7 The Skin Microbiome
The Skin Microbiome
The microorganisms that inhabit the largest human organ are important in a variety of ways in regard to host health. The skin microbiome defends against pathogens, educates the immune system, helps wound healing, and moderates progression of diseases, and in return receives nutrients and real estate for colonization, creating a symbiotic establishment (Byrd et al., 2018). As the primary external interface to the environment, the skin serves as the initial physical barrier against invasion of potential pathogens. The territory of the skin itself is harsh for most microbes; its cool, acidic, dry, and considered nutrient poor, and so only those organisms that have adapted to these conditions can successfully colonize it. A majority of these microbes rely on obtaining nutrients from sweat, sebum, and dead skin cells by using proteases and lipases to break apart various compounds to liberate usable resources (Byrd et al., 2018). Though, there are adverse conditions and a general lack of food for microbes on the skin, there is still quite a diverse community which is unique to certain individuals and body locations.
Better characterization of the skin microbiome and its site-specific diversity can allow for greater understanding of skin diseases such as atopic dermatitis, acne, rosacea, and psoriasis that are associated with dysbiosis (Grice and Segre, 2011). The role of resident and transient microorganisms are important in the onset and progression of these types of diseases, and their study may help in diagnosis and treatment protocols.
Composition and Stability
Within a single square centimeter on the skin there can be up to one billion microorganisms, and this mixed community of bacteria, viruses, protozoa, fungi, and mites can be both good and bad for host health (Grice and Segre, 2011, Weyrich et al., 2015). Overall, there are four main bacterial phyla that constitute the human skin microbiome: Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes (in descending order of abundance) (Grice et al., 2009). Microbial composition primarily depends on the specific location of skin site, and particularly whether it is dry, moist, or sebaceous (i.e. oily). Moist areas like the bend of the elbow or the feet harbor bacteria like Staphylococcus or Corynebacterium species and tend to have higher species diversity, while sebaceous locations promote the growth of Propionibacterium species and are lower in diversity (Grice et al., 2009, Oh et al., 2016, Byrd et al., 2018).
The composition of fungi on the skin also depends on location and physiological properties. Fungal members of the skin microbiome primarily consist of species from the genus Malassezia, with some from Penicillium and Aspergillus, and less of a few other genera. Specifically, the community of fungi on the feet have a high amount of diversity and it tends to change more over time as compared with other locations on the body. This may be due to environmental exposure, sock and shoe usage, or the fact that specific sites like plantar heels, toe webs and toenails are commonly infected by fungal pathogens, which can be difficult to treat. (Findley et al., 2013).
Small arthropods less than half a millimeter also colonize the skin and makeup part of the microbiota. Two species of mites from the genus Demodex utilize lipids produced in the sebaceous regions of the skin; the larger species D. folliculorum tends to cluster around hair follicles while the smaller D. brevis situated near the eyelid rim is more antisocial (Schommer and Gallo, 2013). These lipid-eating mites normally have a symbiotic relationship with humans, however, they could potentially serve as mechanical vectors for transport of pathogenic bacteria, and their population buildup and/or associated events of dysbiosis could promote inflammatory reactions (Lacey et al., 2009, Lacey et al., 2011).
Eukaryotic viruses on the skin are primarily transient, exhibit lower site-specific affinity, and the most different from person to person. This is likely due to the fact that they are obligate intracellular pathogens with special constraints. Also, maybe as expected, various bacteriophage abundance in certain sites is dependent on the corresponding bacterial genera (Oh et al., 2016).
Microbial communities on the skin remain stable despite the constantly changing external environment that humans bring about. Over both short- and long-term time intervals, sebaceous sites are the most stable, and moist areas like the feet are the least stable. Interestingly, dry sites with high environmental contact and disruption, like the palms of hands, exhibit community stability over time (Oh et al., 2016). Though, variability and stability may be dependent on individual host habits and lifestyles. At an early age, however, there are drastic changes in the skin microbiome until it becomes established. At birth, the baby transitions from an essentially sterile environment in the womb, to open air and constant microbial exposure where initial colonization of the skin begins. The method of delivery also affects initial community composition on the skin. When a baby is born conventionally through the vaginal canal, the members of the skin microbiome reflect the vaginal microbiome, and if born via cesarean section, the infant’s skin community more closely resembles that of the mother’s skin (Dominguez-Bello et al., 2010). In the initial few months, the skin community predominately consists of Streptococci and Staphylococci bacteria, but as aging ensues the abundance of these genera decrease and diversity and numbers of others begins to increase and level out (Capone et al., 2011). This has long-term effects on health, as the evolution of an infant’s skin microbiome helps to regulate and mature both the skin and immune system.
