Epigenetic Effects in Children With Cow's Milk Allergy Treated With Different Formulas (EPICMA II)

Epigenetic Effects Involved in Children With Cow's Milk Allergy: A Possible Effect of Hypoallergenic Formulas

Lactobacillus GG (LGG) is able to exert long lasting effects in children with atopic disorders. Nutramigen LGG accelerates tolerance acquisition in infants with cow's milk allergy. The mechanisms of these effects are still largely undefined. The effect of LGG could be related at least in part by the immunoregulatory role played by LGG. This probiotic can balance the generation of cytokines possibly involved in IgE- or non-IgE-mediated cow's milk allergy Interleulkin (IL)-4, IL-5, IL-10, IFN-γ , TGF-β, and TNF-Υ), which can contribute to modulation of inflammatory processes. The investigators have demonstrated that children with IgE-mediated CMA produce significantly higher level of IL-4 and IL-13 in response to cow's milk protein, and that tolerance is associated with a marked reduction of IL-13 production and a concomitant increased frequency of IFN-γ releasing cells. Epigenetics studies the heritable (and potentially reversible) changes of the genome inherited from one cell generation to the next which alter gene expression but do not involve changes in primary DNA sequences, highlighting the complexity of the inter-relationship between genetics and nutrition. There are three distinct, but closely interacting, epigenetic mechanisms (histone acetylation, DNA methylation, and non-coding microRNAs) that are responsible for modifying the expression of critical genes associated with physiologic and pathologic processes. The profile of epigenetic modifications associated with Th lineage commitment, coupled with the sensitivity of the early developmental period, has led to speculation that factors that disrupt these pathways may increase the risk of allergic diseases. Specifically, effects on DNA methylation and endogenous histone deacetylase inhibitors acting on specific pathways (Th1 and T regulatory cell differentiation) may favour Th2-associated allergic differentiation. MicroRNAs are another structural components of an epigenetic mechanism of post-transcriptional regulation of messenger RNA translation. It has been recently identified a specific Th2-associated microRNA (miR-21) that is critical for the regulation of Th cell polarization. It has been previously demonstrated an inverse DNA methylation pattern of cytokines involved in Th2 response (IL-4, IL-5) compared with cytokines involved in Th1 response (IL-10, INF- y) in children with CMA acquiring oral tolerance, with the most pronounced effects in those treated with Nutramigen LGG.

Expression of miR-125b miR-146 miR-155 miR-29a/b miR-27 miR-128 let-7 family miR-21 miR-126 miR-145 miR-106a miR-375 miR-193a

Rate of patients with acquisition of tolerance to cow milk protein (rate of patients with outgrown cow's milk allergy)

Methylation rate (%) of interleukin IL-4, IL-5, IL-13, IL-10, IFN-γ, FoxP3, GATA3, T-bet, TGF-β, IL-17, IL-25, IL-12, IL-22, IL-6, IL-23 children with cow's milk allergy

Serum levels (pg/ml) of interleukin IL-4, IL-5, IL-13, IL-10, IFN-γ, FoxP3, GATA3, T-bet, TGF-β, IL-17, IL-25, IL-12, IL-22, IL-6, IL-23 in children with cow's milk allergy

Inclusion Criteria: children with cow's milk allergy Exclusion Criteria: Concomitant chronic systemic diseases, congenital cardiac defects, active tuberculosis, autoimmune diseases, immunodeficiency, chronic inflammatory bowel diseases, celiac disease, cystic fibrosis, metabolic diseases, malignancy, chronic pulmonary diseases, malformations of the gastrointestinal tract, suspected eosinophilic esophagitis or eosinophilic enterocolitis, suspected food-protein-induced enterocolitis syndrome, suspected cow's milk protein-induced anaphylaxis, still on exclusion diet with one of the study formulas or with another dietary regimen because of cow's milk allergy, other food allergies.