Abstract:This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
“…One quite surprising finding of this study was that, in contrast to our hypothesis and results from our previous epigenome-wide study on the effects of perinatal L. reuteri treatment on cord blood CD4+ cells 39 , a larger proportion of the CpG sites were hypermethylated when comparing either of the intervention groups to the double placebo group. This finding could have several explanations.…”
Section: Discussioncontrasting
confidence: 99%
“…36,37 A study on epigenomic modulation of combined L. rhamnosus GG/Bifidobacterium lactis in obesity 38 revealed general hypomethylation, in line with findings from our previous study investigating L. reuteri in allergy prevention. 39 In newborns whose mothers had been supplemented with L. reuteri throughout the last month of pregnancy, this loss of methylation in CD4+ cord blood cells was prominent in genes related to immune activation. 39 This indicates that treated children received a head-start in their immune maturation, which hence may affect the development of allergic disease.…”
Section: Introductionmentioning
confidence: 98%
“…39 In newborns whose mothers had been supplemented with L. reuteri throughout the last month of pregnancy, this loss of methylation in CD4+ cord blood cells was prominent in genes related to immune activation. 39 This indicates that treated children received a head-start in their immune maturation, which hence may affect the development of allergic disease. However, in the context of combining probiotics and ω-3 fatty acids, neither clinical outcomes nor epigenetic effects have yet been studied.…”
Background: Environmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or ω-3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns in cord blood samples from children in a randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and ω-3 fatty acid treatment. To this end, >866 000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n=18, single treatments: probiotics n=16, ω-3 n=15, and double placebo: n=14). Statistical and bioinformatic analyses identified treatment-associated differentially methylated CpGs and genes, which were used to identify treatment-induced network modules. Pathway analyses inferred biological relevance, and comparisons were made to an independent allergy data set.
Results: Comparing the active treatments to the double placebo group, most differentially methylated CpGs and genes were hypermethylated, suggesting induction of transcriptional inhibition. The double-treated group showed the largest number of differentially methylated CpGs, of which many were unique, suggesting synergy between interventions. Clusters within the double-treated network module consisted of immune-related pathways, including T cell receptor signalling, and antigen processing and presentation, with similar pathways revealed for the single-treatment modules. CpGs derived from differential methylation and network module analyses were enriched in an independent allergy data set, particularly in the double-treatment group, proposing treatment-induced DNA methylation changes as relevant for allergy development.
Conclusion: Prenatal L. reuteri and/or ω-3 fatty acid treatment results in hypermethylation and affects immune- and allergy-related pathways in neonatal T helper cells, with potentially synergistic effects between the interventions and relevance for allergic disease. Further studies need to address these findings on a transcriptional level, and whether the results associate to allergy development in the children. Understanding the role of DNA methylation in regulating effects of perinatal probiotic and ω-3 interventions may provide essential knowledge in the development of efficacious allergy preventive strategies.
“…One quite surprising finding of this study was that, in contrast to our hypothesis and results from our previous epigenome-wide study on the effects of perinatal L. reuteri treatment on cord blood CD4+ cells 39 , a larger proportion of the CpG sites were hypermethylated when comparing either of the intervention groups to the double placebo group. This finding could have several explanations.…”
Section: Discussioncontrasting
confidence: 99%
“…36,37 A study on epigenomic modulation of combined L. rhamnosus GG/Bifidobacterium lactis in obesity 38 revealed general hypomethylation, in line with findings from our previous study investigating L. reuteri in allergy prevention. 39 In newborns whose mothers had been supplemented with L. reuteri throughout the last month of pregnancy, this loss of methylation in CD4+ cord blood cells was prominent in genes related to immune activation. 39 This indicates that treated children received a head-start in their immune maturation, which hence may affect the development of allergic disease.…”
Section: Introductionmentioning
confidence: 98%
“…39 In newborns whose mothers had been supplemented with L. reuteri throughout the last month of pregnancy, this loss of methylation in CD4+ cord blood cells was prominent in genes related to immune activation. 39 This indicates that treated children received a head-start in their immune maturation, which hence may affect the development of allergic disease. However, in the context of combining probiotics and ω-3 fatty acids, neither clinical outcomes nor epigenetic effects have yet been studied.…”
Background: Environmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or ω-3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns in cord blood samples from children in a randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and ω-3 fatty acid treatment. To this end, >866 000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n=18, single treatments: probiotics n=16, ω-3 n=15, and double placebo: n=14). Statistical and bioinformatic analyses identified treatment-associated differentially methylated CpGs and genes, which were used to identify treatment-induced network modules. Pathway analyses inferred biological relevance, and comparisons were made to an independent allergy data set.
Results: Comparing the active treatments to the double placebo group, most differentially methylated CpGs and genes were hypermethylated, suggesting induction of transcriptional inhibition. The double-treated group showed the largest number of differentially methylated CpGs, of which many were unique, suggesting synergy between interventions. Clusters within the double-treated network module consisted of immune-related pathways, including T cell receptor signalling, and antigen processing and presentation, with similar pathways revealed for the single-treatment modules. CpGs derived from differential methylation and network module analyses were enriched in an independent allergy data set, particularly in the double-treatment group, proposing treatment-induced DNA methylation changes as relevant for allergy development.
