Skin and gut microbiome in atopic dermatitis: Mechanisms and therapeutic opportunities

Abstract

The pathogenesis of atopic dermatitis (AD) comprises a combination of genetic, immune, and microbial factors. An imbalance in skin and gut microbiota composition, termed dysbiosis, may contribute to AD pathogenesis and severity through overgrowth of pathogenic microbes and suppression of healthy commensal colonization. These, in turn, promote barrier disruption and pro‐inflammatory responses. The skin and gut microbiota composition plays crucial roles in AD, namely as early predictive biomarkers of AD onset; indicators of treatment response; and as future novel therapeutics such as probiotics, fecal, and skin microbiota transplantation. Such interventions aim to directly “reset” and restore a healthy microbial equilibrium, thereby fundamentally repairing barrier function, regulating immune homeostasis, and establishing new adjunctive pathways for the long‐term management of AD.

Gut‐skin axis in atopic dermatitis. This figure illustrates the bidirectional interactions between the skin and gut microenvironments, which play a crucial role in immune regulation and atopic dermatitis (AD) pathogenesis. On the left, under healthy conditions, the intact skin and gut epithelial barriers maintain microbiome and immune homeostasis. A balanced microbiota composition is supported by microbial metabolites, such as short‐chain fatty acids (SCFAs), which promote T regulatory cell (Treg) responses, maintaining immune equilibrium. On the right, in AD, there is disruption of the skin epithelial barrier, and an overgrowth of pathogenic microbes like Staphylococcus aureus and reduced abundance of beneficial commensal bacteria. The gut also exhibits barrier dysfunction and microbial dysbiosis, and a loss of protective microbes. These aberrations lead to immune dysregulation, characterized by a shift toward pro‐inflammatory Th2 cytokine production, which disrupts immune homeostasis. This results in systemic inflammation, contributing to the pathogenesis and persistence of AD.

Key message.

Skin–gut microbiota imbalance plays a critical role in atopic dermatitis. Microbial signatures may predict disease onset and treatment outcomes. Restoring microbial balance offers new therapeutic opportunities for atopic dermatitis.

1. INTRODUCTION

Atopic dermatitis (AD) is a complex inflammatory skin condition with a multifactorial pathogenesis, involving genetic predisposition, immune dysregulation, environmental exposures, and alterations in skin–microbiome interactions. Recent studies emphasize the crucial roles of skin and gut microbiota in AD, highlighting their complex relationship with the immune system. AD skin typically shows low microbiota diversity and an overabundance of harmful bacteria like Staphylococcus aureus (S. aureus), which correlates with disease severity. ¹ This microbial imbalance, known as “dysbiosis”, negatively impacts immune responses, disrupting skin barrier function, which exacerbates disease severity. ² , ³

Disruption of the intestinal barrier is likewise crucial in AD pathogenesis. Aberrations in gut microbiota composition and their metabolites may compromise this barrier, triggering systemic immune responses and skin inflammation. ⁴ These mechanisms involve reduced tight junction protein expression and increased intestinal permeability, which allows microbial metabolites and food antigens to enter the systemic circulation, ⁵ , ⁶ thereby influencing skin barrier function and the systemic immune responses through the modulation of T cell differentiation and cytokine expression. ⁷

The “gut‐skin axis” refers to the network of interactions between the gut and skin epithelial barriers, which plays a crucial role in the development of AD. Immune cells and inflammatory mediators originating from the intestine migrate to the skin via lymphatics and blood, inducing cutaneous inflammatory responses. ⁸ Conversely, skin inflammation may compromise the integrity of the intestinal barrier and alter gut microbiota composition through gut‐homing cytokine signaling, thereby establishing a vicious cycle. ⁹

Understanding these complex interactions behind AD pathogenesis lays the groundwork for future novel therapeutics. Early life is crucial for host–microbe interactions, as initial microbial colonization significantly impacts immune development and tolerance. ¹⁰ Therefore, early interventions, such as dietary modification and microbiota management, are vital for the prevention and management of these conditions.

