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. 2025 May 4;5(4):100377. doi: 10.1016/j.xjidi.2025.100377

The Role of Skin Dysbiosis and Quorum Sensing in Atopic Dermatitis

Hiroki Okamoto 1, Shuo Li 2, Yuumi Nakamura 1,2,∗
PMCID: PMC12162026  PMID: 40510906

Abstract

The skin microbiome plays a crucial role in the pathogenesis of atopic dermatitis (AD), a chronic inflammatory skin disorder strongly associated with microbial dysbiosis, particularly Staphylococcus aureus colonization. However, the mechanisms linking S aureus to AD remain insufficiently understood. This review explores the impact of the quorum-sensing (QS) system, particularly the accessory gene regulator Agr, in AD development and progression. By examining key microbial–host interactions, we provide insights into how QS influences skin inflammation and dysbiosis. Furthermore, we discuss the potential of microbiome-targeted therapeutic strategies to mitigate or prevent AD, highlighting their implications for future research and clinical applications.

Keywords: Atopic dermatitis, Skin microbiome, Staphylococcus aureus, Quorum sensing

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by severe itching and recurring eczema and is mainly caused by skin barrier dysfunction and allergic responses. It affects approximately 20% of children and 10% of adults in developed countries, with increasing global prevalence (Odhiambo et al, 2009; Silverberg and Hanifin, 2013). AD presents significant psychosocial challenges and is frequently associated with other allergic conditions, including asthma, a progression termed the ‘atopic march’ (Spergel and Paller, 2003; Williams, 2000).

AD is primarily driven by a T helper 2 (Th2)–dominant immune response, marked by elevated levels of IL-4, IL-13, and IL-31, which contribute to allergic inflammation and pruritus (Sonkoly et al, 2006). In addition, impairment of the epidermal barrier, primarily due to reduced filaggrin (FLG) expression and increased transepidermal water loss, facilitates the penetration of allergens, further exacerbating inflammation (Kim et al, 2008; Werfel et al, 2016). Recent advances in immunological research have provided significant insights into the pathophysiology of AD, leading to the development of targeted therapies that have revolutionized treatment strategies. However, despite these therapeutic advancements, there is still no definitive cure or preventive measure for AD. This highlights the need for a more comprehensive understanding of the disease, particularly regarding the skin microenvironment and its interactions with immune responses. Variations in lipid balance, pH, and moisture content across different skin regions (ie, sebaceous, moist, and dry regions) influence the microbial composition (Grice et al, 2009; Zeeuwen et al, 2013). Approximately 40 strains and 106 bacteria per cm2 inhabit the skin, with composition influenced by host health, sampling site, age, and sex (Belkaid and Segre, 2014; Gallo, 2017; Grice et al, 2009; Grice and Segre, 2011). The major genera include Staphylococcus, Corynebacterium, Cutibacterium, Micrococcus, and Acinetobacter, with skin microbiome diversity being lower than that of the gut microbiome (Scharschmidt and Fischbach, 2013). Certain bacterial taxa, particularly those within the phylum Actinobacteria, have adapted to thrive on dry, nutrient-poor mammalian skin surfaces. Some species possess lipid-modifying enzymes that allow them to utilize skin lipids as energy sources (Kengmo Tchoupa et al, 2023). Although most microorganisms are considered harmless or beneficial to the host, certain bacteria can exhibit pathogenicity under specific conditions (Cogen et al, 2008). For instance, S aureus is a harmless commensal bacterium found on the skin of 10–20% of healthy individuals (Scharschmidt and Fischbach, 2013). However, it is present on the lesional skin of nearly 90% of patients with AD, and its prevalence significantly increases during acute exacerbations of the condition (Kong et al, 2012; Leyden et al, 1974). Although S aureus is rarely found in large numbers on healthy skin, it becomes more abundant in AD lesions, contributing to disease pathogenesis. This review examines the role of skin microbiota in the pathogenesis of AD, with a particular focus on S aureus.