Conclusion: Prenatal L. reuteri and/or ω-3 fatty acid treatment results in hypermethylation and affects immune- and allergy-related pathways in neonatal T helper cells, with potentially synergistic effects between the interventions and relevance for allergic disease. Further studies need to address these findings on a transcriptional level, and whether the results associate to allergy development in the children. Understanding the role of DNA methylation in regulating effects of perinatal probiotic and ω-3 interventions may provide essential knowledge in the development of efficacious allergy preventive strategies.
“…Animal models of psychological stress demonstrate a shift in gastrointestinal (GI) microbiota composition and function [22][23][24] , and there is evidence that this is also true during pregnancy 25,26 . Shifts in microbial homeostasis during gestation can impact establishment of the founding infant microbiome [27][28][29][30] and have long-term implications for offspring immune development 31,32 . Whether gestational insults also shift endogenous microbes at reproductive tissue sites is still controversial 33,34 , although translocation of microbes and bacterial peptidoglycan across the maternal-fetal interface during pregnancy has been documented in rodents 35,36 .…”
Maternal stress during pregnancy is widespread and is associated with poor offspring outcomes, including long-term mental health issues. Prenatal stress-induced fetal neuroinflammation is thought to underlie aberrant neurodevelopment and to derive from a disruption in intrauterine immune homeostasis, though the exact origins are incompletely defined. We aimed to identify divergent immune and microbial metagenome profiles of stressed gestating mice that may trigger detrimental inflammatory signaling at the maternal–fetal interface. In response to stress, maternal glucocorticoid circuit activation corresponded with indicators of systemic immunosuppression. At the maternal–fetal interface, density of placental mononuclear leukocytes decreased with stress, yet maternal whole blood leukocyte analysis indicated monocytosis and classical M1 phenotypic shifts. Genome-resolved microbial metagenomic analyses revealed reductions in genes, microbial strains, and metabolic pathways in stressed dams that are primarily associated with pro-inflammatory function. In particular, disrupted Parasutterella excrementihominis appears to be integral to inflammatory and metabolic dysregulation during prenatal stress. Overall, these perturbations in maternal immunological and microbial regulation during pregnancy may displace immune equilibrium at the maternal–fetal interface. Notably, the absence of and reduction in overt maternal inflammation during stress indicates that the signaling patterns driving fetal outcomes in this context are more nuanced and complex than originally anticipated.
“…Bacteria may also influence allergies through microbial‐derived products 20 and indirectly by breastmilk consumption 21 . Although various mechanisms of actions have been studied, 22 much remains to be explored in relation to probiotics and the microbiota. …”
Immunology and genetics of asthma, and probiotics in the treatment of atopic dermatitisThis past year has been disrupting, but also seen positive challenges in many aspects. And we would like to start this first issue of 2021 with a positive message. COVID-19 vaccines are coming, and hopefully, they will largely contribute to controlling the spread of the pandemic. Common vaccines trigger an immune response by an antigen-driven stimulus. However, the SARS-CoV-2-induced pandemic control is addressed not only by classic vaccine strategies but also by new, RNA-based strategies. The first review of this issue by Eberhardt and Siegrist assesses the various immunization strategies and their limitations to the pediatric population. 1 In addition, with the second wave (or third wave for some regions) pediatricians will be faced with more patients suffering from the multisystem inflammatory syndrome in children (MIS-C). The second review also addresses COVID-19 in pediatrics and discusses potential explanations for progression from "classic" COVID-19 to MIS-C. 2Asthma is a common disease in childhood, with still unmet needs regarding the understanding of immune mechanisms of progressions, as well as optimization of treatment by immunomodulators. 3,4 The first study I wish to comment on in this editorial is published by Beatriz Sastre and colleagues who investigated immune mechanisms underlying the development of recurrent wheezing after bronchiolitis in infancy. 5 Cells obtained from nasopharyngeal aspirates were sorted by flow cytometry to isolate type 2 innate lymphoid cells (ILC2). Cell mRNA expression was analyzed for a variety of inflammatory factors, and a large panel of pro-inflammatory and immunomodulatory factors, as well as lipid mediators and nitrites, was evaluated by ELISA and Luminex. They observed a higher expression of the ST2 + IL-33 receptor in the ILC2 population from the bronchiolitis group. This expression receptor could be increased by the presence of IL-1β, IL-2, or lipid mediators such as cysteinyl leukotrienes (LTC4 or LTE4) or prostaglandin D2. They conclude by mentioning that bronchiolitis patients had a higher percentage of ILC2 cells in the nasal aspirate and that this population of cells, by providing specific inflammatory signals, could play a significant role in the development of wheezing episodes later in life. Other studies and a review have recently addressed cell-related mechanisms of asthma and confirm the recent interest in innate-immunity-related mechanisms of asthma. [6][7][8]
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