Perinatal and Early-Life Nutrition, Epigenetics, and Allergy

Abstract

Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.

Keywords: DNA methylation; allergic disease; asthma; breastfeeding; environmental factors; epigenetic mechanisms; histone modifications; metabolic programming; microRNA (miRNA); microbiome; milk; neonatal T cells; nutritional interventions; perinatal; polyunsaturated fatty acids (PUFA); vitamins.

Figure 1

Molecular basics of the epigenetic mechanisms and their role in the expression control. For details, please refer to the main text, Chapter 1.2. Epigenetic mechanisms. Me, methylation; Ac, acetylation; P, phosphorylation; mRNA, messenger RNA.

Figure 2

Schematic representation of the maturation of T cells perinatally, their regulation by protein kinase C ζ (PKCζ), and the influence of nutrients on predisposition to allergy. The immature T cells at birth can exhibit different levels of PKCζ, despite showing a dominance of interleukin 4 (IL-4) production over interferon γ (IFN-γ). Low levels promote skewing towards a type 2 T helper (Th2) cytokine profile and are associated with allergy development. Cytokines from the type 1 T helper (Th1) and Th2 cells influence the production of immunoglobulin E (IgE) and the effector cells, mast cells, basophils, and eosinophils of the allergic reaction. Omega-3 polyunsaturated fatty acid (ω3 PUFA) supplementation leads to upregulation of PKCζ expression via an epigenetic mechanism, rebalancing the skewed Th2 development and preventing allergy. The pictures shown in this diagram are from the annual reports of the Robinson Research Institute, University of Adelaide. IgM, immunoglobulin M; FcεR1, high-affinity IgE receptor.

Figure 3

Protein kinase C (PKC) isoform expression in mouse neonates is upregulated in the first 4 weeks of life to near adult levels. Nylon wool column purified splenic T cells from 14 newborn Swiss white mice or 28-day-old mice were lysed and equivalent amounts of protein were resolved by western blot [66]. PKC isoform expression was visualized using isoform-specific polyclonal antibodies (PKC βI, βII, δ, ε, θ, and ζ) followed by densitometric band analysis using Image Quant software. Data are expressed as mean ± standard error of the mean of PKC isoform expression for newborn and day-28 mice relative to the PKC isozymes from T cells of adult mice. Statistics: *, p < 0.05; **, p < 0.01.

Figure 4

Changes in protein kinase C ζ (PKCζ) levels in human cord blood (CB) CD4⁺ and CD8⁺ T cells during in vitro maturation. T cells expressing low PKCζ levels were matured by culturing the CB mononuclear cells in the presence of phytohemagglutinin (PHA; 2 μg/mL) and interleukin 2 (10 ng/mL) [63]. Levels of PKCζ were measured by flow cytometry. Results are mean ± standard deviation of 4 experiments [66]. Statistics: **, p < 0.01; ***, p < 0.001. PE, phycoerythrin; MFI, mean fluorescence intensity, expressed as a % of standard value of cryopreserved T cells from adults measured in the same experimental run.

Figure 5

Summary of the effects of omega-3 polyunsaturated fatty acids (ω-PUFA) on epigenetic modifications related to immune function and allergy. For details, please refer to the main text, Chapter 3.1. FA. Th2 (cells), type 2 T helper (cells); IL, interleukin; TGF-β, transforming growth factor β; IFN-γ, interferon γ; TNF-α, tumor necrosis factor α; PGD2, prostaglandin D2; LTB₄, leukotriene B₄; HDAC4, histone deacetylase 4 gene; PDK4, pyruvate dehydrogenase kinase 4 gene; MSTN, myostatin gene; IFNA13, interferon α 13 gene; ATP8B3, ATPase phospholipid transporting 8B3; GABBR2, γ-aminobutyric acid type B receptor subunit 2; AKT3, AKT serine/threonine kinase 3; ATF1, activating transcription factor 1; IGFBP5, insulin like growth factor binding protein 5; miRNA, microRNA; PRKCZ, protein kinase C ζ gene; CD14, CD14 molecule gene; IL13, IL-13 gene; TBX21, T-box 21 gene; IFNG, IFN-γ gene; FADS (1/2), fatty acid desaturase (1/2) gene; ELOVL5, ELOVL fatty acid elongase 5 gene.

Figure 6

Epigenetic effects of dietary- and microbiome-derived fatty acids and their relationship with allergic diseases. For details, please refer to the main text, Chapter 3.1. FA. ^† Regarding the perinatal period. As mentioned in the main text, the impact of a given lipid on the risk of allergic conditions is not univocal. More research is needed to further clarify the links between these lipids in early life and the risk of allergic conditions. *Olive oil is known as an important source of n-3 polyunsaturated fatty acids (PUFA). ALA, alpha linolenic acid; BDNF-AS, brain-derived neurotrophic factor antisense RNA; CD14, CD14 molecule; Cebpa, CCAAT/enhancer binding protein alpha gene; DHA, docosahexaenoic acid; ELOVL5, ELOVL fatty acid elongase 5; EPA, eicosapentaenoic acid; FADS1/2, fatty acid desaturase 1/2 gene; FOXP3, forkhead box P3 gene; HDAC, histone deacetylases; HDAC9, histone deacetylase 9; IFNG, interferon gamma gene; IL7R, interleukin 7 receptor; IL10RA, interleukin 10 receptor subunit alpha; IL13, interleukin 13; miRNAs, micro RNAs; MUFA, monounsaturated fatty acids; Pparg, peroxisome proliferator activated receptor gamma gene; PRKCZ, protein kinase C zeta gene; SCFA, short-chain fatty acids; SFA, saturated fatty acids; TBX21, T-box transcription factor 21 gene; TFA, trans fatty acids; TNF, tumor necrosis factor.

Figure 7

Summary of the epigenetic effects of vitamins D and A potentially relevant for allergy predisposition. For details, please refer to the main text, Chapter 3.2. Vitamins. Treg (cells), regulatory T (cells); IgE, immunoglobulin E; IL, interleukin; Th2 (cells), type 2 T helper (cells); ILC-2, type 2 innate lymphoid cells; NF-κB p65, a p65 subunit of the nuclear factor κB transcription complex; Th17 (cells), type 17 T helper (cells); Foxp3, forkhead box P3; RXRA, retinoid X receptor alpha gene; IG-DMR, intergenic differentially methylated region; H19ICR, H19 imprinting control region; PDGF, platelet-derived growth factor; ALP, alkaline phosphatase; HDAC2, histone deacetylase 2; GRE, glucocorticoid response element; DUSP1, dual specificity phosphatase 1 gene; IFN-γ, interferon γ; MICAL3, microtubule-associated monooxygenase, calponin and LIM domain-containing 3; Th9 (cells), type 9 T helper (cells).

Figure 8

Perinatal epigenetic effects of microbes and parasites in the context of allergies. For details, please refer to the main text, Chapter 4. Effects of microbes and parasites on epigenetic signatures and their relation to allergies. SCFA, short-chain fatty acids; RSV, respiratory syncytial virus. Created with BioRender.com.