Shared epigenetic mechanisms in atopic dermatitis and food allergy: a review of immune dysregulation at the skin–gut axis

Abstract

Atopic dermatitis and food allergy frequently coexist and are central features of the atopic march, which describes the progression from eczema to allergic rhinitis and asthma. Classical genetic factors, such as FLG mutations, account for only a partial contribution to disease susceptibility. Recent research highlights epigenetic regulation, including DNA methylation, histone modification and noncoding RNAs, as pivotal determinants of immune dysregulation and barrier dysfunction. This review systematically examines shared epigenetic signatures between atopic dermatitis and food allergy, with particular emphasis on the interleukin (IL)-4/IL-13 axis, FOXP3 methylation and epithelial gene silencing at the skin–gut interface. By integrating evidence from genome-wide methylation and transcriptomic studies, it is proposed that epigenetic plasticity underlies the immune barrier crosstalk that drives atopic comorbidity. Elucidating these mechanisms provides a foundation for biomarker discovery and the development of personalized epigenetic therapies in allergy and dermatology.

Atopic dermatitis and food allergy frequently co-occur along the atopic march, yet the mechanisms linking these conditions remain incompletely defined. This review highlights how epigenetic regulation of barrier and immune pathways, particularly involving Th2 cytokines, filaggrin and regulatory T cells, coordinates immune dysregulation across the skin–gut axis. Understanding these shared epigenetic programmes offers new opportunities for biomarker discovery and disease-modifying intervention in atopic disease.

Introduction

Atopic dermatitis and food allergy are complex, polygenic disorders shaped by both genetic susceptibility and environmental exposure. Although these conditions frequently co-occur, the mechanisms linking them remain incompletely defined. The skin and gut epithelia serve as primary immune barriers, regulating tolerance and inflammation in response to microbial, dietary and environmental cues. Genetic studies, particularly those identifying FLG loss-of-function variants, have clarified the role of epidermal barrier dysfunction; however, genetic risk alone does not explain discordance in identical twins, implicating epigenetic regulation.¹

These mechanisms dynamically regulate transcriptional responses to allergens and inflammation. In atopic dermatitis and food allergy, altered methylation of T helper 2 (Th2) cytokine promoters [interleukin (IL)-4, IL-13] and FOXP3, a key regulator of immune tolerance, contributes to immune polarization.² These epigenetic profiles are further shaped by environmental exposures during critical developmental windows.

Growing evidence suggests that epigenetic alterations occur across multiple barrier tissues rather than in isolation. This has focused attention on the skin–gut axis, a bidirectional network in which epithelial integrity, microbial composition and immune signalling jointly influence allergic susceptibility. Disruption of cutaneous barrier function in early atopic dermatitis may epigenetically prime immune cells and lower tolerance to dietary antigens in the gut.³ This framework offers a mechanistic basis for the atopic march and supports examination of shared epigenetic signatures across tissues and environmental contexts. By integrating genetic, immunological and environmental data, this review examines how epigenetic crosstalk at the skin–gut interface contributes to the development and persistence of atopic disease.

Genetic and epigenetic foundations of the atopic march

The atopic march describes the progression from atopic dermatitis in infancy to food allergy, allergic rhinitis and asthma later in childhood. Genetic susceptibility contributes to this trajectory, with FLG loss-of-function mutations among the most consistently identified risk factors. FLG encodes a structural protein essential for epidermal barrier integrity, and its deficiency increases trans­epidermal water loss and allergen penetration.⁴ However, FLG mutations alone are neither necessary nor sufficient to drive the atopic march, as many carriers remain asymptomatic and disease severity varies substantially. These observations indicate that genetic predisposition alone cannot fully explain disease initiation or progression.

Epigenetic mechanisms have therefore emerged as key modulators translating genetic risk into clinical disease. DNA methylation at immune-related loci, including Th2 cytokine genes (IL4, IL13) and regulatory pathways such as FOXP3, differs between individuals with atopy and those without, and influences immune polarization and tolerance.² These epigenetic signatures are dynamic and responsive to early-life exposures, including microbial diversity, nutrition, antibiotic use and air pollution. Longitudinal birth cohort studies show that epigenetic changes detectable in infancy may precede allergic disease onset, supporting a model in which early epigenetic programming establishes susceptibility along the atopic march.⁵ Together, genetic susceptibility and epigenetic plasticity form an integrated framework in which inherited barrier vulnerability is shaped and amplified by environmental influences over time.