Hot Spot Quiz
Immune System Interaction
Exposure to potentially pathogenic microorganisms at a young age can help educate the immune system. Immediately after childbirth, initial skin colonization by microorganisms is allowed without the classical inflammatory response, though shortly after this period, these microbes promote the development of distinct components of the immune system for future pathogen encounters (PrabhuDas et al., 2011, Naik et al., 2012, Naik et al., 2015, Belkaid and Harrison, 2017). This has been observed in infant’s skin microbiome and an early colonization of Staphylococcus aureus being associated with a lower risk of developing atopic dermatitis, as the immune system is prepared for this organism that can exacerbate and perpetuate the disease (Kennedy et al., 2017, Blicharz et al., 2019). S. aureus can further modulate the immune system through toxin production and colonization, which initiates leukocyte responses and stimulates the adaptive and innate immune systems (Niebuhr, et al., 2011, Nakamura et al., 2013, Nakatsuji et al., 2016). Skin colonization of Staphylococcus epidermidis elicits similar immune responses, and a pre-association with this microbe could help defend against certain fungal and parasitic skin infections (Naik et al., 2012, Naik et al., 2015). Further investigation of microbe and immune system interactions will help uncover exact molecular functions and relationships, which could have future implications in therapy and treatment of skin diseases (Byrd et al., 2018).
Pathogens, Dysbiosis, and Skin Diseases
The skin microbiome also contributes to human health and combating infectious diseases in a preventative measure. In addition to educating the immune system, the commensal microorganisms that call the epidermis home help to prevent pathogen invasion by physically taking up niches and secreting certain antimicrobial compounds. For example, S. epidermidis, which is a part of the normal microbial flora of the skin, produces antimicrobial peptides and proteases that selectively targets and inhibits growth of pathogens such as S. aureus (Cogen et al., 2010, Iwase et al., 2010, Schommer and Gallo, 2013).
Though many commensal microorganisms on the skin can help to prevent pathogen colonization, these microbes themselves may be opportunistic pathogens and can cause an infection when certain conditions arise. For example, S. epidermidis is a common cause of infections when transmitted from the skin into the body, usually through a medical procedure like catheterization (Otto, 2012). Staphylococci are known for their ability to form biofilms on medical devices, which make them more difficult to treat (Otto, 2009). The fungi, Candida albicans, is another normal skin resident that can cause opportunistic infections. It is thought that disruption of the normal skin flora, through means such as antibiotic therapy, could induce virulence factor production by the yeast, resulting in penetration of epidermal tissue and a subsequent case of candidiasis (Kuhbacher et al., 2017). Other skin diseases associated with dysbiosis, or various skin pathogens, include atopic dermatitis, acne, rosacea, psoriasis, and chronic wound healing.
Atopic dermatitis (AD), the most common form of eczema, is a chronic inflammatory condition of the skin that is caused by a mutation in several genes, including the fillagrin gene responsible for encoding a protein that helps maintain epidermal health (Bierber, 2008). AD is characterized by itchy, dry rashes that become vulnerable to infection when the skin barrier is breached by constant scratching, and occurs more frequently in areas that become lower in microbial diversity due to an altered physiology (Weyrich et al., 2015). S. aureus colonization is directly related to disease severity of AD, as it produces virulence factors that disrupt the integrity of the skin barrier. There is also an increase in abundance of S. epidermidis, and Clostridium and Serratia species, and this increase of select species suggests that a lower amount of microbial diversity plays a role in the progression of AD (Kong et al., 2012, Oh et al., 2013, Williams and Gallo, 2015). Selectively targeting pathogens such as S. aureus for treatment of AD proves to be difficult as the normal microbiota also suffers resulting in dysbiosis.