2. INTERACTIONS BETWEEN SKIN MICROBIOTA AND THE SKIN BARRIER IN AD

Microbial communities significantly impact the skin barrier in AD. A balanced microbial community plays a crucial role in maintaining skin barrier function by stimulating the production of anti‐inflammatory cytokines, thereby preserving immune homeostasis and protecting the skin barrier. For instance, commensal bacteria such as Staphylococcus epidermidis enhance keratinocyte connections and promote skin barrier repair through the secretion of substances like lipopeptides. ¹¹

Conversely, microbial dysbiosis contributes to skin barrier disruption. For instance, in patients with AD, the disruption of skin microbiota composition, reflected in reduced overall diversity, excessive proliferation of S. aureus, ¹² and reduced abundance of beneficial bacteria such as Propionibacterium and Corynebacterium, is associated with disease severity. ¹³ S. aureus has the capacity to compromise the integrity of keratinocyte tight junctions, induce apoptosis, degrade essential skin barrier proteins such as filaggrin, and inhibit the expression of host antimicrobial peptides through the secretion of various toxins (δ‐toxin, α‐toxin), as well as proteases. ¹⁴ Furthermore, S. aureus disrupts the normal functioning of the host immune system, leading to the overexpression of inflammatory factors and exacerbating the symptoms of AD ² , ⁹ , ¹⁴ , ¹⁵ (Figure 1).

FIGURE 1.

Gut‐skin axis in atopic dermatitis. This figure illustrates the bidirectional interactions between the skin and gut microenvironments, which play a crucial role in immune regulation and atopic dermatitis (AD) pathogenesis. On the left, under healthy conditions, the intact skin and gut epithelial barriers maintain microbiome and immune homeostasis. A balanced microbiota composition is supported by microbial metabolites, such as short‐chain fatty acids (SCFAs), which promote T regulatory cell (Treg) responses, maintaining immune equilibrium. On the right, in AD, there is disruption of the skin epithelial barrier, and an overgrowth of pathogenic microbes like Staphylococcus aureus and reduced abundance of beneficial commensal bacteria. The gut also exhibits barrier dysfunction and microbial dysbiosis, and a loss of protective microbes. These aberrations lead to immune dysregulation, characterized by a shift toward pro‐inflammatory Th2 cytokine production, which disrupts immune homeostasis. This results in systemic inflammation, contributing to the pathogenesis and persistence of AD.

Microbial dysbiosis may also disrupt key enzymes involved in lipid metabolism, altering the composition and structure of essential skin barrier components like ceramides and fatty acids, which further weaken the skin barrier. ¹⁶

Studies have also reported an increase in the diversity of non‐Malassezia fungi (predominantly Aspergillus, Candida albicans, and Cryptococcus diffuses) on the skin of AD patients. ¹⁷ A small pilot study which utilized sequencing of skin samples to explore fungal colonization patterns in 8 AD patients and 8 healthy controls revealed that the fungal taxonomic diversity at both the genus and species levels was higher in AD patient samples, with a more pronounced diversity of non‐Malassezia fungi in AD patients. ¹⁸ The compromised skin barrier in AD could also limit lipids needed for Malassezia growth. ¹⁹ Additionally, changes over time may affect the fungal microbiota structure.

Significant differences in skin microbial metabolites have also been observed between healthy controls versus AD patients. Short‐chain fatty acids (SCFAs), such as propionic acid and butyric acid, are crucial for maintaining the acidic pH of the skin, inhibiting pathogen growth, and regulating local immune responses. ²⁰ , ²¹ Research shows that healthy individuals have higher skin surface SCFA levels compared to those with AD. A Korean study using 16S rRNA sequencing and gas chromatography also found that patients with higher Skin Keratinization Function Index (SCFI) levels—a metric assessing transepidermal water loss (TEWL) indicating better skin hydration—had higher levels of propionic acid and Propionibacterium acnes compared to those with lower SCFI values or drier skin. Additionally, there was a negative correlation between the abundance of Propionibacterium spp. and S. aureus. ²⁰

3. ROLE OF THE GUT MICROBIOTA IN AD

The intestinal barrier serves as a crucial defense mechanism, safeguarding the body against external pathogens and harmful substances. It comprises mechanical, chemical, biological, and immune barriers that collectively maintain physiological intestinal functioning. ²² The intestinal barrier serves as a crucial defense mechanism against external pathogens and harmful substances. ²³ , ²⁴ , ²⁵ , ²⁶ while the biological barrier is predominantly composed of gut microbiota, which impede pathogen colonization via competitive exclusion and sustain microbial homeostasis. The immune barrier encompasses gut‐associated lymphoid tissues (GALT), immune cells such as macrophages, dendritic cells, and intraepithelial lymphocytes, as well as secretory immunoglobulin A (sIgA). This intricate system facilitates host defense by preserving a dynamic equilibrium between immune tolerance and inflammatory responses.