The Role of Skin Microbiota in Human Skin Immunity

The initial microbial colonization of an infant's skin is influenced by the delivery route. Infants born through vaginal delivery acquire a skin microbiota similar to the maternal vaginal microbiota, whereas those delivered through cesarean section have skin microbiota that resemble the maternal (Mueller et al, 2015). This early colonization can activate the host immune system, although the effectiveness of maternal–child microbial seeding interventions for cesarean delivery remains controversial (Hourigan et al, 2022). In mouse studies, the colonization of S epidermidis, a representative normal skin microbiota species, recruits CD4+ regulatory T cells to the skin during the neonatal period, promoting tolerance to resident microbes (Naik et al, 2015; Scharschmidt et al, 2015). As individuals grow, the skin microbiota undergoes significant changes, particularly in the seborrheic areas, as sebaceous glands develop during puberty (Oh et al, 2012; Si et al, 2015). Once adulthood is reached, the skin microbiota stabilizes and remains consistent throughout the year (Oh et al, 2016). The skin microbiota includes resident microorganisms that form the core microbiome and transient microorganisms that are influenced by the external environment and disappear within hours to days (Dréno et al, 2016). The core microbiome coexists symbiotically with the host and plays a crucial role in maintaining skin homeostasis (Naik et al, 2015; Sanchez Rodriguez et al, 2014). Epidermal keratinocytes produce antimicrobial peptides (AMPs) that protect them from pathogens. Key AMPs, such as cathelicidin and β-defensin, exhibit broad-spectrum antimicrobial activity (Gallo and Hooper, 2012; Nagy et al, 2006; Zipperer et al, 2016).

Healthy skin remains infection free despite low AMP expression, largely because of the resident microbiota that produces antimicrobial substances, creating chemical barriers on the skin. Certain bacteria also regulate AMPs, enhancing neutrophil migration and function against pathogens, such as S aureus (Pasparakis et al, 2014; Zhang et al, 2015). S epidermidis, a common colonizer of the human skin, induces IL-1α expression while suppressing IL-1 receptor antagonist expression in the epidermis (Naik et al, 2012). This modulation promotes the production of IL-17A and IFNγ by skin resident CD8+ T cells, thereby enhancing the innate immune response against pathogens (Naik et al, 2015). These interactions between the host and microbiota are crucial for barrier maturation and wound healing (Di Domizio et al, 2020; Uberoi et al, 2021), thereby supporting overall skin health and immunity (Naik et al, 2012).

Staphylococcus and Skin Microbiome in AD

Dysbiosis, an imbalance in the microbial composition, is prevalent in inflammatory skin diseases (Catinean et al, 2019). It is characterized by reduced microbial diversity, often due to the dominance of specific species, along with alterations in the overall microbial composition. The pathogenesis of AD is now understood to be more complex, particularly the relationship between skin dysbiosis and S aureus colonization (Paller et al, 2019). The presence of S aureus in the skin lesions of patients with AD was first noted in the 1960s (Selwyn, 1963). The skin microbiota of individuals with AD typically shows decreased diversity, a lack of certain commensal bacteria, and an increase in the genus Staphylococcus (Kong et al, 2012; Tay et al, 2021). Longitudinal studies using 16S ribosomal RNA gene sequencing of pediatric AD skin samples have demonstrated that during flare ups, the abundance of S aureus significantly increases, accompanied by an increase in the skin commensal S epidermidis (Byrd et al, 2017; Kong et al, 2012). The prevalence of S aureus correlates with disease severity, and its density increases as AD worsens (Tauber et al, 2016; Totté et al, 2016). However, microbiome analysis data in AD cannot distinguish whether dysbiosis is merely a consequence of the disease or one of its causative factors. Therefore, the accessory gene regulator (Agr) quorum-sensing (QS) system has been investigated as a target to analyze how the increase of S aureus exacerbates AD skin pathology.

The Agr-QS System of S aureus in AD

The QS system is the ability of bacteria to detect the cell population density and adjust gene expressions (Rutherford and Bassler, 2012). Many bacteria secrete chemical signaling molecules called autoinducers. As a bacterial population grows, and the surrounding concentration of autoinducers reaches a specific threshold concentration, bacteria change and modify their behavior by altering the expression of various genes. S aureus possesses an autoregulatory operon, Agr system, as a QS function (Novick and Geisinger, 2008).

The QS mechanism in S aureus relies on the autoregulatory agr operon, which comprises 4 genes: agrA, agrB, agrC, and agrD (Novick and Geisinger, 2008). AgrA acts as an extracellular transcription factor, AgrB is a membrane-bound peptidase, AgrC functions as a receptor, and AgrD serves as an intracellular signaling molecule. S aureus communicates by secreting an exocrine autoinducing peptide (AIP) derived from AgrD (Novick and Geisinger, 2008).