Psoriasis is similar to AD in that the disease results in inflamed, scaly skin plaques that are itchy and painful. This condition is also associated with altered microbial diversity, and there is an association with the development of psoriasis and oral streptococcal infections, though the connection is not exactly known (Norlind, 1955, Owen et al., 2000). Within psoriatic lesions, there is an increase Proteobacteria and Firmicutes, a decrease in Actinobacteria, and specifically a decrease within the genera Propionibacterium (Gao et al., 2008, Fahlen et al., 2012, Statnikov et al., 2013). Though there is a decrease in general of microbial diversity in psoriatic lesions, there hasn’t been any specific microbial causative agent identified for the disease.
Rosacea is a common chronic dermatosis which primarily manifests as persisting erythema (redness), telangiectasia (dilated or broken blood vessels), bulging, swelling, and/or raised patches in superficial facial skin (Picardo and Ottaviani, 2014). Like other cutaneous diseases, development of rosacea is linked with skin microbiome composition, and how those communities influence skin immune responses. In particular, an increase in Demodex mite abundance and density is observed in those with rosacea. They potentially contribute to the disease state through immune system activation, damaging epithelial tissue, and/or the exposure of antigenic proteins of bacteria released from their digestive tract (Forton and Seys, 1993, Georgala et al., 2001, Lacey et al., 2007, Koller et al., 2011, Casas et al., 2012, Forton, 2012, ). The induced reactions from microbiome shifts, genetics, and environmental factors then likely invoke other inflammatory triggers, which includes overgrowth of certain bacteria like S. epidermidis (Schommer and Gallo, 2013).
Acne (acne vulgaris) is a skin condition that results from hair follicles and sebaceous glands that are clogged with oil, bacteria, and dead skin cells, which creates whiteheads and blackheads. Propionibacterium acnes is a primary etiological agent in acne; it’s secretion of lipases, proteases, and hyaluronidases damage skin pores and induce inflammatory responses (McKelvey et al., 2012). Although this species of microbe is part of the normal skin microbiota, there are differences in certain strains of P. acnes that may explain differential virulence. Some disease-associated strains also have genes for antibiotic resistance, making treatment options other than chemotherapy a necessity (Fitz-Gibbon et al., 2013). Other commensal microorganisms, like S. epidermidis, could interact with P. acnes and be implicated in acne formation also, further demonstrating that residents can become pathogenic when opportunistic conditions arise (Bek-Thomsen et al., 2008, Weyrich et al., 2015, Dreno et al., 2017).
Chronic skin wounds (duration longer than three months) and their capacity to heal are also affected by the skin microbiome, especially in those individuals who are elderly, obese, immunocompromised, or diabetic (Weyrich et al., 2015, Byrd et al., 2018). Though the lesions or ulcers may not be initially caused by a microorganism, their presence, infection, and polymicrobial biofilm formation can be deleterious to the healing process and cause further complications (McKelvey et al., 2012, Wolcott et al., 2013). Analysis of skin wound microbiomes have shown a compilation of a diverse array of genera, but that microbial diversity is lower as compared with healthy skin (Gardiner et al., 2017, Kalan et al., 2019). Perhaps a higher microbial diversity allows for easier elimination of potential pathogens from the wound and promotes faster healing. An increase in facultative anaerobes, specifically the genus Enterobacter, are significant indicators in the persistence of chronic wounds and their lack of healing, possibly due to their versatile metabolism (Verbanic et al., 2020). Antibiotic therapy is an option to eliminate certain bacterial pathogens for chronic wounds, however, the resulting changes in the microbiome and addressing fungal and viral constituents may necessitate multiple different treatment approaches (Price et al., 2009). Further studies are needed in order to see whether individual therapy and targeted therapeutic intervention would promote faster healing in cases with chronic wounds (Kong, 2011, Weyrich et al., 2015, Verbanic et al., 2020).
It is likely that changes in microbial community composition and the elicited immune response work in combination with host genetics and other environmental factors to cause various cutaneous disorders (Weyrich et al., 2015 ). This makes treatment of these complex conditions difficult, and targeting a few potential pathogens is rarely successful, especially if it is not known whether their presence is a cause or effect. So, future therapeutic efforts may focus on a similar approach to treating gut dysbiosis with FMT, and as so, use healthy skin microbiota transplants to repair and stabilize the skin microbiome for patients inflicted with skin diseases (Williams and Gallo, 2015).