The gut microbiota plays a key role in regulating barrier functions (Figure 1). Symbiotic microbiota contribute to intestinal barrier integrity by promoting tight junction protein expression via epithelial cell signaling. For instance, Bifidobacterium and Lactobacillus upregulate the expression of tight junction proteins such asZO‐1 and Occludin, which reduce gut permeability. ²⁷ Metabolites produced by gut microbiota (microbiota metabolites), such as SCFAs, also exert immunoregulatory effects on the intestinal barrier. SCFAs represent the primary products of dietary fiber fermentation by the gut microbiota. In particular, butyric acid has been shown to modulate gene expression in intestinal epithelial cells, stimulate mucus secretion and cell proliferation, and enhance intestinal barrier function through the inhibition of histone deacetylase. ²⁸ SCFAs also modulate immune cell function, facilitate the differentiation of regulatory T cells (Tregs), and enhance the production of anti‐inflammatory cytokines, such as IL‐10, through their interaction with G protein‐coupled receptors (GPR41, GPR43, GPR109a). Furthermore, the gut microbiota plays a crucial role in modulating the function of intestinal immune cells, thereby maintaining immune homeostasis and supporting barrier integrity. Certain probiotic strains are also capable of inducing the differentiation of regulatory T cells (Tregs), attenuating inflammatory responses, and reducing immune‐mediated disruption of the intestinal barrier. ²⁹

Conversely, dysbiosis—defined as an imbalance in gut microbiota composition—manifests as an increased abundance of pathogenic bacteria accompanied by a reduction in commensal species. This imbalance leads to the production of pro‐inflammatory substances that compromise intestinal barrier integrity and promote intestinal permeability, which is referred to as the “Leaky Gut Hypothesis”. ³⁰

A growing body of research suggests a strong association between aberrant gut microbiota composition and AD. Specifically, several studies have consistently demonstrated that the alpha diversity of gut microbiota in AD patients is reduced compared to healthy individuals, indicating a lower contraction in species richness and skewed relative abundance distributions that may impair ecological stability and functional resilience of the microbial community. ³¹ , ³² A cross‐sectional study of 172 subjects (49 with eczema and 123 healthy controls) found that gut microbiota diversity, particularly bifidobacteria, was significantly reduced in eczema patients aged 2–3 years compared to healthy controls. ³¹ Another study revealed a decreased relative abundance of beneficial bacteria, including Bifidobacterium, Lactobacillus, and Faecalibacterium, in the gut microbiota of AD patients compared to healthy controls. Conversely, there was an increase in certain harmful bacterial species, such as Bacteroides, Clostridium, and Klebsiella. Additionally, alterations in the Firmicutes to Bacteroidetes ratio were noted. ³³ A separate study utilizing 16S rRNA targeted metagenomic analysis revealed a reduction in SCFAs‐producing bacteria (such as Bifidobacterium, Blautia, and Coprococcus) in the gut of AD patients, while an increase was observed in Faecalibacterium, Oscillospira, Bacteroides, and Parabacteroides, ³³ compared to healthy individuals.

A significant correlation between alterations in gut microbiota composition, intestinal permeability, and AD incidence also exists. The hypothesis posits that dysbiosis of the gut microbiota may result in compromised intestinal epithelial barrier function and reduced expression of tight junction proteins. ⁴ , ³⁴ Consequently, antigens, pathogens, and their metabolites present in the gut may translocate into the bloodstream, thereby activating the immune system and eliciting systemic inflammatory responses, such as interleukin IL‐4, IL‐6, and tumor necrosis factor alpha (TNF‐α), which further intensify the inflammatory response in the skin, ultimately leading to the onset and exacerbation of AD symptoms. ³⁵ Increased intestinal permeability may also, in turn, exacerbate gut microbial dysbiosis and impair microbiota–immune homeostasis, creating a vicious cycle facilitating the development of AD.