As the population density increases, AIP concentration increases, eventually binding to AgrC on the cell membrane. This interaction activates AgrA through phosphorylation, forming an AgrA/AgrC dimeric signal transduction system. Activated AgrA binds to the Agr operon, triggering transcription from bidirectional promoters P2 and P3 (Novick and Geisinger, 2008). Transcription from the P2 promoter generates RNAII, which participates in a positive feedback loop, amplifying the Agr-QS signal, a phenomenon often termed the “QS circuit.” Concurrently, the transcription of RNAIII occurs, leading to the expression of various virulence factors, including δ-toxin (also known as phenol-soluble modulin [PSM] γ), proteases, and lipases (Novick and Geisinger, 2008). Notably, RNAIII also represses the expression of adhesion-related genes, thereby modulating the ability of bacteria to adhere to surfaces. Downstream of Agr-QS, cytotoxic toxins such as PSMα and PSMβ are expressed independently of RNAIII, enhancing the pathogen's competitive advantage in the host environment (Le and Otto, 2015). Agr-QS mechanisms are crucial for the timely expression of virulence factors during infection, affecting both acute and chronic phases (Le and Otto, 2015; Yarwood et al, 2004) (Figure 1). This intricate Agr-QS network exemplifies how S aureus responds to environmental cues, emphasizing the role of bacterial communication in its pathogenicity and survival. This allows S aureus to maintain the community balance and prevent starvation (Miller and Bassler, 2001; Rutherford and Bassler, 2012).

Figure 1.

Figure 1

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Role of Staphylococcus aureus Agr-QS–regulated Agr virulence.S aureus consistently secretes AIP, thereby informing each other of their own cell population density. When the population density reaches a certain threshold, they turn on virulence gene expression. The receptor AgrC on the cell surface detects AIP, leading to the phosphorylation of AgrA. AgrA then binds and activates the P2 and P3 promoters in the agr operon. The P2 promoter drives the expression of the agrBDCA operon, thus regulating the Agr-QS system. AgrD is cleaved by the membrane-bound peptidase AgrB, forming AIP, which subsequently activates the agr operon in a positive feedback mechanism. Meanwhile, the P3 promoter regulates the expression of various toxins, including δ-toxin. AD, atopic dermatitis; Agr, accessory gene regulator; AIP, autoinducing peptide; PSM, phenol-soluble modulin; QS, quorum sensing.

δ-Toxin and PSMs in S aureus Pathogenicity

Given the Agr-QS characteristics discussed earlier, S aureus, which proliferates on the AD skin, is predicted to express QS-dependent toxins and molecules. To test this hypothesis, Nakamura et al (2013) established a mouse model in which S aureus activated Agr-QS in the skin and confirmed that this induced dermatitis. Furthermore, δ-toxin, an extracellular toxin produced through the activation of Agr-QS in S aureus, was found to promote mast cell degranulation in vitro. This further revealed that skin colonization with wild-type S aureus, which is not deficient in δ-toxin, promoted IgE and IL-4 production in vivo. This discovery establishes a link between S aureus and type 2 responses in AD. Elevated levels of δ-toxin were also detected in S aureus extracted from the lesional skin of patients with AD (Nakamura et al, 2013). It has been reported in murine studies that δ-toxin present on the skin also enhances epicutaneous sensitization to food allergens in an IL-1α–dependent manner, thereby promoting the development of food allergy (Yamada et al, 2023). Notably, PSMα, particularly PSMα3, damages keratinocytes in the epidermis and promotes the release of alarmins such as IL-1α and IL-36α (Nakagawa et al, 2017). The Th2 and IL-17 pathways have been observed in pediatric and extrinsic AD cases (Esaki et al, 2016; Suárez-Fariñas et al, 2013). Given that PSMα and δ-toxins are regulated by the Agr-QS, these findings suggest a link between the S aureus Agr-QS system and the pathogenesis of AD. Recently, it has been shown that the Agr-QS–dependent serine protease V8 from S aureus directly activates pruriceptive sensory neurons by cleaving proteinase-activated receptor 1, which induces itching (Deng et al, 2023). Taken together, these findings demonstrate that the pathogenicity of S aureus in AD is driven by QS-dependent toxins and proteases (Figure 2).

Figure 2.

Figure 2

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Agr-regulated toxins and protease in AD. When Staphylococcus aureus colonizes the skin surface and triggers the quorum-sensing system, upon detecting PSMα, keratinocytes release IL-1α and IL-36α, which in turn promote the induction of γδ T cells and ILC3 that produce IL-17. IL-17 recruits neutrophils, thereby eliciting a protective immune response against bacteria. δ-Toxin triggers the degranulation of mast cells, inducing IL-4 and IgE, which contribute to the development of Th2 inflammation. V8 from S aureus directly activates pruriceptive sensory neurons by cleaving PAR1, which induces itch. AD, atopic dermatitis; Agr, accessory gene regulator; ILC3, innate lymphoid cell 3; PAR1, proteinase-activated receptor 1; PSM, phenol-soluble modulin; Th2, T helper 2.

