Asthma and allergy are the most common chronic inflammatory diseases, especially in children (1). The prevalence of asthma is elevated in economically developed countries in Western and Eastern Europe and higher in the United States compared to other countries (2, 3). A progressive increase in the prevalence of asthma in low-income countries has also been observed (4, 5), which makes asthma prevalent worldwide. According to the World Health Organization over 80% of asthma-related deaths occur in low- and low-middle-income countries, and difficulties in accessing treatment and management are also related to that (6). On the other hand, the prevalence of eczema, allergic rhinitis, and food allergies in childhood is distributed differently between tropical countries and temperate zones (7–14). Geographic differences in the prevalence of allergies between and within populations may reflect both exposure to common environmental factors and a host genetic background, which can either increase or decrease risk (15). In terms of genetics, large genome-wide association studies (GWAS) initiatives were unable to completely explain such high and still increasing prevalence of allergic disorders as well as their phenotypic heterogeneity (1). Among the top pathways linked to asthma in such initiatives, include those related to epithelial barrier dysfunction and reduction of immune tolerance (16). In addition, studies have found not only shared but also distinct genetic components between asthma subtypes, indicating that heterogeneity is related to individual genotype (17, 18) but still do not completely explain everything.

Thus, the knowledge about the interactions between the genetic pool and the environment is increasing with several lines of evidence explaining those trends (19–21). In this context, some hypotheses explain the links between environmental changes that occurred in recent decades with the prevalence of allergies across the globe, such as urbanization, housing condition, diet, and fewer exposures to organisms such as bacteria, virus and helminths (21, 22). In fact, there is a link between the higher incidence of allergic diseases and reduced infections/exposure to organisms in Western countries and across the globe and this has been studied for several years now and appears to reflect the economy and sanitation in each territory. Additionally, the degree of industrialization and consequent changes in the habits and lifestyle of the population imply that limited exposure to several environmental factors for reducing biodiversity may contribute to an increased risk of developing or exacerbating asthma and allergies (23). David Strachan observed in 1989 that infections transmitted in early childhood, through contact between older siblings, could restrict the development of allergies (22, 24). Urbanization and improvements in hygiene, better housing conditions, and reduced chances of cross-infection in younger members of the family are the basis for what we know as the “hygiene hypothesis” (24). The initial mechanistic explanation of the hygiene hypothesis emphasized the role of Th1 cells in regulating Th2 responses. Later, the role of regulatory T cells was emphasized in the regulation of both Th1 and Th2-induced inflammatory responses through mechanisms that include the production of regulatory cytokines (25). The mechanistic pathways of the hygiene hypothesis were described extensively in the literature, other theories amplified the initial concept such as the “old friends” hypothesis (26) and, afterwards, the biodiversity hypothesis, proposed by The Karelia Allergy Study from 1998 (27). Both theories attempt to explain the impact of modifications in human living conditions and habits on the prevalence of immune-mediated diseases (28, 29).

Studies show that early exposure to antibiotics during childhood increases the risk of developing allergic diseases (30) and also regular anthelmintic use (31). Numerous epidemiologic studies reinforce that the increase in allergic diseases, eczema, and food allergies is inversely related to parasitic infections (32–36). Soil biodiversity and climatic characteristics of a country are also determinants in the types of environmental exposures and consequent development of infectious diseases and allergic sensitization. The climate and biodiversity of the tropics (fauna and flora) favor intestinal helminth infections and the dissemination of human infectious diseases transmitted by vectors like insects (37–42). According to (6), Soil-transmitted helminth infections are distributed in tropical and subtropical areas, with the highest incidence in sub-Saharan Africa, the Americas, China, and East Asia.