Figure 1, and Tables 1 and 2 summarize this genetic–epigenetic architecture by integrating key barrier and immune pathways with associated epigenetic modifications and clinical outcomes. Inherited susceptibility, most notably FLG loss-of-function variants, establishes baseline epidermal vulnerability, while epigenetic regulation of epidermal differentiation genes (FLG, LORICRIN, IVL), Th2 cytokine loci (IL4, IL13) and immune regulatory pathways (FOXP3, STAT6) determines whether this risk manifests clinically. Environmental exposures, including microbial diversity, diet, antibiotics and pollutants, further modulate these epigenetic states, reinforcing the concept that the atopic march reflects a dynamic, environmentally responsive epigenetic programme rather than a purely genetic trajectory.

Figure 1.

Conceptual framework. This depicts a developmental model of the atopic march in which inherited barrier defects (e.g. FLG variants) interact with environmental modifiers (microbiome, diet, antibiotics, pollutants) to shape epigenetic regulation, including DNA methylation, histone modifications and microRNA (miRNA) activity, within a critical early-life window (*). During neonatal and early infancy stages, key epigenetic switches are engaged, notably interleukin (IL)-4/IL-13-mediated T helper 2 (Th2) polarization and repression of barrier genes such as FLG, establishing early immune skewing and barrier dysfunction. These changes are reinforced during infancy through sustained chromatin remodelling, while epigenetic instability at the FOXP3 locus in early childhood contributes to impaired regulatory T-cell (Treg) function and loss of immune tolerance. A self-reinforcing feedback loop is illustrated in which Th2 cytokines promote continued barrier gene repression, enhancing allergen penetration and perpetuating immune activation, thereby driving progression from atopic dermatitis to food allergy and asthma. Created with BioRender.

Table 1.

Summary matrix

Gene/pathway	Dominant epigenetic modification	Functional immune/barrier effect	Clinical outcome in atopic march
FLG	Promoter hypermethylation; cytokine-induced chromatin repression	Reduced FLG expression; impaired epidermal integrity	Early-onset AD → increased allergen sensitization
LORICRIN/IVL (EDC genes)	Histone deacetylation; loss of activating marks	Defective terminal keratinocyte differentiation	Persistent eczema; chronic barrier dysfunction
IL4/IL13	Promoter hypomethylation; permissive histone acetylation	Stable Th2 cytokine transcription	IgE class switching; eosinophilic inflammation
FOXP3	Altered TSDR methylation; context-dependent histone acetylation	Treg instability or enhancement	Impaired or restored immune tolerance
STAT6	Cytokine-responsive chromatin accessibility	Reinforced Th2 lineage commitment	Disease persistence and progression
miR-155/miR-21	miRNA-mediated post-transcriptional regulation	Skewed T-cell differentiation	Increased disease severity

A summary matrix links key genes and pathways (FLG, LORICRIN/IVL, IL4/IL13, FOXP3, STAT6, miR-155/miR-21) to dominant epigenetic modifications, functional immune or barrier effects, and associated clinical outcomes along the atopic march. AD, atopic dermatitis; EDC, epidermal differentiation complex; miRNA, microRNA; Th2, T helper 2; Treg, regulatory T cell; TSDR, Treg-specific demethylated region.

Table 2.

Environmental modulation of epigenetic risk

Exposure	Epigenetic target	Effect on immune programming	Clinical relevance
Microbial diversity	Immune gene methylation	Enhanced tolerance pathways	Reduced atopy risk
Antibiotic exposure	Global methylation shifts	Th2 bias	Increased FA, asthma risk
High-fibre diet	Histone acetylation (via SCFAs)	Treg differentiation	Protective immune phenotype
Pollutants/smoke	Immune gene methylation	Chronic inflammation	AD severity

Environmental modulation of epigenetic risk demonstrates how microbial diversity, antibiotic exposure, diet and pollutants influence immune gene methylation and tolerance pathways, thereby altering atopy risk. AD, atopic dermatitis; FA, food allergy; SCFA, short-chain fatty acid; Th2, T helper 2; Treg, regulatory T cell.

