of age. An urbanized structure of the airway and gut microbiotas was associated with an increased risk of asthma coherently during multiple time points and also with the risks of eczema and sensitization. Conclusion Our findings suggest that urbanization-related changes in the infant microbiota may elevate the risk of asthma and atopic traits, probably via cross talk with the developing immune system. The airways may facilitate this effect, as they are open for colonization by environmental airborne microbes and serve as an immune interface.

Introduction. Acute otitis media (AOM) is the most common bacterial infection in early childhood, but the underlying mechanisms making some children more susceptible are poorly understood. Aim. To examine the associations between bacterial airway colonization in early life and the risk of AOM and tympanostomy tube insertion (TTI), and whether such associations are modulated by an insufficient local immune mediator response to bacterial colonization. Methodology. Bacterial cultures from hypopharyngeal samples were obtained at 1 week, 1 month and 3 months of age in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort comprising 700 children. Twenty immune mediators were quantified from airway mucosal lining fluid sampled at 1 month. AOM symptoms were registered in a daily diary until 3 years. Information on TTI in the first 3 years was obtained from national registers. Results. Children colonized with Streptococcus pneumoniae at 1 month of age had increased incidence of AOM [aIRR 2.43 (1.14–5.21)] and children colonized with Moraxella catarrhalis at 1 month or Haemophilus influenzae at 3 months had an increased risk of TTI [aHR 1.45 (1.00–2.10) and 1.73 (1.10–2.71)]. There were no associations between the local immune mediator response to colonization and risk of AOM or TTI. Conclusion. Pathogenic bacterial airway colonization in early life was found to be associated with an increased risk of otitis media, albeit not consistently. These associations were independent of the local immune response to colonization.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28×10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95×10−10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.

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 can 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 700 mother-child dyads from the COPSAC2010 cohort.The maternal vaginal microbiota was evaluated in the third trimester and compared with the children’s fecal and airway microbiota.The vaginal samples displayed known stable community state types and only 1:6 changed over time. Only one OTU was significantly transferred to children’s fecal compartment, but an inflated number had positive transfer odds. A few taxonomic families showed early transfer enrichment to vaginally-born children, indicating vertical transfer, while half of the observed transfer effects were delivery mode independent enrichment with attenuating strength over time, indicating a common reservoir.

Studies suggest an association between maternal vitamin D status during pregnancy and offspring anthropometry and bone mineralization, but investigations are few and with mixed results.To investigate the effect of a high dose vs standard dose of vitamin D supplementation in pregnancy on anthropometric and bone outcomes until age 6 years in the offspring.A prespecified analysis of a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort that included 623 pregnant mothers and their 584 children. Data were analyzed between January 2019 and September 2019.Vitamin D supplementation of 2800 IU/d (high-dose) vs 400 IU/d (standard-dose) from pregnancy week 24 until 1 week after birth.Longitudinal anthropometry assessments including length/height, weight, and body mass index until age 6 years and bone mineral content (BMC) and bone mineral density (BMD) at age 3 years and 6 years from dual-energy radiography absorptiometry scans.At age 6 years, 517 children (89%) completed the clinical follow-up. All participants were Danish and white; 261 were boys and 256 were girls. A mixed-effects model analysis of dual-energy radiography absorptiometry scan outcomes from ages 3 years and 6 years showed that children in the vitamin D vs placebo group had higher whole-body BMC: mean difference adjusted (aMD) for age, sex, height, and weight was 11.5 g (95% CI, 2.3-20.7; P = .01); higher whole-body-less-head BMC aMD was 7.5 g (95% CI, 1.5-13.5; P = .01); and higher head BMD aMD was 0.023 g/cm2 (95% CI, 0.003-0.004; P = .03). The largest effect was in children from vitamin D-insufficient mothers (30 ng/mL; to convert to nanomoles per liter, multiply by 2.496) and among winter births. In a post hoc analysis, we found borderline lower incidence of fractures in the vitamin D group (n = 23 vs n = 36; incidence rate ratio, 0.62 [95% CI, 0.37-1.05]; P = .08), but no differences in any anthropometric outcomes. Adjustment for a concomitant ω-3 polyunsaturated fatty acids intervention did not change the results.High-dose vitamin D supplementation in pregnancy improved offspring bone mineralization through age 6 years compared with the standard dose, suggesting an increased recommended gestational intake, which may influence peak bone mass, fracture risk, and risk of osteoporosis later in life. We found no supplementation effect on anthropometric outcomes.ClinicalTrials.gov Identifier: NCT00856947.

