Abstract
INTRODUCTION
The microbial community residing on human skin consists of a diverse array of bacteria, viruses, fungi, and archaea that engage in active interplay with the host. 1 Dysbiosis of this microbial community is a hallmark of inflammatory skin diseases, particularly atopic dermatitis (AD), where a dominance of Staphylococcus aureus is frequently observed. However, the role of other staphylococci, most notably Staphylococcus epidermidis, in AD pathogenesis and maintenance of skin health is increasingly recognized as being multifaceted and critical. When accounting for all skin environments, such as hair follicles and sebaceous glands, the cumulative habitable space for microbes exceeds 30 m2, ranking it among the largest epithelial interfaces with microorganisms. 2 Bacterial populations occupy every skin layer, from the outermost stratum corneum to deeper dermal regions. 1 Initial microbial colonization during early life influences proper skin maturation3,4 and regulates gene activity. 5 Additionally, these microbes prevent pathogen invasion through processes known as colonization resistance, 6 which involve nutrient competition, antimicrobial peptide (AMP) production, and immune system modulation. 7 Overall, microbial preservation of skin barrier function is crucial for maintaining health and preventing disease, 7 a balance that is disrupted in AD.
S. epidermidis, a coagulase-negative bacterium, is a prevalent skin resident detected across most body sites via culturing and metagenomic studies. 8 Early classification relied on coagulase activity to differentiate pathogenic S. aureus from other staphylococci. 8 While S. epidermidis was once considered a general representative of coagulase-negative staphylococci (CoNS), modern research reveals significant genetic and functional diversity within this group.9,10 Although often viewed as a harmless or even advantageous skin commensal involved in barrier formation and pathogen suppression, emerging data indicate that S. epidermidis exhibits a more complex ecological role than once assumed, 11 especially in disease states like AD. Historically labeled an “accidental pathogen” due to infections arising from resident strains,12,13 S. epidermidis is now a leading cause of implant-related infections in the United States, with treatment-resistant biofilms posing significant health care challenges. 14 Moreover, the worldwide dissemination of three nearly pan-resistant S. epidermidis strains heightens clinical alarm. 15 However, these characterizations oversimplify a highly adaptable organism. This review explores how to reconcile the extensive diversity of S. epidermidis strains with its dual role in the specific context of AD, where it can function as both a beneficial commensal and a potential pathobiont, influencing disease severity and offering novel therapeutic avenues.
THE PATHOBIONT: S. Epidermidis IN AD PATHOGENESIS
In the dysbiotic environment of AD, certain strains of S. epidermidis can transition from a commensal to a pathobiont, directly contributing to disease pathology through specific virulence mechanisms. Beyond its role as a harmless resident, S. epidermidis frequently adopts a dual identity as an opportunistic pathogen. 11 Variations in its prevalence have been linked to skin conditions such as AD, 16 dandruff,17,18 seborrheic dermatitis, and rosacea.19,20 While these associations in other dermatoses highlight its potential for pathogenicity, this review will focus specifically on its direct mechanistic role in AD. Moving beyond general microbial imbalance, this section explores S. epidermidis’s role in AD, virulence factor expression, and the broader health consequences of its dual nature.
Disease Manifestations and Virulence in AD
A particularly troubling trait of S. epidermidis is its tendency to trigger opportunistic infections, often originating from resident strains. 21 While it is a major culprit in implant-related infections, prosthetic valve endocarditis, and pacemaker infections,14,22 posing severe risks to patients and burdening health care systems and its role in cutaneous inflammation is of primary relevance to AD. Additionally, S. epidermidis accounts for 30%–40% of hospital-acquired bloodstream infections, typically arising from biofilm-laden catheter infections that spread systemically. 22 These infections are challenging to manage and may result in life-threatening conditions like sepsis, septic shock, or endocarditis. 23 In premature infants, S. epidermidis bloodstream infections are a leading cause of late-onset sepsis, potentially causing lasting neurological damage or cerebral palsy. 24 This systemic pathogenic potential underscores the capacity of specific lineages to cause harm, a trait that can be mirrored in its contribution to AD pathology when the skin barrier is compromised. Overall, it remains a significant threat, especially to immunocompromised individuals and those with inflammatory skin diseases like AD.
