AD stands as a significant clinical and public health concern worldwide, characterized by chronic inflammation, intense itching, and a compromised skin barrier (9). The global prevalence of AD has been increasing over the past decades, affecting over 20% of children and 10% of adults worldwide (10). The 2019 Global Burden of Diseases data shows 171 million cases of AD worldwide, with a 28.6% increase in prevalence since 1990 (133 million) and a strong association with higher socioeconomic development (11). This rise not only highlights the pressing need for effective management strategies but also underscores the multifactorial nature of AD, influenced by genetic, immunological, psychological, and environmental factors like the skin microbiome (12).

Central to this discussion on AD pathology is the role of S. aureus. While S. aureus often coexists harmlessly with its host, its colonization is not just prevalent in individuals with AD but also plays a pivotal role in exacerbating the condition. Numerous studies have revealed a significantly higher rate of S. aureus colonization in AD patients compared to healthy individuals (13–15). The primary source of S. aureus contamination in AD patients is self-colonization from the nasal passages (11), spreading to the skin through direct contact, especially in areas with a compromised skin barrier. Research indicates that up to 70–90% of AD patients are colonized by S. aureus on lesional skin, a strong contrast to 20–30% in healthy individuals colonized by S. aureus in the nose (16, 17). This heightened prevalence is not limited to lesional skin; non-lesional skin of AD patients also exhibits higher colonization rates (17, 18). AD is more prevalent and severe in children, particularly infants and young children aged 5–9 years, while adults experience a lower prevalence and more localized symptoms as they age. In pediatric AD patients, the prevalence of S. aureus nasal colonization ranges from 46.4 to 82.2%, compared to 19.4 to 34.1% in the control group, while in adults with AD, nasal colonization rates are between 62.0 and 69.8% (19). For skin colonization, the rate of S. aureus increases with age in AD patients, with colonization rates of 50% in infants, 80% in children, and 87.5% in adults for acute lesions, and 18.5% in infants, 41.8% in children, and 48.9% in adults for chronic lesions (20). This increased burden of S. aureus correlates with both skin microbiome dysbiosis and heightened disease severity during flares (13, 14).

The impact of S. aureus colonization on AD symptoms is profound and multifaceted, involving the direct effects of bacterial colonization, the impact of toxins produced by S. aureus, and the induction of inflammatory responses that worsen AD symptoms (Figure 1). The abnormal proliferation of S. aureus in AD leads to dysbiosis of the skin microbiome, significantly reducing overall microbial diversity and weakening the skin barrier. This increases susceptibility to irritants, allergens, and pathogens (21), disrupts the skin immune response, and exacerbates inflammation (22). Recent studies reveal that early-onset barrier dysfunction triggers immune responses to commensal organisms, with S. aureus forming antimicrobial-resistant biofilms that influence keratinocyte biology and contribute to AD-associated inflammation (23). In addition, IL-9 is differentially produced by skin-tropic and extracutaneous memory T cells in response to various allergens like house dust mites and staphylococcal enterotoxin B, enabling patient stratification based on allergen sensitization and highlighting the key role of S. aureus in immune polarization in AD patients (24). Genetic mutations, such as those in the filaggrin gene, impair the skin barrier and create a favorable environment for S. aureus colonization (25). Psychological factors like stress impose unneglectable influences on the skin’s immune response, as stress-induced neuropeptide mediators affect immune and skin cells, increasing mast cell activity and nerve interactions (26, 27). Yet, direct studies specifically linking stress to particular strains of S. aureus are limited. The altered skin microenvironment in AD, including reduced antimicrobial peptide production (28) and increased skin pH, further supports S. aureus proliferation in a pH-dependent manner (29).

S. aureus binds more efficiently to AD skin due to specific receptors and binding proteins like fibronectin-and fibrinogen-binding proteins, which are upregulated in AD’s inflammatory milieu (30, 31). Once colonized, S. aureus exacerbates AD through the production of virulence factors (VF) that act as superantigens, inducing a disproportionate immune response and increased inflammation (30, 32). S. aureus also secretes enzymes like proteases and lipases that degrade crucial skin barrier proteins, increasing permeability and facilitating the entry of other allergens and pathogens (33, 34). Furthermore, the ability of S. aureus to form biofilms complicates eradication, as biofilms resist antimicrobial agents and host immune responses, making colonization persistent (35). These interactions highlight the need for targeted therapies addressing both the pathogen and immune dysregulation to effectively manage AD.

The clinical implications of S. aureus in AD are significantly influenced by its strain diversity. Previous research has shown significant differences between S. aureus strains from AD patients and healthy individuals (14, 36, 37), indicating that AD-associated strains have a selective advantage in inflamed skin. Additionally, studies further revealed a high degree of strain diversity of S. aureus within AD (7, 8), with specific strains or clonal complexes (CC) of S. aureus like CC1 being more frequently associated with AD (36, 38), highlighting the significance of strain diversity.

The diversity of S. aureus strains complicates the management of AD in several ways.