Barrier dysfunction and immune epigenetic programming in atopic disease

The epidermal barrier plays a central role in limiting allergen penetration and maintaining immune homeostasis. In atopic dermatitis, reduced FLG expression compromises stratum corneum integrity and promotes transcutaneous allergen exposure. Although FLG loss-of-function variants increase disease risk, diminished FLG expression also occurs in individuals without these mutations, implicating regulatory mechanisms beyond DNA sequence variation.⁴ Epigenetic processes, including DNA methylation and histone modification, regulate transcription of epidermal differentiation complex genes essential for barrier formation, as summarized in Table 3.

Table 3.

Epigenetic repression of epidermal differentiation programmes

Barrier gene/component	Epigenetic modification	Upstream driver	Functional consequence
FLG	Promoter hypermethylation	IL-4/IL-13	Persistent FLG suppression
LORICRIN/IVL	Histone deacetylation	Chronic Th2 inflammation	Impaired cornified envelope formation
CLDN1	DNA methylation	Inflammatory cytokine milieu	Increased epidermal permeability

A matrix summarizes epigenetic repression of key epidermal differentiation and tight junction genes (FLG, LORICRIN/IVL, CLDN1), including promoter methylation and histone deacetylation driven by inflammatory cytokines, resulting in impaired cornified envelope formation and increased epidermal permeability. IL, interleukin; Th2, T helper 2.

Th2 cytokines characteristic of atopic inflammation, particularly IL-4 and IL-13, induce epigenetic repression of barrier genes by promoting chromatin remodelling and methylation at the FLG, LORICRIN and IVL loci, resulting in sustained dysfunction even after inflammation resolves.⁶ This establishes a feed-forward loop in which immune-driven epigenetic changes further weaken the barrier, increase allergen exposure and perpetuate inflammation (Figure 2). These modifications are partially reversible, supporting therapeutic strategies that combine immune modulation with barrier repair.

Figure 2.

(a) A schematic illustrates a self-reinforcing barrier–immune feedback loop in which T helper 2 (Th2) cytokines [interleukin (IL)-4, IL-13] induce epigenetic repression of epidermal differentiation genes, leading to persistent barrier dysfunction and increased allergen penetration. Keratinocyte-derived alarmins (TSLP, IL-33) further amplify immune activation and Th2 polarization. Created with BioRender.com.

Epigenetic regulation also shapes keratinocyte-mediated immune signalling. Atopic keratinocytes exhibit altered expression of antimicrobial peptides and alarmins such as thymic stromal lymphopoeitin (TSLP) and IL-33, with increased enhancer accessibility priming epithelial cells for exaggerated immune responses to environmental stimuli.^7,8 Together, these findings indicate that epigenetic dysregulation within the epidermis not only permits allergen entry, but also promotes downstream immune polarization, as outlined in Table 4.

Table 4.

Epigenetic priming of epithelial–immune signalling pathways

Signal/cell type	Epigenetic change	Downstream effect	Feedback on barrier
TSLP	Enhancer priming	DC activation → Th2 polarization	Further repression of barrier genes
IL-33	Loss of repressive histone marks	ILC2 and Th2 activation	Sustained epithelial inflammation
Th2 cells	Stable cytokine locus accessibility	Chronic IL-4/IL-13 production	Delayed barrier repair
Tregs	FOXP3 locus instability	Reduced suppression	Failure to resolve inflammation

Epigenetic priming of epithelial–immune signalling pathways shows how enhancer accessibility and loss of repressive histone marks at alarmin and cytokine loci promote dendritic cell activation, group 2 innate lymphoid cells (ILC2) activation and sustained T helper 2 (Th2) responses. DC, dendritic cell; IL, interleukin; Treg, regulatory T cell; TSLP, thymic stromal lymphopoeitin.

Immune tolerance is further disrupted through epigenetic alterations in regulatory T cells (Tregs). Methylation instability at the FOXP3 locus reduces Treg suppressive capacity in atopic dermatitis and food allergy, promoting enhanced Th2 responses and allergic sensitization, particularly during early development.^9,10 Environmental exposures, including microbial diversity, nutrition and inflammatory cytokines, modulate FOXP3 methylation, illustrating how external factors shape immune tolerance through epigenetic programming.

Additional epigenetic layers reinforce Th2 polarization. Increased histone acetylation at Th2 cytokine promoters enhances chromatin accessibility and facilitates rapid transcription following allergen exposure. MicroRNAs (miRNAs) such as miR-155 and miR-21 regulate T-cell differentiation and cytokine signalling pathways relevant to atopy.¹¹ Collectively, these mechanisms stabilize allergic immune memory and reinforce Th2 polarization along the atopic march (Figure 3).