Colonization of S aureus in the Skin of Infants

The presence of S aureus in AD lesions is well-documented; however, the timing of their colonization is unknown. AD often begins during infancy (Langan et al, 2020). To investigate the mechanism of S aureus colonization before the onset of AD, we performed whole-genome sequencing of S aureus strains isolated from the cheek skin of 268 Japanese infants. At the age of 1 month, approximately 45% of the infants harbored S aureus. However, this early colonization did not correlate with the risk of developing AD by the age of 1 year. In contrast, infants with S aureus colonization at the age of 6 months exhibit a significantly higher incidence of AD. Whole-genome sequencing of S aureus strains isolated from infants who did not develop AD revealed multiple mutations in the agr region, suggesting a dysfunctional QS system. In contrast, no mutations were detected in strains isolated from infants with AD. Notably, S aureus strains sampled from non-AD infants at the age of 6 months exhibited significantly suppressed RNAIII expression (Nakamura et al, 2020). These findings suggest that S aureus colonization with a functional Agr-QS system contributes to the development of pediatric AD. Interestingly, although the pathogenicity and skin colonization mechanisms driven by Agr-QS are critically important in the context of AD and skin infections, it has also been shown that in other infections such as nosocomial infections, biofilm formation, and the acquisition of antimicrobial resistance, Agr-QS positivity may not necessarily be advantageous for S aureus (He et al, 2023; Yamazaki et al, 2024).

Of course, numerous previous studies have also reported that factors other than the Agr-QS of S aureus contribute to the pathogenesis of AD. Specifically, S aureus adapts to the AD skin environment and ensures its survival by expressing Agr-QS, which in turn exacerbates AD skin pathology.

Interaction of S aureus and Other Bacterial Species

Bacterial interactions, both competitive and symbiotic, shape colonization dynamics and microbial composition. Although interspecies bacterial cell-to-cell signaling within the human body remains largely unexplored, extensive research has been conducted on signaling mechanisms mediated by Agr-QS and other molecular pathways in S aureus. For instance, S epidermidis secretes the serine protease Esp, which inhibits biofilm formation by S aureus and epithelial colonization (Iwase et al, 2010). In addition, PSMγ and PSMδ, secreted by S epidermidis, directly induce the leakage of lipid vesicles, exhibiting selective antibacterial activity against S aureus (Cogen et al, 2010). S lugdunensis produces lugdunin, an AMP that efficiently suppresses S aureus growth and colony formation. Notably, S aureus did not develop resistance to prolonged lugdunin exposure, suggesting that it has potential as a treatment for antibiotic-resistant bacterial strains (Zipperer et al, 2016). Furthermore, fengycins, which are lipopeptides from Bacillus spp, have been identified as inhibitors of staphylococcal colonization and have gained attention as probiotics (Piewngam et al, 2018). Research has also advanced on the relationship between Malassezia and AD. In AD-associated microbiomes, the overall abundance of the genus Malassezia, particularly M globosa, is significantly reduced (Chng et al, 2016). Among the secreted aspartyl proteases produced by M globosa, MgSAP1 has been found to inhibit biofilm formation without affecting the survival rate of S aureus (Ianiri et al, 2018; Li et al, 2018).

Clinically, C acnes is considered to have the most prominent inhibitory effect on S aureus. However, conflicting reports exist regarding the interaction between C acnes and S aureus. C acnes is known to increase essential lipids, including triglycerides, ceramides, cholesterol, and free fatty acids, through the activation of peroxisome proliferator–activated receptor-α and FLG in keratinocytes, improving innate barrier function (Almoughrabie et al, 2023; Jung et al, 2022). In contrast, coproporphyrin III produced by the acne-causing bacterium C acnes aggregates S aureus and enhances biofilm formation (Wollenberg et al, 2014).

Moreover, C striatum inhibits S aureus toxin production downstream of the Agr-QS system and promotes biofilm formation by altering its gene expression to promote commensal-like behavior and suppress pathogenicity (Ramsey et al, 2016). In addition, several coagulase-negative Staphylococcus and Corynebacterium species contribute to the elimination of S aureus by producing antimicrobial substances and quorum-quenching systems that negatively regulate Agr-QS (Nakatsuji et al, 2017). Thus, commensal skin bacteria interact to establish and maintain a balanced skin microbiome through mechanisms such as Agr-QS and other signaling pathways.