Elevated blood levels of intestinal permeability‐related biomarkers, such as lipopolysaccharide binding protein, intestinal fatty acid binding protein, and regenerated islet‐derived protein 3A, found in AD patients suggest the presence of a compromised barrier function. ³⁶

Studies further suggest that increased intestinal permeability in AD patients is linked to disease severity and recurrence. A study with 50 AD patients and 25 healthy controls found higher levels of intestinal barrier‐related biomarkers (LBP, Reg3A, I‐FABP) and cytokines (IL‐10, IL‐22) in patients that were positively correlated with AD clinical scores (EASI and SCORAD), suggesting that intestinal barrier dysfunction may significantly contribute to AD pathogenesis. ³⁶

4. INVESTIGATIVE BIOMARKERS OF FUTURE AD DEVELOPMENT

Identification of preclinical biomarkers of AD is key toward understanding why some high‐risk infants develop clinical AD while others do not, and may help individualize targeted strategies for AD prevention. ³⁷ Several studies have now examined the role of various skin biomarkers, obtained mainly through non‐invasive techniques like skin tape strips, in predicting future AD onset.

Levels of natural moisturizing factors (NMFs), which are filaggrin breakdown products, were found to be lower in infants with AD compared to controls. ³⁸ Recent skin biopsy transcriptomic studies reveal downregulation of barrier‐related genes, including those involved in terminal differentiation (LCE1F/2B/2C/2D, FLG, SCEL) and tight junctions (CLDN8/11/23). ³⁹ Lipids are essential components of the epidermal barrier and consist of ceramides, cholesterol, and free fatty acids. Kim et al. discovered a reduced amount of total ceramides, ceramides with fatty acid chains longer than C22, and esterified ultra‐long‐chain ceramides in the lesional skin of 27 Korean children with AD compared to the skin of 18 age‐matched healthy controls. Sphingomyelins and SCFAs were increased in children with AD, but not nonhydroxylated ceramides. ⁴⁰ In Chinese infants with AD, Zhang et al. discovered notably lower NP‐Cer levels but higher NH‐Cer, NS‐Cer, AP‐Cer, and hydroxylation, along with longer carbon chains of free FAs compared to controls. In a prospective study, reduced free phytosphingosine in stratum corneum (SC) tape strips at 2 months showed the highest prediction accuracy (76%) among single biomarkers. ⁴¹

Recent research has also utilized SC tape strips to identify immune biomarkers that predict AD. Higher TARC/CCL17 levels in skin tape strips collected from 2‐month‐old infants were associated with increased risks of developing AD by age 2 in both full‐term and preterm children. Additionally, elevated TARC/CCL17, IL‐8, and IL‐18 levels at age 2 months increased the likelihood of moderate‐to‐severe AD by up to five times. ⁴² A study in 75 high‐risk Korean infants and 12 controls (non‐atopic family history) found that higher TSLP expression at 2 months was associated with an increased likelihood of developing AD by age 24 months. ⁴³ Sato et al. examined various immunologic mediators in healthy children without AD aged 3–48 months and identified four skin biomarkers (hBD‐1, IL‐1RA, IL‐36γ, and S100A8/9) that predicted AD development within a year in high‐risk children. Additionally, elevated S100A8/9 levels in 8‐week‐old high‐risk infants with a wild‐type FLG genotype predicted AD by 6 or 12 months. ⁴⁴ Understanding biomarkers that predict AD in infancy could enhance prevention strategies for AD and related conditions. Future comprehensive studies are essential to determine the predictive value of these biomarkers and their clinical impact on preclinical AD and other atopic conditions (Table 1). Improved knowledge of pre‐AD changes will enable more targeted interventions to prevent or reduce AD and its comorbidities. ³⁷

TABLE 1.

Predictive biomarkers of atopic dermatitis development.

Category	Specific biomarker(s)	Predictive value
Skin Barrier Biomarkers	↓ Natural moisturizing factors (NMFs)	Lower in infants who later developed AD 38
	↓ Barrier‐related genes (LCE1F/2B/2C/2D, FLG, SCEL, CLDN8/11/23)	Downregulated prior to AD onset 39
	Ceramide profiles altered (e.g. ↓ long‐chain ceramides, NP‐Cer, ↑ NH‐Cer, NS‐Cer, AP‐Cer)	Reduced in AD skin; predictive of AD onset 40 , 41
	↓ Free phytosphingosine	76% prediction accuracy for AD at 2 months 41
Immune Biomarkers	↑ TARC/CCL17, ↑ IL‐8, IL‐18	Elevated levels in infancy predict moderate‐to‐severe AD by age 2 42
	↑ TSLP	Predicts AD at 24 months 43
	↑ hBD‐1, IL‐1RA, IL‐36γ, S100A8/9	Elevated levels predict AD development within a year 44
Gut Microbiota Biomarkers	↓ Gut microbiota diversity	Reduced diversity precedes AD onset 45
	↓ Bifidobacterium	Lower in infants who develop AD 45 , 46
	↑ Klebsiella	Higher in infants who develop allergies 46
	↑ Klebsiella/Bifidobacterium ratio	Predicts allergic diseases by age 3 46
	↑ Fecal calprotectin (>90%)	Predicts AD and asthma by age 6 47

