Randomized controlled trial on the influence of dietary intervention on epigenetic mechanisms in children with cow’s milk allergy: the EPICMA study

Abstract

Epigenetic mechanisms could drive the disease course of cow’s milk allergy (CMA) and formula choice could modulate these pathways. We compared the effect of two different dietary approaches on epigenetic mechanisms in CMA children. Randomized controlled trial on IgE-mediated CMA children receiving a 12-month treatment with extensively hydrolyzed casein formula containing the probiotic L.rhamnosus GG (EHCF + LGG) or with soy formula (SF). At the baseline, after 6 and 12 months of treatment FoxP3 methylation rate and its expression in CD4 + T cells were assessed. At same study points IL-4, IL-5, IL-10, and IFN-γ methylation rate, expression and serum concentration, miRNAs expression were also investigated. 20 children (10/group) were evaluated. Baseline demographic, clinical and epigenetic features were similar in the two study groups. At 6 and 12 months, EHCF + LGG group showed a significant increase in FoxP3 demethylation rate compared to SF group. At the same study points, EHCF + LGG group presented a higher increase in IL-4 and IL-5 and a higher reduction in IL-10 and IFN-γ DNA methylation rate compared to SF group. A different modulation of miR-155, -146a, -128 and -193a expression was observed in EHCF + LGG vs. SF. Dietary intervention could exert a different epigenetic modulation on the immune system in CMA children.

Dietary Prevention of Atopic March in Pediatric Subjects With Cow's Milk Allergy

“…This study demonstrated that treatment with EHCF+LGG is characterized by a more pronounced effect on FoxP3 demethylation compared to soy formula and by a higher methylation status of IL-4 and IL-5 and a lower methylation status of IL-10 and IFN-γ (17). Moreover, children treated with EHCF+LGG showed a selected miRNA expression toward a Th1-oriented response, leading to the activation of immune tolerance mechanisms (17). However, the impact of diet on epigenetic mechanisms may not only be direct but also mediated by the GM (84).…”

“…Moreover, the production of the tolerogenic cytokine IL-10 was higher in Jurkat T cells that underwent a casein hydrolysate stimulus (79). Preliminary data by our group suggest that formula choice is able to induce immune system modulation through epigenetic mechanisms in CMA infants (17,82,83); specifically, evidence suggests that EHCF+LGG is able to modulate GM, raising the abundance of selected genera (Roseburia, Coprococcus, and Blautia) with increased production of butyrate (16). A significant difference in DNA methylation of Th2 and Th1 cytokine (IL-4, IL-5, IL-10, and IFN-γ) genes and of FoxP3, the transcription factor that modulates the fate of Tregs, was observed in infants treated with EHCF+LGG who develop immune tolerance compared to children who received other formulas (82,83).…”

“…A longitudinal study, the EPICMA trial, compared the DNA methylation of FoxP3, Th1/Th2 cytokine genes, and allergy-related microRNAs (miRNAs) profile in IgE-mediated CMA infants taking EHCF+LGG compared to soy formula. This study demonstrated that treatment with EHCF+LGG is characterized by a more pronounced effect on FoxP3 demethylation compared to soy formula and by a higher methylation status of IL-4 and IL-5 and a lower methylation status of IL-10 and IFN-γ (17). Moreover, children treated with EHCF+LGG showed a selected miRNA expression toward a Th1-oriented response, leading to the activation of immune tolerance mechanisms (17).…”

“…Figure 1 depicts the natural history of AM in CMA children. According to data from several clinical studies, up to 45% of CMA children develop other atopic manifestations later in the life, also after the immune tolerance acquisition to cow milk proteins (3,5,(16)(17)(18). The development of AM is driven by genetic predisposition, but environmental factors may play a key role in its clinical expression.…”

Gestational Dysfunction-Driven Diets and Probiotic Supplementation Correlate with the Profile of Allergen-Specific Antibodies in the Serum of Allergy Sufferers

“…One of the most promising types of therapy is based on nutrigenomics. The role of foetal programming in the prevention and therapy of various inflammatory and atopic diseases are also the widely discussed randomized controlled trials on the influence of dietary intervention on epigenetic mechanisms in children who suffered from cow’s milk allergy that have already done [ 12 ] Maternal dietary patterns may prevent or reduce hypersensitivity with significant reduction especially in IgG-mediated diseases [ 13 ]. A successful protocol for IgE-mediated reactions still remains a challenge, but there have been several studies published describing correlations between maternal dietary components that works preventively through epigenetic activation of mechanisms against asthma, wheezing and allergic rhinitis [ 14 ].…”