Figure 3.

This figure illustrates how epigenetic mechanisms sustain bidirectional feedback between epidermal barrier dysfunction and immune activation in atopic dermatitis. T helper 2 (Th2) cytokines induce epigenetic repression of epidermal differentiation genes, leading to persistent barrier impairment. Concurrently, epigenetic priming of epithelial alarmins such as thymic stromal lymphopoietin and interleukin-33 amplifies dendritic cell activation and Th2 polarization. Immune cells acquire stable epigenetic modifications that reinforce allergic memory and further suppress barrier repair, establishing self-perpetuating inflammatory loops that contribute to disease chronicity and progression along the atopic march. HDAC, histone deacetylase. Created with BioRender.

These insights support emerging translational strategies. Biologic therapies targeting IL-4 and IL-13 signalling, such as dupilumab, may exert durable effects by indirectly reshaping epigenetic programmes that maintain Th2 polarization.¹² Nutritional and microbiome-based interventions provide complementary approaches, as short-chain fatty acids (SCFAs) produced by fibre-fermenting gut microbes influence histone acetylation and enhance Treg function, linking diet and microbial metabolism to immune tolerance.^13,14 Together, pharmacological, dietary and microbiome-directed strategies converge on shared epigenetic pathways, supporting integrated approaches to disrupt progression along the atopic march.

Additional insight into the role of primary barrier dysfunction in systemic immune programming is provided by monogenic disorders that represent severe models of epithelial compromise. Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome, associated with mutations in desmosomal components such as desmolglein 1, is characterized by early-onset dermatitis accompanied by multisystem allergic manifestations. In these conditions, structural barrier defects alone are sufficient to drive sustained Th2 polarization and immune dysregulation. Such observations support the concept that epidermal barrier failure may act as an initiating event in the development of systemic atopic disease, with downstream effects potentially reinforced through epigenetic mechanisms.

Gut barrier and microbiome–epigenetic interactions

The intestinal epithelium is central to immune tolerance by regulating antigen exposure, microbial interactions and downstream immune signalling. In food allergy, increased intestinal permeability facilitates abnormal exposure to dietary antigens and promotes immune sensitization. While genetic influences on gut barrier function have been identified, epigenetic regulation of epithelial and immune genes is increasingly recognized as a key determinant of intestinal homeostasis. Altered DNA methylation of tight junction genes, including CLDN1 and OCLN, has been reported in allergic disease, linking epigenetic dysregulation to barrier dysfunction and enhanced allergen translocation.¹⁵

The gut microbiome shapes host epigenetic landscapes through microbial metabolites and immune signalling pathways. SCFAs produced by dietary fibre fermentation modulate chromatin accessibility in immune cells. These effects promote regulatory T-cell differentiation and support immune tolerance to dietary antigens.^13,16 Dysbiosis, characterized by reduced microbial diversity and depletion of SCFA-producing taxa, is consistently associated with increased risk of food allergy and atopic disease, implicating microbiome-driven epigenetic modulation in allergic susceptibility.

Early-life exposures critically influence microbiome–epigenetic interactions. Mode of delivery, antibiotic exposure, infant feeding practices and dietary patterns induce durable epigenetic changes that shape immune development and allergic risk.^5,17 Antibiotic-associated reductions in microbial diversity during key developmental windows correlate with altered methylation at immune-regulatory loci and increased incidence of food allergy and asthma. These findings suggest that epigenetic programming of the gut–immune interface may precede clinical disease, positioning the microbiome as both a mediator and modulator of the atopic march.

In addition to local effects within the intestinal environment, gut-derived microbial metabolites exert systemic epigenetic influence on peripheral tissues, including the skin. SCFAs, particularly butyrate, function as histone deacetylase inhibitors, modulating chromatin accessibility in immune cells and promoting regulatory T-cell differentiation by stabilizing FOXP3 expression. These systemic immunoregulatory effects may indirectly support epidermal barrier integrity by attenuating Th2-driven inflammation. Conversely, reductions in SCFA-producing microbial populations associated with dysbiosis may diminish this regulatory capacity, thereby contributing to persistent immune activation and impaired barrier repair. These observations further support a bi­directional model of interaction between the gut microbiome and cutaneous immune responses.