Compared to S. aureus, S. epidermidis possesses a limited set of virulence factors, many of which serve dual roles in colonization and infection, such as proteases, lipases, and phenol-soluble modulins (PSMs). 21 While most strains lack potent toxins, enterotoxin genes were recently detected in nine S. epidermidis isolates. 25 Genomic studies have uncovered a broader array of virulence-related genes (eg, those involved in biofilm formation, adhesion, hemolysis, and enzymatic activity) than previously recognized, likely due to the bacterium’s genetic adaptability 26 (Table 1).
Dual Roles of Staphylococcus epidermidis: Key Commensal Benefits and Pathogenic Threats
MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; PIA, polysaccharide intracellular adhesin.
The pathogenic potential of S. epidermidis appears context-dependent. 27 Unlike S. aureus, where hypervirulent clonal lineages exist, 28 no single S. epidermidis lineage consistently exhibits heightened pathogenicity. 29 A 2020 metagenomic study of healthy skin isolates found that virulence genes were unevenly distributed among individuals and skin regions. 27 The same study revealed frequent horizontal gene transfer, with numerous plasmid and bacteriophage sequences identified in these isolates. 27 Many plasmids harbored multiple resistance genes and were widespread across body sites, suggesting active gene exchange during colonization and a possible reservoir for virulence or resistance traits even in healthy individuals. 27
Recent studies (2020 30 and 2021 31 ) have elucidated the critical role of the cysteine protease EcpA in S. epidermidis pathogenicity in AD. EcpA degrades critical skin proteins, including desmoglein-1 (a corneodesmosome component) and the AMP LL-37. 31 Elevated ecpA expression correlated with S. epidermidis abundance in severe AD lesions, linking bacterial presence to disease mechanisms. 31 EcpA also exacerbates skin damage in Netherton syndrome, where a spink5 gene mutation disrupts protease regulation, impairing the epidermal barrier. 30 In both conditions, S. epidermidis levels and ecpA transcription were tightly linked. 30 Mouse studies showed that high EcpA-producing S. epidermidis strains induced skin damage akin to S. aureus staphopain-producing strains, 28 confirming EcpA’s role in these disorders. However, the reason for variable EcpA expression among S. epidermidis strains, despite universal ecpA gene presence, remains unclear. 31
Biofilm Production and Implications in AD
Biofilm formation represents another key mechanism by which S. epidermidis may exacerbate AD. The mechanisms governing S. epidermidis biofilm formation have been thoroughly examined in prior reviews.22,32 Key to this process is the synthesis of polysaccharide intracellular adhesin (PIA or poly-N-acetylglucosamine [PNAG]) by the icaADBC operon. 33 PIA consists of β-1,6-linked N-acetylglucosamine polymers and shields established biofilms from immune attacks, antibiotics, and mechanical stress.22,34,35 While PIA may theoretically help retain moisture on skin surfaces, this hypothesis remains untested. 36 The ica locus has been inconsistently linked to distinguishing pathogenic from commensal strains. 37 Clinical isolates, including those from high-shear environments like catheters, often carry icaADBC but exhibit variable PIA production. 34 Intriguingly, over half of such isolates form biofilms via ica-independent pathways, with some strains alternating between polysaccharide and protein-based biofilm formation. 34 Notably, most S. epidermidis from healthy skin lack the ica locus, and its presence appears to reduce fitness during skin colonization. 38
As an alternative, S. epidermidis constructs protein-rich biofilms using surface proteins like Aap. Initial surface attachment relies on the A domain,33,39 while biofilm maturation requires 1 SepA protease cleavage of the A domain to expose the B domain 40 and 2 zinc-dependent “zippering” of B-domain G5 repeats to form a stable matrix. 41 The S. aureus protein SasG employs an analogous zinc-mediated mechanism. Clinically, S. epidermidis and S. aureus can co-assemble biofilms via SasG–Aap interactions, hinting at collaborative roles in infections, though their skin biofilm dynamics remain uncertain. 42