5. MICROBIOTA AS BIOMARKERS OF FUTURE AD DEVELOPMENT

Comparative analyses of the gut microbiota between AD patients and healthy individuals have shown that alterations in the abundance of specific bacterial genera in early life possess prognostic significance.

In a prospective study involving 100 infants, researchers found that infants who developed AD within their first year exhibited lower gut microbiota diversity during the early months of life, with distinct differences in the abundance of specific bacterial taxa compared to infants without AD. ⁴⁵ Another prospective cohort study analyzed fecal samples and allergy status in 21 allergic infants (with eczema and/or allergic rhinitis) and 18 healthy controls at 18 months. The authors found that infants who later developed allergies had lower Bifidobacteria and higher Klebsiella levels at 3 months of age compared to infants who remained healthy. A higher Klebsiella/Bifidobacterium ratio at 3 months was linked to a greater risk of allergic diseases by age 3 years. ⁴⁶ The delayed colonization of Bifidobacteria, limited microbial diversity, and early enrichment of Escherichia coli and Klebsiella in the gastrointestinal tract of infants with AD during the early postnatal period may thus serve as a composite predictive biomarker for AD but would require further validation in other cohorts.

Other gut microbiome‐related indicators could also serve as prospective diagnostic biomarkers. A study found that infants with fecal calprotectin levels above 90% at 2 months of age had a significantly increased risk of developing AD and asthma at 6 years old, suggesting that high fecal calprotectin levels may be an early biomarker for the onset of AD ⁴⁷ (Table 1).

6. THE SKIN‐GUT‐IMMUNE AXIS

The interactions between the skin and gut microbiota and the immune system are complex and play a critical role in maintaining immune homeostasis in AD pathogenesis. The “gut‐skin axis” represents the complex network of interactions between gut and skin microbiota; the respective epithelial barriers and skin inflammation ⁴⁸ (Figure 1). Cutaneous dysbiosis, such as increased S. aureus proliferation on AD skin, triggers keratinocytes to release pro‐inflammatory cytokines (TSLP, IL‐25, IL‐33) into the systemic circulation, which reaches the gut, activating type 2 innate lymphocytes and Th2 cytokines in the intestinal barrier. This, in turn, alters gut permeability and microbiota composition, creating a feedback loop that maintains inflammation. ⁴⁹ , ⁵⁰ , ⁵¹

Intestinal immune cells, such as Th17 and dendritic cells, also migrate to the skin and influence inflammation, ⁸ , ⁵² , ⁵³ as seen in AD and psoriasis. Recent research indicates that gut microbiota affect skin barrier function and keratinocyte differentiation through pathways like aryl hydrocarbon (Aryl Hydrocarbon Receptor, AhR) and vitamin D receptors (Vitamin D Receptor, VDR). ⁵¹ , ⁵⁴

Gut microbiota metabolites, including SCFAs, tryptophan metabolites, and bile acids, play crucial immunoregulatory roles in the gut‐skin axis. SCFAs inhibit the release of pro‐inflammatory cytokines, thereby maintaining intestinal immune homeostasis and mitigating skin inflammation. ⁵⁵ Gut microbes metabolize tryptophan into AhR ligands that influence keratinocyte differentiation and skin barrier protein expression. ⁵⁶ While AhR regulates cell proliferation and differentiation, excessive activation due to metabolic disturbances can cause oxidative stress and disrupt vascular homeostasis. ⁵⁷ Other microbial metabolites like indole derivatives likewise activate AhR, affecting immune responses and skin barrier function. In AD patients, toxic metabolites like indole sulfate accumulate, disrupting skin vascular homeostasis and worsening neuroinflammation and itching. ⁵⁸ In AD patients, dysfunction of the AhR signaling pathway has been implicated in the disease's pathogenesis.