Conclusion
The skin microbiome is incredibly complex, resilient, and has a strong influence on health and disease. Characterization and defining a normal skin microbiome could help in future diagnosis and treatment of disease, although factors like differences in host genetics, lifestyles, and particular skin locations must be accounted for. As research and medical technologies advance, it may be possible to utilize these microbial neighbors on the skin in efforts to promote better overall health.
Check Your Understanding
- What features of human skin affect the composition and stability of its microbiome?
- How is the skin microbiome influenced in early life, and what implications does this have in human health?
- What diseases are associated with dysbiosis of the skin microbiome? How do these come about and what particular microorganisms are associated with each?
- How do certain members of the skin microbiome impede the healing process of chronic wounds?
Media Attributions:
- Video 1 – A mixed community of skin microbiome representatives influences cutaneous processes by Research Square. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/
- Video 2 – Eczema, Immunity, and the Skin Microbiome – Heidi Hong by National Human Genome Research Institute. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/
- Video 3 – Expansion of known skin microbes could aid skin health research by Research Square. Licensed under Creative Commons: By Attribution 3.0 License https://creativecommons.org/licenses/by/3.0/
- Hot Spot Quiz Image – Skin Microbiome by Jane Ades, NHGRI under Public Domain
References
- Bek-Thomsen, M., Lomholt, H. B., & Kilian, M. (2008). Acne is Not Associated with Yet-Uncultured Bacteria. Journal of Clinical Microbiology, 46(10), 3355–3360. https://doi.org/10.1128/JCM.00799-08
- Belkaid, Y., & Harrison, O. J. (2017). Homeostatic Immunity and the Microbiota. Immunity, 46(4), 562–576. https://doi.org/10.1016/j.immuni.2017.04.008
- Bierber, T. (2008). Mechanisms of disease: atopic dermatitis. N Engl J Med, 358, 358-1483.
- Blicharz, L., Rudnicka, L., & Samochocki, Z. (2019). Staphylococcus aureus: an underestimated factor in the pathogenesis of atopic dermatitis? Postepy Dermatologii i Alergologii, 36(1), 11–17. https://doi.org/10.5114/ada.2019.82821
- Byrd, A. L., Belkaid, Y., & Segre, J. A. (2018). The human skin microbiome. Nature Reviews Microbiology, 16(3), 143–155. https://doi.org/10.1038/nrmicro.2017.157
- Capone, K. A., Dowd, S. E., Stamatas, G. N., & Nikolovski, J. (2011). Diversity of the Human Skin Microbiome Early in Life. Journal of Investigative Dermatology, 131(10), 2026–2032. https://doi.org/10.1038/jid.2011.168
- Casas, C., Paul, C., Lahfa, M., Livideanu, B., Lejeune, O., Alvarez-Georges, S., Saint-Martory, C., Degouy, A., Mengeaud, V., Ginisty, H., Durbise, E., Schmitt, A. M., & Redoulès, D. (2012). Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation. Experimental Dermatology, 21(12), 906–910. https://doi.org/10.1111/exd.12030
- Cogen, A. L., Yamasaki, K., Sanchez, K. M., Dorschner, R. A., Lai, Y., MacLeod, D. T., Torpey, J. W., Otto, M., Nizet, V., Kim, J. E., & Gallo, R. L. (2010). Selective Antimicrobial Action Is Provided by Phenol-Soluble Modulins Derived from Staphylococcus epidermidis, a Normal Resident of the Skin. Journal of Investigative Dermatology, 130(1), 192–200. https://doi.org/10.1038/jid.2009.243
- Dominguez-Bello, M. G., Costello, E. K., Contreras, M., Magris, M., Hidalgo, G., Fierer, N., & Knight, R. (2010). Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proceedings of the National Academy of Sciences, 107(26), 11971. https://doi.org/10.1073/pnas.1002601107
- Dreno, B., Martin, R., Moyal, D., Henley, J. B., Khammari, A., & Seité, S. (2017). Skin microbiome and acne vulgaris: Staphylococcus, a new actor in acne. Experimental Dermatology, 26(9), 798–803. https://doi.org/10.1111/exd.13296