While S. aureus exacerbates AD severity, some patients show S. epidermidis dominance.16,43,44 Staphylococcal biofilms localize specifically to lesional sweat ducts in AD, with S. epidermidis isolates from these sites exhibiting robust biofilm production. These biofilms may obstruct sweat ducts and worsen symptoms by promoting itch, though the underlying mechanisms need clarification.45,46
A 2021 study of 400 pediatric patients in the MPAACH cohort, the first U.S. longitudinal study exploring AD-asthma progression, used electron microscopy to detect staphylococcal biofilms on skin cells in most samples. Co-colonization with S. aureus and S. epidermidis occurred in 19% of cases, with synergistic biofilm growth observed in vitro. Such cooperativity may influence disease severity and treatment resistance, though further research is needed. 47
Biofilms likely represent only one phase of S. epidermidis colonization in AD, as dispersal, triggered by activation of the agr quorum sensing system, 48 completes the biofilm cycle. 22 This suggests a dynamic equilibrium: agr-expressing cells colonize niches like sweat ducts, suppress agr to form biofilms, then reactivate agr to disperse, and spread. Future studies may reveal how these regulatory shifts impact AD progression.
THE PROTECTOR: ANTIMICROBIAL STRATEGIES OF S. Epidermidis AND THEIR RELEVANCE TO AD
In contrast to its pathogenic potential, S. epidermidis also employs a repertoire of strategies to suppress S. aureus, a primary driver of AD inflammation, positioning it as a key player in maintaining cutaneous homeostasis. S. epidermidis engages in competitive interactions with both pathogenic microbes and resident skin flora to establish ecological dominance. This section examines these competitive dynamics and their consequences for cutaneous health, with a focus on their relevance to AD.
Quorum Sensing Disruption
A key competitive strategy among CoNS involves interference with the conserved agr quorum sensing system. 49 While best characterized in S. aureus, where it controls virulence expression and facilitates skin infection, 50 research has primarily focused on how CoNS like S. epidermidis suppress S. aureus virulence through interspecies competition.51-53 S. epidermidis produces autoinducing peptide I, the first identified agr inhibitor in staphylococci, potentially explaining its dominance over S. aureus on healthy skin. 54
However, the agr system also governs virulence factors in S. epidermidis itself. It regulates the cysteine protease EcpA (discussed previously) while simultaneously controlling colonization mediators like the Geh lipase, PSMs, and SepA/Esp proteases. 55 Functional agr signaling proved essential for S. epidermidis colonization in ex vivo models, indicating dual roles in both commensalism and potential pathogenicity. 55
Recent work revealed that Staphylococcus hominis, another skin commensal, produces an AIP that inhibits S. epidermidis agr activity and reduces EcpA production. 31 Such interspecies quenching may explain S. epidermidis overgrowth in AD lesions, where reduced CoNS diversity diminishes inhibitory AIP diversity. 31
Antimicrobial Warfare
The healthy skin microbiome features numerous antimicrobial-producing CoNS strains, and their depletion correlates with S. aureus colonization. Though metabolically costly, bacteriocin production represents a critical competitive strategy.56-58 While most bacteriocins target specific organisms, some S. epidermidis strains produce broad-spectrum antimicrobials, including epidermicin (active against S. aureus and vancomycin-resistant enterococci) and lantibiotics like nukacin IVK45 and epilancin 15X. These compounds may shape microbial community structure, though their ecological distribution requires further study.59-61
S. epidermidis also employs non-bacteriocin strategies against S. aureus. Certain strains synthesize 6-thioguanine, a purine analog that inhibits S. aureus growth, purine biosynthesis, and virulence while preventing skin necrosis. However, this biosynthetic pathway appears rare among S. epidermidis strains compared to other CoNS, suggesting it represents a secondary competitive mechanism. 62
Nasal Niche Competition Against S. aureus