The tropics are also marked by sharp economic and social inequalities that reflect health and sanitary conditions and an increased risk of spreading fecal-oral transmission diseases (toxoplasmosis, giardiasis, hepatitis A, worms). In addition, the relationship between helminths and allergies is complex and is influenced by the parasite burden, chronicity, first infection or reinfection, coinfections, and parasite species present in the environment (33). In contrast, allergic sensitization to house dust mite species such as Dermatophagoides pteronyssinus, D. farina, and Blomia tropicalis is prevalent in the tropics, markedly in individuals living in better sanitary conditions and urban areas (43–45).

The importance of environmental exposures does not underestimate the fundamental participation of the family history of atopy and/or asthma and genetic background. Thus, we still have an enormous challenge to explain the occurrence of allergies and asthma. Increasing attention has been given to epigenetic modifications, i.e., modifications in DNA without sequence changes, triggered by individual exposure to environmental factors, for instance, by products of combustion, drugs, diet, and infections. Epigenetic mechanisms, such as DNA methylation and histone modifications, can modulate gene expression upon exposure to a specific environmental agent (46). Such biochemical alterations can alter different targets within the body, leading to the risk or protection of several conditions. In this review, we present the concept of holobiont and discuss how exposure to different organisms, including bacteria, viruses, and helminths, can lead to epigenetic modulations and how this modulation correlates with allergic diseases, taking into account different genetic backgrounds of several ancestral populations.

Exposures during the peri- and post-natal periods are critical for the host's immune homeostasis, reflecting immune maturation, the development of immune tolerance mechanisms, and susceptibility to disease, also known as the first “window of opportunity” (111). This exposure includes fetal environment conditioned to the individual to the mother's lifestyle, type of delivery, diet, use of antibiotics, exposure to other children and animals, and contact with parasites and environmental microbes (112). Studies have reported that exposure to specific immunostimulatory molecules (from helminths and bacteria mainly) in childhood could reduce or block allergic disease development or progression (113). In embryonic development the immunological regulation of pregnancy is complex and an increased production of Th2 cytokines is observed, along with decreased production of Th1 cytokines. In addition, TGF-β1 appears to be involved in the differentiation of the trophoblast being an important inducer of regulatory T cells (CD4 + CD25 +) and Th17 cells, this seems to be essential for avoiding fetal allorejection (114, 115). Microbial exposures in childhood determine factors in modulation and gradual replacement for T cells and cytokines other than Th2 (116).

Moreover, universal initiatives seeking to improve the population's health conditions, such as immunization in children, improved hygiene and sanitation, access to clean water, indiscriminate use of antibiotics and anti-parasitic drugs, have been implied in reducing opportunities of microorganism's exposure/infections in early childhood with decreased Th1 responses and or decreasing Treg activation and polarizing the immune response to the Th2 profile, breaking homeostasis. Changes in the exposure of antigen patterns, including proteins released from environmental particles or infections in childhood, can impact the diversity of commensal microorganisms that make up the microbiota (117).

The use of antibiotics by mothers during pregnancy is associated with a child's asthma risk, promoting an imbalance between commensal, and pathogenic bacteria (118). Changes in the colonization of the lung microbiota of neonatal mice have (119, 120) been associated with decreased aeroallergen responsiveness induced by Helios– regulatory T cells (Helios– Treg cells) activated depending on interaction with programmed death-ligand 1 early in life, widely known as a regulator of allergic responses. Imbalance in the formation of these cells implies increased susceptibility to atopy in adulthood (119). Likewise, the altered composition of the airway microbiota is often found in asthmatic patients (120, 121). This could be explained partially by differences in environment.

Currently, epigenetics can be defined as changes above the DNA without changing the nucleotide sequence (162). Different mechanisms of epigenetic regulation have been described, such as DNA methylation, histone modifications and non-coding RNAs. Since the first Waddington epigenetics works (163, 164), many studies have been conducted to determine the influences of epigenetics in several conditions. The epigenetic mechanisms are widespread in the different cell types of the human body, including cells that participate in an immune response pathway directly involved in the etiopathogenesis of asthma and other allergic diseases. Understanding the impact of epigenetic changes on the normal and abnormal functioning of these cells, therefore, is an important piece to compose the complex puzzle that allergic diseases represent. Bellow, are described the main mechanisms of epigenetics-induced changes in gene expression.

