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Combined prenatal Lactobacillus reuteri and ω-3 supplementation synergistically modulates DNA methylation in neonatal T helper cells

By Johanna Huoman, David Martinez Enguita, Elin Olsson, Jan Ernerudh, Lennart Nilsson, Karel Duchen, Mika Gustafsson, Maria C Jenmalm

Posted 26 Mar 2021
medRxiv DOI: 10.1101/2021.03.25.21254287

BackgroundEnvironmental 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 {omega}-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 {omega}-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, {omega}-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. ResultsComparing 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. ConclusionPrenatal L. reuteri and/or {omega}-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 {omega}-3 interventions may provide essential knowledge in the development of efficacious allergy preventive strategies. Material in electronic repository12 Supplementary Figures, 11 Supplementary Tables mainly collected in Supplementary Appendix.

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