While S. aureus typically colonizes the anterior nares without symptoms,51,52 such colonization often precedes infections at distant skin sites.52,53 Conversely, nasal S. epidermidis dominance correlates with reduced pathogen abundance, 54 mirroring its skin protective role. One competitive mechanism involves S. epidermidis secretion of the Esp protease, which dismantles S. aureus biofilms by cleaving key matrix proteins (FnbA, Efb, and Spa). 55 However, the potential counter role of S. aureus’s homologous V8 protease remains unexplored. 56
Additional strategies include competition for binding sites on nasal epithelial cell debris (squames) through homologous surface proteins Aap (S. epidermidis) and SasG (S. aureus), though their direct competitive interaction requires clarification. 57 Furthermore, S. epidermidis stimulates nasal keratinocytes to produce AMPs (LL-37 and hBD3) that target S. aureus, reinforcing its role in nasal microbial defense. 54
Therapeutic Potential of S. epidermidis in AD
The dual nature of S. epidermidis in AD presents a unique therapeutic opportunity: to selectively harness its protective strains while inhibiting its pathogenic ones. Growing evidence suggests S. epidermidis could serve as a valuable biotherapeutic agent for managing dysbiotic skin conditions like AD and psoriasis.47,58,59 Current approaches include:
Live probiotic administration Prebiotic supplementation to favor beneficial strains Postbiotic delivery of microbial derivatives
60
Critical to clinical success is selecting strains whose anti-inflammatory benefits outweigh potential virulence risks. Early trials demonstrate promise-facial application of lyophilized S. epidermidis significantly improved skin hydration and lipid content versus controls. 61 Strains producing Esp protease could potentially replace mupirocin for nasal S. aureus decolonization, provided their growth and pathogenicity are controlled.61,62
Innovative strategies like nutrient auxotrophy (eg, alanine-dependent engineered strains) enable precise modulation of bacterial colonization without antibiotic markers.
62
Combination therapies also show potential, particularly for AD:
A topical mix of S. epidermidis and S. hominis significantly reduced S. aureus burden in AD patients within 24 hours,
45
demonstrating a direct therapeutic application. Coadministration with Staphylococcus cohnii improved disease metrics in S. aureus-infected mice. Lactobacillus brevis (though not a skin native) enhanced S. epidermidis recolonization and barrier function in xerosis patients.
63
While these findings are encouraging, significant challenges remain. Comprehensive safety assessments must address, especially for application on compromised AD skin:
Innate and acquired virulence factors Pervasive methicillin resistance Other antibiotic resistance patterns
Further research is needed to fully characterize risks before clinical implementation.
CONCLUSION
This review synthesizes the complex, strain-specific duality of S. epidermidis in AD. It can act as a pathobiont, directly contributing to AD pathology through virulence factors like the EcpA protease and lesional biofilms, or as a protector, engaging in microbial antagonism to suppress S. aureus and support skin barrier function. The key take-home message is that the net impact of S. epidermidis in AD is context-dependent, determined by the specific strains present, the host’s skin microenvironment, and the diversity of the surrounding microbial community. This nuanced understanding underscores a critical clinical implication: future AD management strategies must move beyond simply eradicating staphylococci and toward selectively modulating the skin microbiome. The promising therapeutic application of protective CoNS consortia highlights this paradigm shift. However, significant knowledge gaps remain. A major challenge is the reliable identification of “safe” beneficial strains versus those with pathogenic potential for therapeutic use. Future research must focus on developing robust diagnostic tools to characterize the functional profile of a patient’s S. epidermidis population and on establishing safety criteria for live biotherapeutic products in the context of compromised AD skin.