Secondary bile acids produced by microbial metabolism, such as lithocholic acid (LCA) and ω‐muricholic acid (ω‐MCA), can enhance the expression of antimicrobial peptides in the skin and respiratory epithelium, improve intestinal barrier function, and regulate the secretion of intestinal peptides, such as glucagon‐like peptide‐1 (GLP‐1). ⁵⁹ Bile acids primarily modulate immune responses via the farnesoid X receptor (FXR) and TGR5. ⁴⁹ Patients with AD often show changes in bile acid profiles, notably reduced ω‐muricholic acid, which weakens bile acid receptor signaling through FXR, negatively impacting Treg cell function. Conversely, a murine model demonstrated the utility of bile acid supplementation in reducing epidermal thickening and cutaneous inflammatory cytokines production, but this has not reached human trials yet. ⁶⁰

7. SKIN AND GUT MICROBIOTA CHANGES IN RESPONSE TO TREATMENT

Effective AD treatment not only reduces symptoms but also alters skin microbiota composition. After 84 days of moisturizer use, 72% of patients demonstrated clinical improvement, alongside restoration of skin microbiota composition to that which mirrored unaffected skin. This included increased microbial diversity, reduced Staphylococcus, and increased Stenotrophomonas abundance. ⁹ In studies focusing on pediatric AD, antibacterial and anti‐inflammatory treatments have been shown to enhance skin bacterial diversity. Topical application of corticosteroids (TCS) or calcineurin inhibitors (TCI) has also been observed to reduce the presence of S. aureus at lesion sites and increase microbial diversity. Post‐treatment, the bacterial composition at lesion sites tends to normalize, resembling that of non‐lesional skin, with microbial diversity returning to levels comparable to that of control skin. In a study of 51 AD patients, participants were divided into a S. aureus dominant group (AD.S) and a non‐dominant group (AD‐ND) based on S. aureus levels. The AD.S group had lower skin microbial diversity and higher disease severity (SCORAD scores) at baseline, but demonstrated increased microbial diversity and decreased S. aureus levels post‐treatment, ⁶¹ supporting the contribution of skin microbiota in AD severity.

Dupilumab, an anti‐IL‐4Rα monoclonal antibody, has demonstrated efficacy in attenuating disease severity and also facilitates the normalization of skin microbiota composition. ⁶² Specifically, it decreased the burden of S. aureus on the skin of AD patients following treatment and modified the fungal community structure by reducing the abundance of Malassezia and enhancing the diversity of non‐Malassezia yeasts. ⁴⁹ While direct evidence exists for dupilumab's effects, the impact of other biologics like IL‐31 inhibitors and JAK inhibitors on microbiota composition is still undocumented. IL‐31 blockade is thought to modulate the skin microbiome primarily through the attenuation of pruritus and scratch‐induced barrier disruption, thereby limiting S. aureus colonization. JAK inhibition exerts broader effects by simultaneously suppressing multiple cytokine pathways—including IL‐4, IL‐5, IL‐13, IL‐22, and IFN‐γ—that impair epithelial integrity and immune–microbial homeostasis, with the consequent restoration of healthy skin and gut microbial communities and epithelial barriers. ⁶²

The oral administration of probiotics, such as specific strains of Lactobacilli and Bifidobacteria, in patients with AD, was associated with a reduction in AD severity (SCORAD). ⁶³ Furthermore, clinical studies found that oral probiotic/prebiotic formulations, such as E3 preparations containing probiotics, prebiotics, and synbiotics, significantly augmented the diversity of gut microbiota in AD patients after an 8‐week treatment period. This was demonstrated by an increased abundance of beneficial bacteria, including Lactobacilli and Streptococci, alongside a reduction in potentially pathogenic bacteria such as Collinsella and Escherichia coli Shigella. ⁶⁴ The optimization of the microbial community structure was significantly correlated with improvements in clinical scores, such as the EASI. The purported mechanism underlying these observations is that the reconstituted microbiota is capable of producing increased levels of SCFAs and tryptophan metabolites, which in turn facilitate the differentiation of regulatory T cells and the secretion of anti‐inflammatory cytokines such as IL‐10 and TGF‐β. ⁶⁵ This process systematically inhibits the Th2 immune response shift. ⁶⁶

In a murine study, oral administration of Lactobacillus casei variety rhamnosus (LCR35) was found to suppress skin symptoms akin to AD and enhance the abundance of Bifidobacterium, Lactobacillus, Enterococcus, and Bacteroidetes fragilis in the gut, while reducing the prevalence of Clostridium species. This suggests that the treatment effectively altered the composition and diversity of the gut microbiota alongside clinical improvement.