The epigenetic mechanisms previously described are present in the different contexts and cell types of the human body, including driven immune cell pathways directly involved in the etiopathogenesis of asthma and other allergic diseases. Understanding the impact of epigenetic changes on the normal and abnormal functioning of these cells, therefore, is an important piece to compose the complex puzzle that allergic diseases represent. Some advances in this direction have recently been achieved. Thus, epigenetic modifications play a role in regulating the expression of cytokines related to T cell differentiation and transcription factors (178). The development of cell types and, consequently, the specificity of immunological responses occur through internal stimuli or driven by stimulatory molecules of microorganisms. They act on surface receptors such as TLR signaling, signal transduction proteins, and lineage-specifying transcription factors, promoting intracellular events. Even the development of T lymphocytes and maturation for helper (CD4+) and cytotoxic (CD8+) cells are influenced by epigenetic control. This promotes CD4+ silencing in CD8+ thymocytes and the development of T helper cell subsets (Th1, Th2, and Th17) accompanied by epigenetic changes (179, 180). Epigenetic changes have also been linked to the activation and polarization of macrophages (M1/M2 phenotypes) (181).

Allergic diseases, e.g., asthma, result from a strong interaction of genetic and environmental components with remarkable phenotypic heterogeneity. This heterogeneity of asthma can be partially explained by dysregulated epigenetic mechanisms correlated with environmental exposures, pharmacological treatments, and airway inflammation and function (182). There is evidence that the induction of Th2 cells, maintenance, and the resurgence of memory Th2 cells are controlled by epigenetic regulation since this induction is mediated by signal transducer and activator of transcription 6 and the consequent production of the Th2 cytokine profile (183). Hypermethylation in GATA3 CpG loci was associated with a decreased risk of asthma at birth (184), and hypomethylation of IL-13 and interleukin 5 receptor subunit alpha (IL5RA) was associated with an increased risk of asthma in teenagers (169).

Epigenetic mechanisms are essential in controlling gene expression or silencing and the consequent balance of Th1/Th2 responses. Corroborating the principle that Th1/Th2 imbalance is involved in the pathogenesis of asthma and atopy, experimental studies in mice showed hypermethylation in the IFN-ɤ gene promoter in TCD4+ cells, leading to the silencing of the IFNG gene (Th1 pattern) (185). During initiation of a Th2 immune response, an increase in histone acetylation was observed at the Th2 cytokine loci. It has been demonstrated that the IL4 and IL13 genes are hypomethylated in asthmatic patients, critical genes in amplifying the Th2 response (186).

A balance of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity has been considered to regulate gene expression. Reduced HDAC expression was observed among adults with severe asthma compared to mild asthma (187). In atopic asthmatic children, a relationship was found between HDAC/HAT activity and increased histone acetylation, and the degree of acetylation was associated with an increase in bronchial hyperresponsiveness (188).

miRNAs have also shown an essential role in the inflammatory response of asthma. Studies have shown that miR-155 and miR-221 are associated with modulation of the Th2 response (189) and hyperproliferation of airway smooth muscle in asthmatic patients, respectively (190). In the asthma context, non-coding RNAs have been observed as markers of disease diagnosis, phenotypes, and response to treatments. For example, a negative correlation between the levels of miR-323-3p and IL22 and IL17 was observed in PBMCs from patients with asthma, suggesting that non-coding RNA acts as negative feedback in the production of these cytokines influencing the immune response of these individuals (191). Moreover, elevated levels of miRNA-21 in the peripheral blood of children with asthma were identified, suggesting that this non-coding RNA may be a biomarker in the diagnosis of asthma (192). Furthermore, high expression of microRNA-155 and decreased expression of Let-7a were observed in the plasma of asthmatic patients and were associated with the degree of asthma severity, suggesting that these markers can be used both in diagnosis and in the prediction of the severity of disease (193).

