The microbiome in patients with atopic dermatitis
Authors: Amy S. Paller, Heidi H. Kong, Patrick Seed, Shruti Naik, Tiffany C. Scharschmidt, Richard L. Gallo, Thomas Luger, Alan D. Irvine
Journal: Journal of Allergy and Clinical Immunology (2018)

As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies. As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies. A multitude of microbiota inhabit our human epithelial surfaces. Although there is increasing evidence that these microbiota, which live in and on our bodies, are important to human health and disease, the many functions and consequences of these resident microbiota remain poorly understood. Given the challenges in being able to adequately culture all microbes present in a given sample, technological advances in genome sequencing have increased the ability to interrogate human epithelial microbiomes (the full collection of microbiota). Several technical advances in the study of the composition and function of the microbiome have collectively enlightened our understanding of the role of the microbiome in both pathogenesis of atopic dermatitis (AD) and in disease modification (Fig 1).1Byrd A.L. Belkaid Y. Segre J.A. The human skin microbiome.Nat Rev Microbiol. 2018; 16: 143-155Crossref PubMed Scopus (917) Google Scholar Although animal models cannot fully recapitulate the human microbiome and disease states, the use of model organisms to deeply investigate host-microbial relationships has elucidated intriguing biological mechanisms. The continued integration of knowledge gleaned from patient-derived microbiota, animal models, and host-microbial interactions will be critical for developing and understanding therapeutic approaches. Prior publications have extensively reviewed the differences in the human skin microbiome based on various factors, including anatomic skin sites, sexual maturity, and skin physiology; this review provides a broad overview of the different aspects of microbiome, immunology, microbiology, and barrier research as related to AD, in particular early host-microbiome events in patients with AD. Here we review the role of the cutaneous microbiome in healthy and AD skin. The complexities of human microbial communities are reflected in the distinct microbiomes observed in the human skin, gut, and respiratory tract, among other body sites. Furthermore, the microbiota in distinct niches undergo changes over the human lifespan. The continual advances in our understanding of the human microbiome and its potential roles in human disease might subsequently lead to preventative and/or therapeutic strategies. Skin microbiome research has highlighted the diversity and skin site specificity of microbial communities on human subjects, such that the different regional skin surfaces have different compositions of microbial communities.2Findley K. Oh J. Yang J. Conlan S. Deming C. Meyer J.A. et al.Topographic diversity of fungal and bacterial communities in human skin.Nature. 2013; 498: 367-370Crossref PubMed Scopus (731) Google Scholar, 3Grice E.A. Kong H.H. Conlan S. Deming C.B. Davis J. 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Fadrosh D. et al.Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation.Nat Med. 2016; 22: 1187-1191Crossref PubMed Scopus (586) Google Scholar Whether early disruption of the microbial community on skin directly affects future risk of inflammatory skin disease remains an open question. However, it is notable that recent longitudinal studies examining the skin microbiome in patients at risk for AD have found alterations in skin flora that predate disease onset.13Kennedy E.A. Connolly J. Hourihane J.O. Fallon P.G. McLean W.H. Murray D. et al.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.J Allergy Clin Immunol. 2017; 139: 166-172Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 22Meylan P. Lang C. Mermoud S. Johannsen A. Norrenberg S. Hohl D. et al.Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy.J Invest Dermatol. 2017; 137: 2497-2504Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Until recently, little was known about the effect of early-life microbial exposures on skin immune function. Modeling this complex relationship in mice has taught us that these early-life interactions are likely to be of equal or greater significance in skin as in other tissues. When neonatal mice are colonized by the commensal bacterium (coagulase-negative Staphylococcus [CoNS]) Staphylococcus epidermidis, they develop a large percentage of Treg cells specific for S epidermidis and mount less inflammation to this microbe on rechallenge in later life. In contrast, delaying S epidermidis exposure until adulthood prevents this protective effect and promotes skin inflammation in responses to this otherwise "healthy" bacterium (Fig 2).22Meylan P. Lang C. Mermoud S. Johannsen A. Norrenberg S. Hohl D. et al.Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy.J Invest Dermatol. 2017; 137: 2497-2504Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar At least 1 factor accounting for this age-dependent difference is the greater density of Treg cells found in neonatal compared with adult skin.23Scharschmidt T.C. Vasquez K.S. Truong H.-A. Gearty S.V. Pauli M.L. Nosbaum A. et al.A wave of regulatory t cells into neonatal skin mediates tolerance to commensal microbes.Immunity. 2015; 43: 1011-1021Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar Intriguingly, these Treg cells are markedly decreased in the skin of young mice raised under gnotobiotic ("germ-free") conditions and in those lacking hair follicles, a major tissue niche for skin CoNS species. Indeed, colonization of hair follicles by commensal microbes appears to stimulate production by isthmus keratinocytes of a chemokine, CCL20, which then helps recruit these Treg cells into the skin (Fig 2, left panel).24Scharschmidt T.C. Vasquez K.S. Pauli M.L. Leitner E.G. Chu K. Truong H.-A. et al.Commensal microbes and hair follicle morphogenesis coordinately drive Treg migration into neonatal skin.Cell Host Microbe. 2017; 21: 467-477Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Thus animal models suggest that mechanisms promoting establishment of a healthy immunologic symbiosis with our skin microbiota are preferentially active early in life and can be facilitated by microbes themselves. Of course, there are notable differences between mice and human subjects with regard to timing of adaptive immune development, composition of skin bacterial communities, and skin structure. Thus how these findings translate to human biology and their implications for disrupting the composition of the neonatal skin microbiota will be a fruitful area of active investigation. Although detailed immunologic phenotyping of neonatal human skin has not yet been undertaken, Treg cells are enriched in pediatric compared with adult human skin.25Cordoro K.M. Hitraya-Low M. Taravati K. Sandoval P.M. Kim E. Sugarman J. et al.Skin-infiltrating, interleukin-22-producing T cells differentiate pediatric psoriasis from adult psoriasis.J Am Acad Dermatol. 2017; 77: 417-424Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar In considering potential translational applications of skin microbiome research, one can envision both corrective interventions to treat an established skin disease and preventative measures to reduce risk of disease onset or mitigate future severity. The latter might be especially relevant for conditions such as AD, in which variable penetrance based on genetic susceptibility and an early age of onset are defining features.26Weidinger S. Beck L.A. Bieber T. Kabashima K. Irvine A.D. Atopic dermatitis.Nat Rev Dis Primers. 2018; 4: 1Crossref PubMed Scopus (273) Google Scholar Continued work to define the early-life influence of skin microbes on cutaneous immune function, both in the context of healthy and barrier-disrupted skin, will be critical to inform future development of prevention-oriented recommendations and microbe-based interventions. The skin presents a physical barrier to harmful agents while establishing a unique innate immune system to regulate resident microbial communities. 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Constantinides M.G. et al.Contextual control of skin immunity and inflammation by Corynebacterium.J Exp Med. 2018; 215: 785-799Crossref PubMed Scopus (92) Google Scholar By contrast, CD4+ TH17 programs are broadly triggered by a wide array of microbes on skin colonization.35Naik S. Bouladoux N. Linehan J.L.1 Han S.J. Harrison O.J. Wilhelm C. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature.Nature. 2015; 520: 104-108Crossref PubMed Scopus (470) Google Scholar Thus it is tempting to speculate that the cutaneous immune system has evolved to sense skin microbial complexity and to use this information as a rheostat to continuously calibrate its function. The myriad of immune cells elicited by commensals have several contextual roles in reinforcing the epidermal barrier. Commensal-specific immune responses help provide heterologous protection against dermal pathogens. By augmenting epidermal antimicrobial function, commensal-specific T cells limit the ability of pathogens, such as Candida albicans, to establish infections.35Naik S. Bouladoux N. Linehan J.L.1 Han S.J. Harrison O.J. Wilhelm C. Commensal-dendritic-cell interac