These results underscore the critical importance of strain-level variation in S. aureus, highlighting the need for precise and individualized approaches in managing AD. Furthermore, these findings emphasize the necessity of considering geographical scale when examining the diversification mechanisms of S. aureus strains. Most observed differences have been region-specific, suggesting these adaptations are spontaneous rather than indicative of a general distinction between AD and HE strains. The broader question of whether these genomic differences and adaptations occur locally or globally remains unresolved. Additionally, a recent study revealed that patient co-factors such as age, sex, and race also significantly impact the variation (5). This raises relevant questions: to what extent do health status, geographical location/scale, and patient co-factors influence S. aureus diversification? Which factors are more critical? Furthermore, given the frequent interactions between humans, livestock, and pets, could these animals serve as hotspots for microevolutionary changes? These questions underscore the complex interplay of factors affecting S. aureus diversification.

Overall, around 15–20% of S. aureus genome is characterized by the presence of numerous mobile genetic elements such as plasmids, transposons, and bacteriophages (45). This genomic plasticity could be a key driver of its pathogenic potential. These MGEs facilitate genetic exchanges, conferring new metabolic capabilities and enabling the rapid acquisition of genes encoding ABRs and VFs. Such genomic adaptability allows S. aureus to swiftly respond to environmental selective pressures, making it a formidable pathogen.

Bacteriophages, known for their host specificity and diverse functional gene repertoire (46), significantly influence bacterial evolution. Embedded within the bacterial genome, prophages are bacteriophage DNA that can be lytic or lysogenic. In particular, lysogenic prophages, dormant within the host genome, could introduce new genes, enhance bacterial metabolic capabilities, and potentially increase pathogenicity, leading to important clinical implications (47). Research indicates that the primary mechanism of horizontal gene transfer in S. aureus is bacteriophage-mediated transduction (48). Therefore, prophages play a pivotal role in the diversification and pathogenicity of S. aureus, significantly influencing its genetic diversity, virulence, and ABR (57). For example, prophages in S. aureus sequence type 398 carry a set of genes encoding VFs, including a tyrosine recombinase linked to biofilm-associated staphylococcal infections, an ATP-dependent Clp protease, and an autolysin Atl involved in mediating adhesion to host tissue (49). Despite advances in understanding S. aureus genetic diversity, the extent to which prophages contribute to this genetic diversity and their link to AD severity remains underexplored. Therefore, profiling the prophages in S. aureus strains is crucial for understanding the relationship between genomic composition, phage-driven adaptation, and resultant phenotypic outcomes of S. aureus strains.

AD is a prevalent and complex condition posing a significant global public health challenge. The diverse strains of S. aureus in AD, varying in virulence, ABR, and metabolic potential, call for advanced research methodologies and innovative treatment strategies.

Traditional treatments for AD, such as systemic glucocorticosteroids and ciclosporin, remain effective for more severe cases. In addition, therapies like topical or systemic antibiotics, topical corticosteroids, calcineurin inhibitors, and supportive options like bleach baths or antiseptics washes are often recommended. However, frequent use of antiseptics can disrupt the balance of the skin’s microbial community, thus should be limited to specific cases and combined with strategies aimed at restoring and maintaining a healthy skin microbiome. Meanwhile, new therapies have been introduced, including biologics like dupilumab and tralokinumab, along with Janus kinase inhibitors such as abrocitinib, baricitinib, and upadacitinib, which offer targeted immunomodulatory effects (50). Addressing psychological stress through behavioral therapy and psychopharmacologic agents (e.g., anxiolytics) could be an additional measure.

Whole-genome sequencing (WGS) and machine learning (ML) technologies offer unprecedented opportunities to decipher the subtle differences between S. aureus strains from AD and HE (51, 52). WGS has revolutionized our understanding of the genetic diversity of S. aureus, allowing for the detailed characterization of strain-specific markers and the identification of VF and ABR genes (53). When coupled with ML algorithms, WGS data can be analyzed to predict strain pathogenicity, ABR profiles, and potential VFs with high accuracy. This integrative approach facilitates the identification of novel biomarkers for S. aureus strains that are specifically associated with AD severity, enabling the development of more advanced diagnostic tools and personalized treatment approaches. Additionally, high-throughput isolation techniques are needed, as current molecular data may lack the necessary resolution for strain-level analyses. Moreover, creating and studying mutants can offer valuable insights into gene functions by allowing researchers to observe the effects of specific gene deletions or modifications, which can uncover potential targets for therapeutic intervention. To gain a systematic perspective, a global approach to characterizing strain variation and S. aureus’s role in AD across different populations and regions can provide valuable insights. Furthermore, alternative therapies like phage therapy and probiotics show promise in restoring skin microbiome balance (54–56) and reducing the risk of dysbiosis associated with broad-spectrum antibiotics. By employing these advanced methods, we can potentially uncover new therapeutic targets or diagnostic markers, facilitating personalized treatment approaches and the development of targeted therapies.