- Fahlén, A., Engstrand, L., Baker, B. S., Powles, A., & Fry, L. (2012). Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin. Archives of Dermatological Research, 304(1), 15–22. https://doi.org/10.1007/s00403-011-1189-x
- Findley, K., & Grice, E. A. (2014). The Skin Microbiome: A Focus on Pathogens and Their Association with Skin Disease. PLOS Pathogens, 10(11), e1004436-. https://doi.org/10.1371/journal.ppat.1004436
- Findley, K., Oh, J., Yang, J., Conlan, S., Deming, C., Meyer, J. A., Schoenfeld, D., Nomicos, E., Park, M., Becker, J., Benjamin, B., Blakesley, R., Bouffard, G., Brooks, S., Coleman, H., Dekhtyar, M., Gregory, M., Guan, X., Gupta, J., … Program, N. I. H. I. S. C. C. S. (2013). Topographic diversity of fungal and bacterial communities in human skin. Nature, 498(7454), 367–370. https://doi.org/10.1038/nature12171
- Fitz-Gibbon, S., Tomida, S., Chiu, B.-H., Nguyen, L., Du, C., Liu, M., Elashoff, D., Erfe, M. C., Loncaric, A., Kim, J., Modlin, R. L., Miller, J. F., Sodergren, E., Craft, N., Weinstock, G. M., & Li, H. (2013). Propionibacterium acnes Strain Populations in the Human Skin Microbiome Associated with Acne. Journal of Investigative Dermatology, 133(9), 2152–2160. https://doi.org/10.1038/jid.2013.21
- Forton, F. M. N. (2012). Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. Journal of the European Academy of Dermatology and Venereology, 26(1), 19–28. https://doi.org/10.1111/j.1468-3083.2011.04310.x
- Forton, F., & Seys, B. (1993). Density of Demodex folliculorum in rosacea: a case-control study using standardized skin-surface biopsy. British Journal of Dermatology, 128(6), 650–659. https://doi.org/10.1111/j.1365-2133.1993.tb00261.x
- Gao, Z., Tseng, C., Strober, B. E., Pei, Z., & Blaser, M. J. (2008). Substantial Alterations of the Cutaneous Bacterial Biota in Psoriatic Lesions. PLOS ONE, 3(7), e2719-. https://doi.org/10.1371/journal.pone.0002719
- Gardiner M, Vicaretti M, Sparks J, Bansal S, Bush S, Liu M, Darling A, Harry E, Burke CM. (2017). A longitudinal study of the diabetic skin and wound microbiome. PeerJ 5:e3543 https://doi.org/10.7717/peerj.3543
- Georgala, S., Katoulis, A. C., Kylafis, G. D., Koumantaki-Mathioudaki, E., Georgala, C., & Aroni, K. (2001). Increased density of Demodex folliculorum and evidence of delayed hypersensitivity reaction in subjects with papulopustular rosacea. Journal of the European Academy of Dermatology and Venereology, 15(5), 441–444. https://doi.org/10.1046/j.1468-3083.2001.00331.x
- Grice, E. A., & Segre, J. A. (2011). The skin microbiome. Nature Reviews Microbiology, 9(4), 244–253. https://doi.org/10.1038/nrmicro2537
- Grice, E. A., Kong, H. H., Conlan, S., Deming, C. B., Davis, J., Young, A. C., Nisc Comparative Sequencing Program, Bouffard, G. G., Blakesley, R. W., Muray, P. R., Green, E. D., Turner, M. L., & Segre, J. A. (2009). Topographical and Temporal Diversity of the Human Skin Microbiome. Science, 324(5931), 1190–1192. https://doi.org/10.1126/science.1171700
- Iwase, T., Uehara, Y., Shinji, H., Tajima, A., Seo, H., Takada, K., Agata, T., & Mizunoe, Y. (2010). Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature, 465(7296), 346–349. https://doi.org/10.1038/nature09074
- Kalan, L. R., Meisel, J. S., Loesche, M. A., Horwinski, J., Soaita, I., Chen, X., Uberoi, A., Gardner, S. E., & Grice, E. A. (2019). Strain- and Species-Level Variation in the Microbiome of Diabetic Wounds Is Associated with Clinical Outcomes and Therapeutic Efficacy. Cell Host & Microbe, 25(5), 641-655.e5. https://doi.org/10.1016/j.chom.2019.03.006