Effective treatment strategies for AD can promote favorable alterations in both gut and skin microbiota, contributing to the restoration of microbial communities toward a composition resembling that of healthy individuals, such as increased bacterial diversity, promotion of beneficial bacterial colonization, inhibition of pathogenic bacterial growth, and enhancement of microbial metabolic function. These microbial‐level improvements are closely linked to the repair of barrier function and the restoration of immune homeostasis, underscoring the significant role of microbial ecological management as a marker of clinical response.

8. SKIN AND GUT MICROBIOTA AS FUTURE THERAPEUTICS

Microbial‐based intervention strategies represent a promising future direction for the treatment of AD, as they focus on restoring a healthy microbiota rather than merely suppressing immune responses. ⁶⁷ From a long‐term perspective, modulating the microbiota is anticipated to enhance patients' immune function and skin barrier integrity, thereby effectively managing AD symptoms and reducing the likelihood of disease recurrence.

Future treatment strategies focusing on microbiota replacement show promise. These approaches aim to harness targeted microbiota transplants, or local microbiota regulators, to achieve restoration of a “healthy” microbiota balance and pro‐immunomodulatory cytokine responses that promote skin recovery and maintain healthy skin barrier function. In novel trials, personalized microbiota transplants like fecal or washed microbiota transplantation have proven effective in “resetting” the microbiome. ⁶⁵ Preclinical studies using a canine AD model show that gut microbiota transplantation shifts the recipient's microbiota toward that of a healthy donor, with better colonization linked to clinical improvement. Successful transplants increased SCFA‐producing bacteria and alpha diversity, regulating the immune microenvironment at the gut‐dermal axis. ⁶⁸

Microbiome‐based therapies offer a promising approach for treating AD by focusing on restoring healthy microbiota rather than just suppressing immune responses. Significant progress has been made in skin microbiota transplantation research. ⁶⁶ Myles et al. showed that Roseomonas mucosa from healthy individuals improved AD‐like symptoms in mice by inhibiting S.aureus, enhancing skin barrier function, and activating immune responses. However, the same bacteria from AD patients worsened symptoms. Notably, live microbial transplantation is essential for therapeutic effectiveness. In 2018, the team conducted the first human clinical trial (BACTERiAD I/II) using localized live microbial transplantation on 10 adults and 5 children with atopic dermatitis. They applied healthy‐derived R. mucosa in increasing doses, resulting in significant reductions in SCORAD scores, itching, and S. aureus load. In the long term, regulating microbiota composition could improve immune function and skin barrier integrity, effectively managing AD symptoms and reducing recurrence risk. ⁶⁹ In randomized, placebo‐controlled Phase II clinical trials, the topical application of R. mucosa did not achieve the anticipated outcomes, despite demonstrating favorable safety profiles. Subsequent mechanistic investigations revealed that the therapeutic efficacy of R. mucosa is intricately associated with its nitrogen‐fixing capabilities and its synthesis of protective lipids, such as ceramides. This metabolic pathway is vulnerable to disruption by environmental pollutants, including diisocyanates, which can lead to decreased ceramide production and, consequently, reduced therapeutic effectiveness. ⁷⁰ These findings underscore the complex interactions between the microbiome and environmental factors, offering a partial explanation for the variability observed in clinical trial results. Furthermore, they suggest that the development of microbial therapies must thoroughly account for potential environmental influences on patient outcomes.

Besides R. mucosa, other symbiotic skin commensal bacteria also show therapeutic promise. Nakatsuji et al. found that coagulase‐negative staphylococci (CoNS) from healthy skin produce antimicrobial peptides that inhibit S. aureus, which are lacking in AD patients. Applying these bacteria from healthy skin in mouse models and human skin ex vivo significantly reduced S. aureus populations. ⁷¹ In 2021, the authors further developed a topical therapy using the naturally occurring skin commensals S. epidermidis S. hominis. Their study confirmed its safety and effectiveness in preclinical models and a phase I trial, showing it can inhibit S. aureus and reduce virulence on AD patients' skin, with some patients experiencing symptom improvement. ⁷² Further human trials are, however, still pending.

