The gut microbiome, which hosts up to 1000 bacterial species that encode about 5 million genes, perform many of the functions required for host physiology and survival. Consequently, it is also known as "our forgotten organ". The recent development of next-generation sequencing technologies has greatly improved metagenomic research. In particular, it has increased our knowledge about the microbiome and its mutually beneficial relationships with the human host. Microbial colonization begins immediately at birth. Although influenced by a variety of stimuli, namely, diet, physical activity, travel, illness, hormonal cycles and therapies, the microbiome is practically stable in healthy adults. This suggests that the microbiome plays a role in the maintenance of a healthy state in adulthood. Quantitative and qualitative alterations in the composition of the gut microbiome could lead to pathological dysbiosis, and have been related to an increasing number of intestinal and extra-intestinal diseases. With the increase in knowledge about gut microbiome functions, it is becoming increasingly more possible to develop novel diagnostic, prognostic and, most important, therapeutic strategies based on microbiome manipulation.

BackgroundDNA methylation of the Th1 and Th2 cytokine genes is altered during cow’s milk allergy (CMA). Forkhead box transcription factor 3 (FoxP3) is essential for the development and function of regulatory T cells (Tregs) and is involved in oral tolerance acquisition. We assessed whether tolerance acquisition in children with IgE-mediated CMA is associated with DNA demethylation of the Treg-specific demethylated region (TSDR) of FoxP3.ResultsForty children (aged 3–18 months) were enrolled: 10 children with active IgE-mediated CMA (group 1), 10 children who outgrew CMA after dietary treatment with an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG (group 2), 10 children who outgrew CMA after treatment with other formulas (group 3), and 10 healthy controls (group 4). FoxP3 TSDR demethylation and expression were measured in mononuclear cells purified from peripheral blood of the four groups of children. FoxP3 TSDR demethylation was significantly lower in children with active IgE-mediated CMA than in either children who outgrew CMA or in healthy children. Formula selection influenced the FoxP3 TSDR demethylation profile. The FoxP3 TSDR demethylation rate and expression level were correlated.ConclusionsTolerance acquisition in children with IgE-mediated CMA involves epigenetic regulation of the FoxP3 gene. This feature could be a new target for preventive and therapeutic strategies against CMA.

BackgroundEpigenetic changes in DNA methylation could regulate the expression of several allergy-related genes. We investigated whether tolerance acquisition in children with immunoglobulin E (IgE)-mediated cow’s milk allergy (CMA) is characterized by a specific DNA methylation profile of Th2 (IL-4, IL-5) and Th1 (IL-10, IFN-γ)-associated cytokine genes.ResultsDNA methylation of CpGs in the promoting regions of genes from peripheral blood mononuclear cells and serum level of IL-4, IL-5, IL-10 and INF-γ were assessed in children with active IgE-mediated CMA (group 1), in children who acquired tolerance to cow’s milk proteins (group 2) and in healthy children (group 3). Forty children (24 boys, aged 3 to 18 months) were enrolled: 10 in group 1, 20 in group 2, and 10 in the control group. The DNA methylation profiles clearly separated active CMA patients from healthy controls. We observed an opposite pattern comparing subjects with active IgE-mediated CMA with healthy controls and group 2 children who outgrew CMA. The IL-4 and IL-5 DNA methylation was significantly lower, and IL-10 and INF-γ DNA methylation was higher in active IgE-mediated CMA patients. Gene promoter DNA methylation rates of all cytokines and respective serum levels were strongly correlated. Formula selection significantly influenced cytokine DNA methylation profiles in group 2.ConclusionsTolerance acquisition in children with IgE-mediated CMA is characterized by a distinct Th1 and Th2 cytokine gene DNA methylation pattern. These results suggest that DNA methylation may be a target for CMA prevention and treatment.