In the context of regulatory T cells (Tregs), cells that play a substantial role in immune homeostasis through mechanisms of tolerance and immune de-activation during a regular immune response and suppression of a self-destructive immune response, the repressive phenotype of Tregs is conferred, in part, by the expression of Forkhead box protein 3 (FOXP3) (194). Hypermethylation of CpG islands in the promoter region in the FOXP3 locus impacts transcriptional silencing and consequent reduction in Treg cell function. Air pollutants have been recognized as acting on epigenetic changes. Increased exposure to polycyclic aromatic hydrocarbons has been associated with an increase in DNA methylation at the FOXP3 locus in peripheral blood mononuclear cells and elevated total IgE with significant effects on asthmatics (195). Furthermore, an increase in FOXP3 DNA methylation has been associated with an increased risk of asthma and persistent wheezing (196).

Figure 1 shows different factors shaping asthma and allergy, such as environmental factors, epigenetic changes, and exposure to holobionts components which can be modulated by disturbances in the homeostasis.

Since immune dysregulation is linked to allergies and asthma through the lack of certain environmental exposure, one could think that potential epigenetic mechanisms may play a role in this phenomenon. A question raised by these new findings is at “what point in the development of the human being the epigenetic mechanisms could act to drive the maturation of the immune system in early life?.” In this sense, in recent years, the hygiene hypothesis has been expanded to encompass the potential effect of prenatal exposure to microbial agents on modulating the individual risk of asthma and other allergic diseases (115). Although some evidence in this regard was already available through epidemiological studies that assessed the impact of maternal microbial exposure on the risk of developing allergic conditions in the offspring (116), the elucidation of the molecular mechanisms underlying these processes has been a relatively new and fascinating field of investigation.

Alterations in the gut microbiota, called dysbiosis, is related to infections and inflammatory diseases and comes with irregular immune responses, e.g., particular inflammatory cytokines (66, 75). Changed gut microbiota can also increase the production of NK-κ-B and TNF-α and the overexpression and activation of Th1 and Th17 cells (197). Studies have shown that changes in the gut bacterial composition and the production of its metabolites can influence epigenetic levels, such as reducing methylation and inhibiting histone deacetylases (197). Specifically, the metabolites influencing epigenetic enzyme activity are a substrate needed for epigenetic changes (197). For example, Butyrate, a metabolite from microbiota, can also inhibit HDAC, increasing the expression of FOXP3 through the acetylation of histone H3 in the promoter and enhancing Treg generation (164).

One of the first mechanistic studies on the allergoprotective effects of maternal exposure to microbes used a mouse model with the farm bacterium Acinetobacter lwoffii (198). In this study, the protective effect for allergic airway inflammation (AAI) in the offspring was dependent on maternal TLR signaling, since this protection was abolished when mothers were knocked out for multiple TLR genes. The authors also demonstrated that the immune dampening observed in the progeny of pregnant mice was not due to microbial components able to pass the fetus-maternal interface and directly activate the developing fetal immune system. This last observation suggests the possible involvement of epigenetic factors operating in the fetuses of mothers exposed to Acinetobacter lwoffii. Indeed, another study by the same group reported epigenetic changes in Th1/Th2 cytokine genes in offspring from pregnant mice exposed to A. lwoffii (199). While the IFNγ promoter on CD4+ T cells exhibited significant protection against the loss of histone 4 (H4) acetylation, with the consequent increase in IFN-ɤ expression in OVA-induced AAI, the IL4 promoter showed a significant decrease in H4 acetylation and diminished gene expression. A protective effect against induced AAI has also been shown in the progeny of pregnant mice exposed to Helicobacter pylori extracts (200). An epigenetic consequence observed in the offspring was the enhanced demethylation of the regulatory T cell-specific demethylated region in Foxp3+ Treg cells. Intriguingly, this protective effect extended to the second generation (F2) of mice exposed to H. pylori antigens during pregnancy, with both sexes exhibiting similar levels of protection. This indicates that the epigenetic changes in the offspring induced by transmaternal exposure to H. pylori may extend to chromosomal loci other than just the TSDR linked to the X chromosome. The transfer of allergoprotective effects during the prenatal phase through maternal infection with the helminth Schistosoma mansoni has also been previously investigated in experimental models of AAI in mice (201). Interestingly, this protective effect was dependent on the stage of the immune responses to S. mansoni in the females at the time of mating. While the offspring of the mothers mated during the Th1 and regulatory phases showed protection against OVA-induced AAI, those born to mothers mated during the Th2 phase showed an exacerbation of the allergic inflammatory response compared to the controls. The authors also demonstrated that the protective effect of transmaternal exposure to S mansoni was mediated by maternally produced IFN-ɤ and not by the transfer of helminth antigens to the fetus. Potential epigenetic changes in the offspring associated with the protective immune phenotype, however, were not further investigated and remain to be clarified (202).

