Skin is the largest organ in the human body.
Skin is a protective barrier that regulates body temperature and is our first line of defense against foreign pathogens, including bacteria and viruses.
Microbiota
The skin is a highly specialized organ that functions as a physical and immunological barrier, where epidermal integrity, immune response and microbiota coexist in a tightly regulated equilibrium (Chen et al., 2018). Recent advances in microbiology and immunology have highlighted the central role of the skin microbiota in maintaining cutaneous homeostasis. This complex ecosystem—comprising bacteria, fungi, archaea and viruses—interacts continuously with the host through interkingdom communication mechanisms, involving biochemical and biophysical signaling pathways that modulate immune responses and barrier function (Byrd et al., 2018).
Disease & the market
Disruption of this equilibrium (dysbiosis) is increasingly recognized as a key driver in the onset and progression of inflammatory dermatoses, including atopic dermatitis and psoriasis. In particular, atopic dermatitis is associated with altered host–microbe interactions and microbial imbalance, often characterized not only by the overgrowth of pathogenic species such as Staphylococcus aureus, but also by a shift toward a more virulent phenotype, contributing to chronic inflammation and barrier impairment (Geoghegan et al., 2018).
In atopic dermatitis, Staphylococcus aureus is no longer considered a secondary colonizer, but a key pathogenic driver that actively contributes to the disease onset and progression (Paller et al., 2019). AD skin is characterized by a severe microbial imbalance, with a marked increase in S. aureus abundance and in parallel loss of microbial diversity. This dysbiotic state closely correlates with disease severity and reflects a permeable environment created by epidermal barrier dysfunction and immune dysregulation (Kong et al., 2012).
Beyond simple colonization, S. aureus directly contributes to skin damage and inflammation through the release of virulence factors, including toxins, proteases, and superantigens. These molecules impair keratinocyte function, degrade structural components of the epidermis, and amplify type 2 immune responses, reinforcing the chronic inflammatory state typical of AD (Nakatsuji et al., 2017).
A critical and increasingly recognized mechanism underlying this process is the production of bacterial extracellular vesicles (BEVs). These nanosized lipid structures act as highly efficient delivery systems, transporting concentrated virulence factors directly to host cells (Kim et al., 2020).
Current treatment
Thanks to their small size, BEVs can penetrate the already compromised epidermal barrier and reach viable keratinocytes. Once internalized, they induce cytotoxic effects, disrupt tight junction proteins such as zona occludens-1 (ZO-1) and claudin-1 (CLDN1), and activate innate immune pathways, further exacerbating inflammation and barrier dysfunction (Hong et al., 2011). Importantly, BEVs enhance the stability and intracellular delivery of toxins, making them more effective than freely released bacterial products. This leads to a self-perpetuating pathogenic loop in which barrier impairment promotes S. aureus colonization, which in turn increases BEV production, amplifying tissue damage and immune activation. In this context, targeting S. aureus BEVs represents a critical therapeutic objective, as blocking their activity may interrupt the cascade of barrier disruption and inflammation at an early stage, addressing one of the upstream drivers of disease rather than its downstream consequences (Liu et al., 2022).
Current therapeutic approaches are primarily based on corticosteroids, calcineurin inhibitors and systemic or topical immunomodulators. While effective in controlling symptoms, these treatments are often associated with safety concerns, especially in long-term use and in pediatric populations, leading to reduced adherence and suboptimal disease management (Eichenfield et al., 2014).
Despite the widespread use of emollients and supportive therapies, these approaches are frequently insufficient to restore the underlying biological balance of the skin.
This scenario highlights a significant unmet need for innovative, non-pharmacological solutions capable of targeting the skin microbiota and its interkingdom interactions, with the aim of restoring skin homeostasis while ensuring safety and tolerability over prolonged use.
References
1. Byrd, A. L., Belkaid, Y., & Segre, J. A. (2018). The human skin microbiome. Nature Reviews Microbiology, 16(3), 143-155.
2. Chen, Y. E., Fischbach, M. A., & Belkaid, Y. (2018). Skin microbiota–host interactions. Nature, 553(7689), 427-436.
3. Eichenfield, L. F., et al. (2014). Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. Journal of the American Academy of Dermatology, 71(1), 116-132.
4. Geoghegan, J. A., Irvine, A. D., & Foster, T. J. (2018). Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship. Trends in Microbiology, 26(6), 484-497.
5. Hong, S. W., et al. (2011). Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation. Allergy, 66(3), 351-359.
6. Kim, G. J., et al. (2020). Staphylococcal enterotoxin B-containing extracellular vesicles induce systemic immune responses. Scientific Reports, 10(1), 1-12.
7. Kong, H. H., et al. (2012). Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Research, 22(5), 850-859.
8. Liu, Q., et al. (2022). Bacterial extracellular vesicles as a novel strategy for skin barrier restoration and immune modulation. Journal of Extracellular Vesicles, 11(4), e12211.
9. Nakatsuji, T., et al. (2017). Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Science Translational Medicine, 9(378), eaah4680.
10. Paller, A. S., et al. (2019). The microbiome in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology, 143(1), 26-35.
References
1. Byrd, A. L., Belkaid, Y., & Segre, J. A. (2018). The human skin microbiome. Nature Reviews Microbiology, 16(3), 143-155.
2. Chen, Y. E., Fischbach, M. A., & Belkaid, Y. (2018). Skin microbiota–host interactions. Nature, 553(7689), 427-436.
3. Eichenfield, L. F., et al. (2014). Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. Journal of the American Academy of Dermatology, 71(1), 116-132.
4. Geoghegan, J. A., Irvine, A. D., & Foster, T. J. (2018). Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship. Trends in Microbiology, 26(6), 484-497.
5. Hong, S. W., et al. (2011). Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation. Allergy, 66(3), 351-359.
6. Kim, G. J., et al. (2020). Staphylococcal enterotoxin B-containing extracellular vesicles induce systemic immune responses. Scientific Reports, 10(1), 1-12.
7. Kong, H. H., et al. (2012). Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Research, 22(5), 850-859.
8. Liu, Q., et al. (2022). Bacterial extracellular vesicles as a novel strategy for skin barrier restoration and immune modulation. Journal of Extracellular Vesicles, 11(4), e12211.
9. Nakatsuji, T., et al. (2017). Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Science Translational Medicine, 9(378), eaah4680.
10. Paller, A. S., et al. (2019). The microbiome in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology, 143(1), 26-35.