Collectively, gut barrier integrity, microbial composition and epigenetic regulation form an integrated system governing immune tolerance to dietary antigens. Disruption of any component, through genetic susceptibility, environmental exposure or microbial imbalance, can induce epigenetic changes that bias immune responses towards allergy. Elucidating these interactions provides a mechanistic framework for microbiome-targeted strategies aimed at restoring immune tolerance and interrupting progression along the atopic march.

The skin–gut axis: bidirectional immune crosstalk

The skin–gut axis provides a unifying framework for how barrier dysfunction at one epithelial site can influence immune responses at another. Both organs are immunologically active and contain resident immune cells that sample environmental antigens and microbial signals. Disruption of epithelial integrity can result in systemic immune activation through shared lymphoid pathways, circulating cytokines and epigenetically primed immune cells. In atopic disease, impaired skin barrier function early in life may act as an initial sensitization site, promoting Th2-skewed immune programming that later manifests as food allergy following oral antigen exposure.^1,18

Transcutaneous allergen exposure in atopic dermatitis induces systemic immune changes that extend beyond the skin. Allergen entry through a compromised epidermis activates keratinocyte-derived alarmins, including TSLP, IL-25 and IL-33, which promote dendritic cell activation and Th2 polarization in draining lymph nodes.^7,19 These activated immune cells circulate systemically with epigenetic profiles that bias subsequent responses towards allergy. Upon later exposure to dietary antigens in the gut, this primed immune state may favour sensitization rather than tolerance, providing a mechanistic basis for the temporal sequence observed in the atopic march. The mechanisms by which this localized immune activation translates into systemic sensitization are an area of active investigation.

A key mechanistic link connecting localized cutaneous inflammation to systemic sensitization involves the acquisition of ­tissue-specific homing properties by activated immune cells. Following transcutaneous allergen exposure, skin-resident dendritic cells migrate to regional lymph nodes, where they promote Th2 polarization under the influence of epithelial-derived cytokines such as TSLP and IL-33. Within this context, activated T cells may upregulate gut-homing receptors, including α4β7 integrin and CCR9, enabling their trafficking to intestinal sites. These cells retain epigenetic modifications, such as permissive chromatin states at Th2 cytokine loci, that facilitate rapid recall responses upon antigen re-exposure. This process provides a plausible mechanistic basis by which immune priming initiated in the skin can influence subsequent responses to dietary antigens in the gut.

Gut-derived immune signals also shape cutaneous inflammation, underscoring the bidirectional nature of this axis. Alterations in gut microbiota composition and increased intestinal permeability permit systemic dissemination of microbial metabolites and immune mediators that influence skin immune responses. SCFAs produced in the gut modulate histone acetylation and Treg function locally and in peripheral tissues, including the skin.¹⁴ Reductions in these immunoregulatory signals due to dysbiosis may exacerbate skin inflammation by weakening systemic immune regulation and promoting Th2-driven pathways.

These processes enable sustained communication between the skin and gut over time. Immune cells exposed to inflammatory cues at either barrier acquire stable modifications, such as altered DNA methylation at cytokine and transcription factor loci, which shape their behaviour upon recirculation. This mechanism may explain why early-life barrier disruption confers persistent allergic risk, even after clinical improvement of dermatitis. Together, these findings define the skin–gut axis as a dynamic immunological network in which epithelial integrity, microbial signals and epigenetic memory converge to regulate allergic susceptibility.

Collectively, these findings support a model in which cutaneous barrier disruption initiates immune activation and epigenetic priming, followed by systemic dissemination of functionally reprogrammed immune cells that influence responses at distal barrier sites, including the gut.

Environmental modulation and therapeutic plasticity of epigenetic programmes

Environmental and lifestyle exposures shape immune development through epigenetic mechanisms, particularly during early life. Microbial exposure, diet, antibiotics, pollution, psychosocial stress and climate-related factors influence DNA methylation, histone modifications and noncoding RNA expression, thereby modulating allergic susceptibility. Environments with high microbial diversity, such as rural or farm settings, are associated with reduced atopic disease risk, probably through epigenetic programming of innate and adaptive immune pathways.^5,20 In contrast, urbanization and reduced microbial exposure promote epigenetic changes that favour Th2 polarization and impair immune tolerance.