In humans, data on epigenetic changes induced by pre- or post-natal exposure to microbial agents and their relationship to asthma and other allergic conditions are still scarce. A pilot study evaluated the effect of maternal exposure to the farm environment on offspring epigenetic changes for genes known to be associated with asthma and allergies (203). Significant differences between non-asthmatic children born to mothers exposed to the farm environment and asthmatic children born to unexposed mothers were observed for the methylation pattern of the ORMDL3 and STAT6 genes in cord blood. In a recent study, Lund et al. (204) reported that changes in the methylation pattern in chromosomal previously linked to asthma, such as the SMAD3 promoter at 15q22.33 and intronic regions of the DDO/METTL24 genes at 6q21, were associated with atopic asthma in children with early rhinovirus-induced wheezing. In turn, DNA methylation changes linked to the prostaglandin D2 synthase gene were associated with non-atopic asthma in children with rhinovirus etiology at the first severe wheezing episode (204). This suggests that the epigenetic changes triggered by the same microbial agent may differ according to the specific phenotype of asthma or other allergic diseases, which needs to be further investigated in the future.

Taken together, although several studies related to epigenetics of asthma and allergies have been published so far, very few initiatives explores the role of the environmental changes, in special, exposure to organisms such as bacteria, fungi, protozoan and helminths as important modulators of those biochemical changes in human DNA. Further studies are needed to better understand such associations.

The usual immunotherapy and pharmacological therapy in the treatment of asthma and allergies act in the modulation of immune responses, with a focus on reducing inflammation and increasing immunological tolerance. This immunological modulation is almost always accompanied by epigenetic changes. It is even possible to distinguish different epigenetic signatures between untreated individuals and individuals under treatment (205).

The use of inhaled corticosteroids (ICS) in the management of moderate to severe asthma is recommended by asthma management guidelines (206) and several studies have shown that corticosteroids are potent epigenetic modifiers (207–209). Children with better response to corticosteroids have been shown to have hypermethylation in Vanin-1 (VNN1) promoter compared to the group with poor response, in addition VNN1 mRNA expression was higher among good responders. VNN1 appears to have an important role in corticosteroid responsiveness among asthmatics, and can be used as a biomarker for treatment response (209, 210). Acetylation of histones by HATs activity was reported to be reduced in asthmatics treated with inhaled steroids (211). Variations in serum IgE concentrations can be influenced by DNA methylation patterns. An association between total serum IgE concentration and low methylation at 36 loci has been demonstrated, this observation may be useful in optimizing therapies with anti-IgE antibodies such as omalizumab (212).