- Kennedy, E. A., Connolly, J., Hourihane, J. O., Fallon, P. G., McLean, W. H. I., Murray, D., Jo, J.-H., Segre, J. A., Kong, H. H., & Irvine, A. D. (2017). Skin microbiome before development of atopic dermatitis: Early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year. Journal of Allergy and Clinical Immunology, 139(1), 166–172. https://doi.org/10.1016/j.jaci.2016.07.029
- Koller, B., Müller-Wiefel, A. S., Rupec, R., Korting, H. C., & Ruzicka, T. (2011). Chitin Modulates Innate Immune Responses of Keratinocytes. PLOS ONE, 6(2), e16594-. https://doi.org/10.1371/journal.pone.0016594
- Kong, H. H. (2011). Skin microbiome: genomics-based insights into the diversity and role of skin microbes. Trends in Molecular Medicine, 17(6), 320–328. https://doi.org/10.1016/j.molmed.2011.01.013
- Kong, H. H., Oh, J., Deming, C., Conlan, S., Grice, E. A., Beatson, M. A., Nomicos, E., Polley, E. C., Komarow, H. D., Program, N. C. S., Murray, P. R., Turner, M. L., & Segre, J. A. (2012). Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Research, 22(5), 850–859. http://genome.cshlp.org/content/22/5/850.abstract
- Kuhbacher, A., Burger-Kentischer, A., & Rupp, S. (2017). Interaction of Candida species with the skin. Microorganisms. 5(2), 32. https://doi.org/10.3390/microorganisms5020032
- Lacey, N., Delaney, S., Kavanagh, K., & Powell, F. C. (2007). Mite-related bacterial antigens stimulate inflammatory cells in rosacea. British Journal of Dermatology, 157(3), 474–481. https://doi.org/10.1111/j.1365-2133.2007.08028.x
- Lacey, N., Kavanagh, K., & Tseng, S. C. G. (2009). Under the lash: Demodex mites in human diseases. The Biochemist, 31(4), 20–24. https://doi.org/10.1042/BIO03104020
- Lacey, N., Ní Raghallaigh, S., & Powell, F. C. (2011). Demodex mites – commensals, parasites or mutualistic organisms? Dermatology, 222(2), 128-30. doi:http://dx.doi.org/10.1159/000323009
- McKelvey, K., Xue, M., Whitmont, K., Shen, K., Cooper, A., & Jackson, C. (2012). Potential anti-inflammatory treatments for chronic wounds. Wound Practice & Research: Journal of the Australian Wound Management Association, 20(2), 86–89. https://search.informit.org/doi/10.3316/informit.656354654775105
- Naik, S., Bouladoux, N., Linehan, J. L., Han, S.-J., Harrison, O. J., Wilhelm, C., Conlan, S., Himmelfarb, S., Byrd, A. L., Deming, C., Quinones, M., Brenchley, J. M., Kong, H. H., Tussiwand, R., Murphy, K. M., Merad, M., Segre, J. A., & Belkaid, Y. (2015). Commensal–dendritic-cell interaction specifies a unique protective skin immune signature. Nature, 520(7545), 104–108. https://doi.org/10.1038/nature14052
- Naik, S., Bouladoux, N., Wilhelm, C., Molloy, M. J., Salcedo, R., Kastenmuller, W., Deming, C., Quinones, M., Koo, L., Conlan, S., Spencer, S., Hall, J. A., Dzutsev, A., Kong, H., Campbell, D. J., Trinchieri, G., Segre, J. A., & Belkaid, Y. (2012). Compartmentalized control of skin immunity by resident commensals. Science (New York, N.Y.), 337(6098), 1115–1119. https://doi.org/10.1126/science.1225152
- Nakamura, Y., Oscherwitz, J., Cease, K. B., Chan, S. M., Muñoz-Planillo, R., Hasegawa, M., Villaruz, A. E., Cheung, G. Y. C., McGavin, M. J., Travers, J. B., Otto, M., Inohara, N., & Núñez, G. (2013). Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature, 503(7476), 397–401. https://doi.org/10.1038/nature12655
- Nakatsuji, T., Chen, T. H., Two, A. M., Chun, K. A., Narala, S., Geha, R. S., Hata, T. R., & Gallo, R. L. (2016). Staphylococcus aureus Exploits Epidermal Barrier Defects in Atopic Dermatitis to Trigger Cytokine Expression. Journal of Investigative Dermatology, 136(11), 2192–2200. https://doi.org/10.1016/j.jid.2016.05.127
- Niebuhr, M., Gathmann, M., Scharonow, H., Mamerow, D., Mommert, S., Balaji, H., & Werfel, T. (2011). Staphylococcal Alpha-Toxin Is a Strong Inducer of Interleukin-17 in Humans. Infection and Immunity, 79(4), 1615–1622. https://doi.org/10.1128/IAI.00958-10
- Norlind, R. (1955). Significance of infections in origin of psoriasis. Acta Rheumatol Scand, 1, 135-44.