Emerging therapies focused on microbiota replacement show promise in restoring microbial balance and promoting immune responses for skin recovery. Techniques like targeted microbiota transplants or topical modulators aim to maintain healthy skin barriers. Recent trials have shown that personalized microbiota transplants, such as fecal or probiotic transplants, effectively “reset” the microbiome. ⁶³ Preclinical studies in canine AD models revealed that gut microbiota transplants can transform recipients' microbiota to resemble healthy donors, improving clinical outcomes. Successful transplants increased beneficial bacteria and diversity, enhancing the gut‐skin immune environment. Combining skin and gut microbiota interventions could lead to comprehensive therapies for restoring microbiota–immune balance in AD patients (Table 2).

TABLE 2.

Novel microbiota‐based therapeutic approaches for atopic dermatitis.

Therapeutic approach	Mechanism/Target	Key findings
Probiotics	Restore gut microbiota diversity, ↑ SCFAs, ↑ Tregs	↓ EASI and SCORAD; Improved inflammation markers 63 , 64 , 66
Combined gut–skin microbiota modulation	Integrate gut‐skin axis restoration and immune homeostasis	Improved barrier and immune regulation 65 , 67
Fecal microbiota transplantation (FMT)	Restore gut microbiome composition and immune modulation	↑ SCFA‐producing bacteria; Improved AD‐like symptoms 68
Skin Microbiota Transplantation	Competition inhibition of S. aureus, enhances skin barrier and restores immune balance	↓ SCORAD, ↓ S. aureus load, Improved symptoms 69 , 70
Topical commensal therapy	Produce antimicrobial peptides, restore microbial balance	Reduced S. aureus colonization, Improved skin barrier 71 , 72
Biologics	Inhibit IL‐4, IL‐13, IL‐31	Attenuate disease severity, Facilitate the normalization of skin microbiota composition Reduces S.aureus and Malassezia 49 , 62
JAK Inhibitors	Suppress multiple cytokine pathways: IL‐4, IL‐5, IL‐13, IL‐22, and IFN‐γ	Restore epithelial and microbial homeostasis 62

9. CONCLUSIONS

The skin and gut microbiota play central roles in the pathophysiology of AD through their interactions with epithelial barriers and the immune system. Evidence indicates that microbial dysbiosis—characterized by reduced diversity, loss of beneficial commensals, and expansion of pathogenic taxa—contributes to disease onset, persistence, and severity. Conversely, emerging data suggest that interventions capable of restoring microbial balance may offer therapeutic benefit and promote long‐term disease control. Despite substantial advancements in identifying microbial signatures linked to AD, significant challenges persist. Current research predominantly emphasizes the correlation between microbial composition and the severity of AD, yet the underlying functional mechanisms remain inadequately understood. To effectively translate microbiota research into clinical interventions, it is imperative to move beyond mere correlations and explore the functional mechanisms, as well as to identify reliable microbial biomarkers, which are crucial for the development of targeted microbial therapies. Furthermore, research must address and overcome numerous challenges, including the impact of environmental factors, such as household microbial sharing, and the considerable inter‐individual variations in microbial composition that occur following antibiotic treatment. ⁷³ Elucidating the functional roles of the microbiota is instrumental not only in uncovering the pathogenesis of AD but also in enhancing our understanding and prevention of its comorbidities, such as food and respiratory allergies. Early life microbiota data may serve as predictive markers for the development of AD, thereby facilitating early intervention and prevention strategies. In addition, microbiota‐based personalized treatment approaches should incorporate host genetics, immune status, and environmental factors to realize the goals of precision medicine.

In conclusion, the integration of microbiota modulation into conventional treatment paradigms represents a promising frontier. Nevertheless, achieving this objective necessitates further longitudinal studies and mechanistic investigations to validate the therapeutic efficacy of microbiota and to determine the optimal timing for interventions.

AUTHOR CONTRIBUTIONS

Binbin Hou: Writing – original draft; investigation; software. Huijia Shao: Writing – original draft. Donglin Yuan: Resources. Elizabeth Huiwen Tham: Writing – review and editing; funding acquisition; investigation; project administration; supervision.

FUNDING INFORMATION

Elizabeth Huiwen Tham is supported by the National Medical Research Council (NMRC) Clinician–Scientist Award (CSA) MOH‐001415.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

Hou B, Shao H, Yuan D, Tham EH. Skin and gut microbiome in atopic dermatitis: Mechanisms and therapeutic opportunities. Pediatr Allergy Immunol. 2025;36:e70265. doi: 10.1111/pai.70265