Development and Application of AD Treatments Targeting S aureus or Utilizing the Skin Microbiome

Recent research on AD has increasingly focused on the role of the skin microbiota, particularly S aureus. Various therapeutic strategies have been explored to target S aureus in AD, including the use of antibiotics and disinfectants. Sodium hypochlorite bleach baths have been employed as a treatment to eradicate S aureus (Chopra et al, 2017). However, some reports suggest that bleach baths have minimal impact on the overall skin microbiota and do not significantly alter S aureus colonization (Gonzalez et al, 2016; Sawada et al, 2019). In addition, although antibiotics have been used to eradicate S aureus, these approaches have proven ineffective and may contribute to microbial dysbiosis and the emergence of antimicrobial-resistant strains (Bath-Hextall et al, 2010). Therefore, Agr-QS in S aureus has garnered significant attention as a potential therapeutic target, and novel approaches utilizing microorganisms that compete with S aureus are under development. S hominis A9 (ShA9), a coagulase-negative Staphylococcus strain, has been studied in a phase I clinical trial in AD (Nakatsuji et al, 2021b). ShA9 produces lantibiotics that exhibit broad-spectrum antimicrobial activity against various strains of S aureus and spare beneficial commensal bacteria such as S epidermidis (Nakatsuji et al, 2021a). Moreover, ShA9-produced AIP antagonistically interferes with the QS of S aureus, suppresses toxin expression, and alleviates dermatitis in a mouse model. Applying a cream containing live ShA9 for 1 week significantly reduced the abundance of S aureus among the resident bacteria and improved dermatitis symptoms (Nakatsuji et al, 2021b).

In addition to therapies targeting Agr-QS, bacteriophage endolysin therapies engineered to specifically target S aureus without affecting commensal skin bacteria have been explored (Shimamori et al, 2021). Clinical trials are underway to investigate maternal–child microbial seeding interventions that aim to partially restore the microbiome, potentially reducing the risk of microbiome-related immune disorders, including AD (Hourigan et al, 2022). Clinical studies have investigated skincare interventions aimed at preventing AD. A study involving 321 participants demonstrated that the early initiation of daily emollient use until 2 months reduces the incidence of AD during the first year of life in high-risk infants (Ní Chaoimh et al, 2023). Longitudinal skin microbiome data collected from neonates to the age of 6 months revealed that infants who later develop AD often show dysbiosis shortly after birth, with higher levels of Streptococcus and lower levels of C acnes. Interestingly, the presence of Streptococcus in newborn skin is inversely correlated with the total amount of moisturizer applied, whereas C acnes abundance is positively correlated with moisturizer use (Aoyama et al, 2024). This may be explained by the fact that the moisturizer, which is similar to vernix caseosa in composition and contains triglycerides and ceramides, is metabolized by C acnes through specific enzymes, potentially accounting for the observed association between moisturizer application and bacterial growth.

Conclusion

Although the link between S aureus and AD pathogenesis is well-established, the therapeutic potential of targeting the skin microbiome remains a subject of ongoing debate. Further research is needed to clarify its role and develop more effective strategies for both the treatment and prevention of AD.

ORCIDs

Yuumi Nakamura: http://orcid.org/0000-0002-5915-0498

Hiroki Okamoto: http://orcid.org/0009-0001-5044-7068

Shuo Li: http://orcid.org/0009-0001-9636-9376

Conflict of Interest

The authors state no conflict of interest.

Acknowledgments

This study was supported by the Japan Society for the Promotion of Science KAKENHI (23K27621) to YN, Japan Science and Technology Agency Fusion Oriented REsearch for disruptive Science and Technology (JPMJFR200Y) to YN, AMEDCREST (23gm1610004h0003) to YN, Japan Agency for Medical Research and Development (23ek0410105s0101) to YN, and LEO Foundation award 2020 to YN.

Author Contributions

Writing - Original Draft Preparation: HO; Writing - Review and Editing: SL, YN

Declaration of Generative Artificial Intelligence (AI) or Large Language Models (LLMS)

The authors did not use AI/LLM in any part of the research process and/or manuscript preparation.

accepted manuscript published online 4 May 2025; corrected proof published online 28 May 2025

Footnotes

Cite this article as: JID Innovations 2025.100377

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