Diet represents a highly modifiable regulator of epigenetic control in atopic disease. Nutrients such as folate, polyphenols, omega-3 fatty acids and dietary fibre influence DNA methylation and histone acetylation. High-fibre diets increase SCFA production, which acts as a histone deacetylase inhibitor and enhances regulatory T-cell differentiation.^13,14 Conversely, Western dietary patterns rich in ultraprocessed foods and saturated fats are linked to inflammatory epigenetic remodelling that reinforces allergic phenotypes.

Environmental pollutants further contribute to epigenetic dysregulation along the atopic march. Tobacco smoke, particulate matter and endocrine-disrupting chemicals alter methylation of immune-regulatory genes and increase allergic risk.^21,22 Psychosocial stress similarly modifies immune epigenetic marks, influencing inflammatory responses and disease severity. Together, these exposures exert cumulative effects on epigenetic programming and highlight opportunities for prevention through modifiable environmental factors.

The plasticity of epigenetic regulation distinguishes it from fixed genetic variation and positions it as a promising therapeutic target. Longitudinal studies indicate that epigenetic signatures associated with allergic disease can shift with inflammatory burden, microbial exposure and lifestyle factors, consistent with fluctuating disease severity and windows for intervention.^5,23

Targeted biologic therapies demonstrate that immune modulation may indirectly reshape epigenetic programmes. Inhibition of IL-4 and IL-13 signalling with agents such as dupilumab reduces inflammation and normalizes transcriptional profiles associated with Th2 polarization and barrier dysfunction.^12,24 Although direct epigenetic effects remain under study, transcriptomic data suggest that sustained cytokine blockade may partially reprogramme immune cells away from pathogenic Th2 states, supporting ­disease-modifying potential rather than purely symptomatic control.

Lifestyle and microbiome-targeted strategies provide complementary routes for epigenetic modulation. Diets rich in fibre and polyphenols enhance SCFA production, influencing histone acetylation and stabilizing regulatory T-cell function.^13,14 Probiotic and prebiotic interventions can also modify immune gene expression and methylation patterns, although effects vary by host genetics, timing and microbial context.^15,17

The reversibility of epigenetic marks has important implications for prevention and treatment. Interventions during early developmental windows may exert durable effects on immune programming, and detection of preclinical epigenetic changes could enable risk stratification and early intervention. As understanding advances, strategies aimed at restoring barrier integrity, immune tolerance and microbial balance may shift atopic disease management from reactive therapy towards modification of disease course.

Biomarker discovery and clinical translation

Identification of epigenetic biomarkers is essential for translating mechanistic insights into clinical practice. In atopic dermatitis and food allergy, epigenetic markers may better reflect disease risk, activity and progression than static genetic variants. Genome-wide methylation and transcriptomic studies reveal differential patterns at immune-regulatory loci, including IL4, IL13, FOXP3 and barrier-related genes, which correlate with disease severity and allergic sensitization.² Importantly, many of these signatures are detectable in peripheral blood, supporting the feasibility of minimally invasive biomarkers that reflect systemic immune programming across the atopic march.

Epigenetic biomarkers may also guide patient stratification and therapeutic decision-making. Variability in response to biologics such as dupilumab suggests underlying differences in immune and epigenetic profiles. Baseline methylation and expression patterns within Th2 and regulatory pathways have been associated with responsiveness to cytokine-targeted therapy.^12,24 Markers linked to regulatory T-cell stability or barrier gene expression may further identify individuals likely to benefit from microbiome- or diet-based interventions, aligning with principles of precision medicine.

Translational challenges remain, including tissue specificity, temporal variability and the need for standardized assays. Epigenetic profiles differ across skin, gut and circulating immune cells, complicating interpretation. However, advances in multi­omics integration and longitudinal cohorts are beginning to link epigenetic changes across tissues and developmental stages.⁵ As analytic methods mature, epigenetic biomarkers may serve as early indicators of allergic risk, tools for monitoring disease progression and endpoints for evaluating preventive strategies, enabling earlier intervention and improved disruption of the atopic march.

Future directions and gaps in knowledge

A persistent challenge in this field is the precise delineation of the developmental window during which epigenetic programming is most susceptible to modification. While clinical data remain limited, findings from preclinical models suggest that early life represents a period of heightened epigenetic plasticity. In neonatal systems, interventions such as microbial modulation, dietary supplementation or cytokine-targeted approaches have been shown to influence epigenetic marks associated with immune tolerance. These observations raise the possibility that early interventions may alter disease trajectories by modifying underlying epigenetic programmes. Translation of these findings into human populations will require carefully designed longitudinal studies with careful consideration of timing, safety and population variability.