Human skin microbiota is thought to be unique according to the individual's lifestyle and genetic predisposition. This is true for the epidermal microbiota, while our findings demonstrate that the dermal microbiota is universal between healthy individuals. The preserved dermal microbial community is compositionally unique and functionally distinct to the specific environment in the depth of human skin. It is expected to have direct contact with the immune response of the human host, and research in the communication between host and microbiota should be targeted to this cutaneous compartment. This novel insight into specific microbial adaptation can be used advantageously in the research of chronic disorders and infections of the skin. It can enlighten the alteration between health and disease to the benefit of patients suffering from long-lasting socioeconomic illnesses., Human skin microbiota has been described as a “microbial fingerprint” due to observed differences between individuals. Current understanding of the cutaneous microbiota is based on sampling the outermost layers of the epidermis, while the microbiota in the remaining skin layers has not yet been fully characterized. Environmental conditions can vary drastically between the cutaneous compartments and give rise to unique communities. We demonstrate that the dermal microbiota is surprisingly similar among individuals and contains a specific subset of the epidermal microbiota. Variability in bacterial community composition decreased significantly from the epidermal to the dermal compartment but was similar among anatomic locations (hip and knee). The composition of the epidermal microbiota was more strongly affected by environmental factors than that of the dermal community. These results indicate a well-conserved dermal community that is functionally distinct from the epidermal community, challenging the current dogma. Future studies in cutaneous disorders and chronic infections may benefit by focusing on the dermal microbiota as a persistent microbial community.

The mother’s vaginal microbiota represents the first microbes to which a child is exposed when delivered vaginally. However, little is known about the composition and development of the vaginal microbiota during pregnancy and birth. Here, we analyzed the vaginal microbiota of 57 women in pregnancy week 24, 36 and at birth after rupture of membranes but before delivery, and further compared the composition with that of the gut and airways of the 1-week-old child. The vaginal community structure had dramatic changes in bacterial diversity and taxonomic distribution, yet carried an individual-specific signature. The relative abundance of most bacterial taxa increased stepwise from week 24 of pregnancy until birth, with a gradual decline of Lactobacillus. Mother-to-child vertical transfer, as suggested by sharing, was modest, with the strongest transfer being for Clostridiales followed by Lactobacillales and Enterobacteriales. In conclusion, late gestation is associated with an increase in maternal vaginal microbiota diversity, and vaginal bacteria at birth only modestly predict the composition of the neonatal microbiota.

Importance: Observational studies have reported an association between high maternal vitamin D levels and improved neurodevelopment in offspring, but no randomized clinical trial (RCT) has investigated these observations.Objective: To determine whether high-dose vitamin D supplementation during pregnancy improves offspring neurodevelopment from birth to age 6 years.Design, Setting, and Participants: This prespecified secondary analysis of a double-blinded, placebo-controlled RCT of high-dose vitamin D3 supplementation vs standard dose during the third trimester of pregnancy was conducted in the unselected prospective mother-child birth cohort at a single-center research unit in Denmark as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC-2010). Participants included pregnant women; women with vitamin D intake greater than 600 IU/d or an endocrine, heart, or kidney disorder, and those who did not speak Danish fluently were excluded. Neurodevelopmental assessments for offspring of these women were performed at ages 0 to 6 years. Children born prematurely (gestational week Interventions: High-dose (ie, 2800 IU/d) vs standard dose (ie, 400 IU/d) vitamin D3 supplementation from pregnancy week 24 until 1 week after birth.Main Outcomes and Measures: The primary outcome of interest was cognitive development assessed at 2.5 years using the Bayley Scales of Infant and Toddler Development. Other neurodevelopmental outcomes included age of motor milestone achievement (Denver Developmental Index and World Health Organization milestone registration), language development (MacArthur-Bates Communicative Development Inventories), general neurodevelopment at age 3 years (Ages and Stages Questionnaire), and emotional and behavioral problems at age 6 years (Strengths and Difficulties Questionnaire).Results: Among 623 women randomized, 315 were randomized to high-dose vitamin D3 and 308 were randomized to standard dose placebo. A total of 551 children were evaluated from birth to age 6 years, (282 [51.2%] boys; 528 [95.8%] White), with 277 children in the high-dose vitamin D3 group and 274 children in the standard dose group. There was no effect of the high-dose compared with standard dose of vitamin D3 supplementation during pregnancy on offspring achievement of motor milestones (β = 0.08 [95% CI, -0.26 to 0.43]; P = .64), cognitive development (score difference: 0.34 [95% CI, -1.32 to 1.99]; P = .70), general neurodevelopment (median [IQR] communication score: 50 [50-55] vs 50 [50-55]; P = .62), or emotional and behavioral problems (odds ratio, 0.76 [95% CI, 0.53 to 1.09]; P = .14). There was no effect on language development expressed by the word production at 1 year (median [IQR], 2 [0-6] words vs 3 [1-6] words; P = .16), although a decreased word production was apparent at 2 years in children in the high-dose vitamin D3 group (median [IQR], 232 [113-346] words vs 253 [149-382.5] words; P = .02).Conclusions and Relevance: In this prespecified secondary analysis of an RCT, maternal high-dose vitamin D3 supplementation during the third trimester of pregnancy did not improve neurodevelopmental outcomes in the offspring during the first 6 years of life. These findings contribute essential information clarifying the effects of prenatal exposure to vitamin D on neurodevelopment in childhood.Trial Registration: ClinicalTrials.gov Identifier: NCT00856947.