- Oh, J., Byrd, A. L., Park, M., Kong, H. H., & Segre, J. A. (2016). Temporal Stability of the Human Skin Microbiome. Cell, 165(4), 854–866. https://doi.org/10.1016/j.cell.2016.04.008
- Oh, J., Freeman, A. F., Program, N. C. S., Park, M., Sokolic, R., Candotti, F., Holland, S. M., Segre, J. A., & Kong, H. H. (2013). The altered landscape of the human skin microbiome in patients with primary immunodeficiencies. Genome Research, 23(12), 2103–2114. http://genome.cshlp.org/content/23/12/2103.abstract
- Otto, M. (2009). Staphylococcus epidermidis — the “accidental” pathogen. Nature Reviews Microbiology, 7(8), 555–567. https://doi.org/10.1038/nrmicro2182
- Otto, M. (2012). Molecular basis of Staphylococcus epidermidis infections. Seminars in Immunopathology, 34(2), 201–214. https://doi.org/10.1007/s00281-011-0296-2
- Owen, C. M., Chalmers, R., O’Sullivan, T., & Griffiths, C. E.M. (2000) Antistreptococcal interventions for guttate and chronic plaque psoriasis. Cochrane Database of Systematic Reviews, 2. Art. No.: CD001976. DOI: 10.1002/14651858.CD001976.
- PrabhuDas, M., Adkins, B., Gans, H., King, C., Levy, O., Ramilo, O., & Siegrist, C.-A. (2011). Challenges in infant immunity: implications for responses to infection and vaccines. Nature Immunology, 12(3), 189–194. https://doi.org/10.1038/ni0311-189
- Price, L. B., Liu, C. M., Melendez, J. H., Frankel, Y. M., Engelthaler, D., Aziz, M., Bowers, J., Rattray, R., Ravel, J., Kingsley, C., Keim, P. S., Lazarus, G. S., & Zenilman, J. M. (2009). Community Analysis of Chronic Wound Bacteria Using 16S rRNA Gene-Based Pyrosequencing: Impact of Diabetes and Antibiotics on Chronic Wound Microbiota. PLOS ONE, 4(7), e6462-. https://doi.org/10.1371/journal.pone.0006462
- Schommer, N. N., & Gallo, R. L. (2013). Structure and function of the human skin microbiome. Trends in Microbiology, 21(12), 660–668. https://doi.org/10.1016/j.tim.2013.10.001
- Statnikov, A., Alekseyenko, A. v, Li, Z., Henaff, M., Perez-Perez, G. I., Blaser, M. J., & Aliferis, C. F. (2013). Microbiomic Signatures of Psoriasis: Feasibility and Methodology Comparison. Scientific Reports, 3(1), 2620. https://doi.org/10.1038/srep02620
- Verbanic, S., Shen, Y., Lee, J., Deacon, J. M., & Chen, I. A. (2020). Microbial predictors of healing and short-term effect of debridement on the microbiome of chronic wounds. Npj Biofilms and Microbiomes, 6(1), 21. https://doi.org/10.1038/s41522-020-0130-5
- Weyrich, L. S., Dixit, S., Farrer, A. G., Cooper, A. J., & Cooper, A. J. (2015). The skin microbiome: Associations between altered microbial communities and disease. Australasian Journal of Dermatology, 56(4), 268–274. https://doi.org/10.1111/ajd.12253
- Williams, M. R., & Gallo, R. L. (2015). The Role of the Skin Microbiome in Atopic Dermatitis. Current Allergy and Asthma Reports, 15(11), 65. https://doi.org/10.1007/s11882-015-0567-4
- Wolcott, R., Costerton, J. W., Raoult, D., & Cutler, S. J. (2013). The polymicrobial nature of biofilm infection. Clinical Microbiology and Infection, 19(2), 107–112. https://doi.org/10.1111/j.1469-0691.2012.04001.x