Although strong evidence links epigenetic mechanisms to atopic dermatitis and food allergy, important gaps remain regarding their coordination across tissues and developmental stages. The predominance of cross-sectional studies limits causal and temporal inference within the atopic march. Longitudinal, multiomic studies initiated in early life are needed to determine whether epigenetic alterations precede disease onset or result from chronic inflammation. Greater inclusion of diverse populations is also necessary, as existing datasets over-represent individuals of European ancestry and may obscure population-specific risk factors.⁵

Tissue specificity represents another critical challenge. Epigenetic profiles differ among skin, gut and circulating immune cells, yet few studies assess multiple compartments within the same individuals. Clarifying how epigenetic programming is co­ordinated across epithelial barriers is essential for understanding the skin–gut axis. Emerging methods such as single-cell epi­genomics and spatial transcriptomics offer promise, but standardized analytic frameworks remain in development. Future research should emphasize integrative strategies combining epigenetic, transcriptomic, microbiome and clinical data.

Therapeutic translation also requires further investigation. Although biologics and lifestyle interventions may indirectly influence epigenetic states, direct epigenetic therapies remain largely unexplored in allergic disease. Identifying reversible modifications, distinguishing pathogenic drivers and defining optimal intervention windows will be key to developing disease-modifying strategies. Ethical considerations surrounding early-life intervention and epigenetic risk stratification must also be addressed.

Overall, progress will depend on integrated basic and clinical research with emphasis on longitudinal design, tissue integration and translational relevance. Addressing these gaps may clarify how epigenetic crosstalk at the skin–gut axis shapes allergic trajectories and enable interventions that modify, rather than simply treat, the atopic march.

Conclusion

This review identifies epigenetic regulation as a central mechanism linking atopic dermatitis and food allergy within the atopic march. While genetic susceptibility, particularly involving barrier genes such as FLG, establishes baseline risk, epigenetic processes largely determine whether this risk manifests clinically. Evidence consistently supports a central role for epigenetic regulation in coordinating immune polarization, epithelial integrity and tolerance across barrier tissues. These mechanisms help explain disease heterogeneity, including discordance among genetically identical individuals, and underscore the importance of ­environment–immune interactions in allergic pathogenesis.

A major theme emerging from this review is the skin–gut axis as a bidirectional immunological network in which barrier disruption, microbial signals and epigenetic memory interact to shape systemic allergic susceptibility. Early-life barrier disruption may initiate immune programming that increases later allergic risk. Conversely, gut dysbiosis and altered microbial metabolites influence systemic immune regulation and cutaneous inflammation via epigenetic control of key pathways. Together, these findings support a model of coordinated dysregulation across epithelial interfaces rather than isolated organ pathology.

The plasticity of epigenetic regulation positions it as both a biomarker of disease trajectory and a therapeutic target. Biologics targeting Th2 cytokines, dietary modification and microbiome-­directed therapies may exert durable effects by reshaping pathogenic epigenetic programmes rather than solely suppressing inflammation. Epigenetic biomarkers detectable in peripheral tissues further offer promise for early risk stratification, personalized therapy and monitoring of disease modification.

Despite progress, challenges remain. Current studies are limited by cross-sectional design, tissue-specific variability and incomplete integration of multiomic data across development. Addressing these gaps will require longitudinal, systems-level approaches integrating epigenetics, transcriptomics, microbiome profiling and clinical phenotyping in diverse populations, alongside careful ethical consideration of early-life risk stratification.

In conclusion, epigenetic crosstalk at the skin–gut axis represents a critical and modifiable driver of atopic disease. By integrating genetic susceptibility with environmental exposure and immune programming, this framework clarifies the frequent coexistence and progression of atopic dermatitis and food allergy, and supports a shift towards prevention, personalization and long-term immune resilience in allergic disease management.

Author contributions

Patrick Steven Tajanlangit (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing [equal]), and Sean Michael Tajanlangit (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing [equal])

Funding sources

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

No new datasets were generated or analysed in this study.

Ethics statement

Not applicable.

Patient consent

Not applicable.