What's the 'Skinny' on Microbiome? Interplay of Immune Cells, Microbes, and Skin Barrier in Health and Disease
Authors: Segre Julie , Kong Heidi , Candotti Fabio , Holland Steven M. , Freeman Alexandra F , Oh Julia , Sokolic Robert A. 
Published: October 2019

Abstract
Culture-based methods have been the primary techniques used to study microbes inhabiting humans; however, many species are not successfully grown in culture. We performed high throughput genomic sequencing surveys to investigate the topographical and temporal complexity of skin microbial communities from 20 skin sites in healthy adults. Significant differences were observed in the bacterial species predominating in particular microenvironments: sebaceous, moist, and dry. Surveying fungal diversity with genomic sequencing, we determined that core body and arm sites were dominated by Malassezia fungi, with species-level classifications revealing greater topographical resolution between sites. Three foot sites, plantar heel, toenail, and toeweb, exhibited tremendous fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that skin physiological attributes and topography differentially shape these two microbial communities. While activated and shaped by microbiota, little is known of how the human immune system regulates the human microbiome, and in turn, how this can result in a disease phenotype. We describe the microbial characteristics of the skin of primary immunodeficiency (PID) patients who share a common phenotype of skin eczema yet have different syndromes arising from monogenic mutations leading to loss of distinct lymphocytic populations. We surveyed the skin microbiomes of 41 individuals with Hyper IgE, Wiskott-Aldrich, and Dedicator of Cytokinesis 8 syndromes and compared them against classical atopic dermatitis (AD) patients and healthy controls at skin sites characteristically affected by eczema, a control site, and a site of pathogen carriage (nares). We found that primary immunodeficiency increases the permissiveness of skin microbial colonization not observed in healthy controls or AD patients. We observed decreased site specificity and longitudinal stability in the PID patients as well as unique colonization by environmental microbiota very rare in healthy or AD controls. We identified taxa correlated and anti-correlated with clinical metamarkers in the PID patients; while Staphylococcus aureus, a known pathogen, was most strongly correlated with disease severity, other staphylococci such as S. haemolyticus and S. epidermidis were significantly overrepresented in the PID individuals. These data provide the first illustration of how PID affects microbial prevalence, diversity, and dynamics in relation to skin disease, gaining insight into host-microbiome interactions and how environmental microbes can uniquely colonize PID patients. This comprehensive survey of the skin microbiome also provided the foundation for analyzing changes in the microbial community associated with common forms of AD, which affect ~15% of U.S. children and ~2% of adults and is associated with Staphylococcus aureus colonization and infection. We studied 10 children with moderate to severe AD at baseline, flare, and post-flare, and healthy controls. Severity was quantified using scoring atopic dermatitis (SCORAD). Samples were obtained from characteristically affected areas, a control site, and nares. Bacterial diversity was dramatically reduced during flare as compared to post-flare and controls. Our studies provide comprehensive characterization of skin microbes in AD and controls confirm the frequent culture-based isolation of S. aureus in AD flares and represent one of the earliest longitudinal investigations of the skin microbiome in a dermatologic disorder.

Disclosures
No relevant conflicts of interest to declare.