Studies evaluating the effectiveness of peanut oral immunotherapy found a great suppressive function of Treg cells and higher levels of FOXP3 hypomethylation among treated individuals (213). In addition, a study involving cow's milk allergy children and dietary intervention using probiotic Lactobacillus rhamnosus (abundant in butyrate-producer bacteria strains) demonstrated that oral tolerance in children with IgE-mediated CMA involves epigenetic regulation of the FOXP3 gene. Difference in the methylation status of FOXP3 was found among children who developed oral tolerance after probiotic therapy (205). Prenatal administration of Acinetobacter lwoffii F78 in murine demonstrated a modulation in Th1/Th2 balance genes, with protection for asthma in the progeny, accompanied by changes in DNA acetylation (199).

Although some studies using probiotic supplementation in animal models have indicated a protective effect of probiotics on asthma and allergic Rhinitis (214, 215), studies in humans are still limited due to couple limitations such as the duration of supplementation.

Many efforts have been focused on understanding and developing microbial therapies using technological approaches involving parasitology, genomics, transcriptomics, and proteomics methods. Currently with the help of bioinformatics and helminth genome sequencing initiatives it is possible through in silico analyzes to identify molecules with potential immunomodulatory properties. These databases are available on WormBase Parasite, HelmDB, and Heminth.net (216–218).

The identification of genomic sequences of helminth parasites known to down-modulate the immune system of mammalian hosts such as Ascaris suum, Necator americanus, Schistosoma mansoni, Strongyloides spp. as mentioned in previous topics in this review, have motivated the development of recombinant helminth proteins with therapeutic potential for immune-mediated diseases such as protease inhibitors, cytokine homologs and lectins (219). High immunogenicity has been observed for these therapeutic recombinant proteins (220) which may be able to mimic the immunomodulation observed in helminth infections. However, standardized studies in humans as well as adequacy of doses and treatment duration are still necessary.

Epigenetic mechanisms play an important role in the regulation of immune response and are strongly influenced by microbial exposures and drug use, advancing the knowledge about such interactions may be used to both development of future target therapeutic strategies for asthma and allergies but also to discover new biological properties in current drugs in use.

The genetic susceptibility to allergic disorders is known be polygenic and recent studies have established that the presence of the gut microbiota is essential for normal gene expression (221, 222). The presence of certain bacterial species in the gut, such as Helicobacter pylori increases the CpG methylation in the promoter region of O6-methylguanine DNA methyltransferase, which ends up decreasing the expression of this DNA methyltransferase in gastric mucosa cells (222).

Lactobacilli and Bifidobacteria are the major source of butyrate and the absence of these species is important. By inhibiting HDACs, butyrate suppresses nuclear NF-κB activation, upregulates PPARɤ expression, and decreases IFNɤ production in the residing gut immune cells, promoting an anti-inflammatory gut environment (222). In a study with patients with allergic rhinitis, blocking the HDAC activity restored the integrity of the nasal epithelium and restored mucosal function and prevented the development of airway inflammation and hyperresponsiveness in experimental models (223).

Studies in dietary manipulation have demonstrated that diets high in methyl-donating nutrients are associated with hypermethylation of the epigenome, impacting the gene expression, especially during early development when the epigenome is first established, and can have long-term effects in adult life (224, 225). According to Bae et al. (225), in humans, methyl donors for DNA methylation are mostly derived from dietary methyl groups nutrients such as folate, vitamin B12, and choline. Methyl donors affect DNA methylation and immune responses such as Th17, Th1/Th2 balance, and Treg generation (225).

Additional studies are needed to better characterize the mechanisms underlying the different asthma phenotypes and their correlation with clinical characteristics, and those that contemplate the complex interaction of different epigenetic mechanisms and those that focus on a single-cell type or investigations at the single cell level (221, 226). In this sense, EWAS can be useful to identify patterns of epigenetic signatures among asthma and allergy phenotypes and clinical characteristics, which reinforces the potential of epigenetic changes as future biomarkers for diagnosis and target personalized therapies.

BF, HF, PM, CM, TS, and CF have contributed for the first draft. HF designed the figure. CF designed the work. All authors listed co-authored and proofread the manuscript and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.