While the existence of skin-associated bacteria and fungi has been long-documented with culture-based studies, genomic sequencing studies enable identification of fastidious organisms and the simultaneous study of individual species and microbial communities. My laboratory has performed foundational studies of both the skin bacterial and fungal communities of healthy volunteer. Our clinical studies have focused on children with moderate to severe AD, who often progress to develop other atopic disorders, such as allergic rhinitis (hay fever) and asthma. Our objective is to investigate whether microbial diversity might serve as a biomarker to predict a change in disease progression and to direct an individual patients treatment. Our human skin microbiome research is carried out under clinicaltrials.gov NCT00605878;PI: Segre. We analyzed the composition of bacterial communities during AD disease states to identify characteristics associated with AD flares and improvement post-treatment27. Disease severity was assessed quantitatively with SCORAD (SCORing AD), a well-validated clinical tool31. Our longitudinal study of pediatric AD patients shows a drop in skin microbial diversity and an increase in Staphylococcus aureus with disease flare (Kong et al, Genome Research, 2012). We found that microbial community structures at sites of disease predilection were dramatically different in AD patients compared with controls. Microbial diversity during AD flares was dependent on recent treatment, with even intermittent treatment linked to greater bacterial diversity. In AD, the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment and correlated with worsened disease severity. These findings demonstrate that, as compared to culture-based studies, higher resolution examination of microbiota associated with human disease provides novel insights into global shifts of bacteria relevant to disease progression and treatment. Our previous human micobiome projects have focused primarily on bacterial diversity for technical reasons, such as DNA preparations, which did not lyse fungi, and for analytic reasons, such as the limited bioinformatics tools. We built a fungal classification database, resolved taxonomic ambiguities, and implemented a pipeline for classification of fungal sequences (Findley et al, Nature 2013). We sequenced and analyzed fungal and bacterial communities of skin sites from healthy adults. Eleven core body and arm sites were dominated by Malassezia fungi, with species-level classifications revealing greater topographical resolution between sites. By contrast, three foot sites, plantar heel, toenail, and toeweb, exhibited tremendous fungal diversity. Our studies show that different forces shape bacterial and fungal communities. Variation in bacterial communities segregated strongly by skin physiology, grouping into sebaceous, moist and dry sites. By contrast, variation in fungal communities segregated more strongly by site location, with feet, arm, head and torso sites forming discrete groups. These results provide a framework to investigate interactions between fungal and bacterial communities in maintaining human health and contributing to disease pathogenesis. Mechanistically, we are assessing the skin microbiomes role in driving AD with animal models recapitulating the skin disorder. Future microbiome studies will integrate genetics of both host (human) and microbes, realizing that we are superorganisms with trillions of microbes living in and on our bodies and integratinng gene-environment interactions.

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Project End
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Budget End
Support Year
13
Fiscal Year
2013
Total Cost
$1,484,781
Indirect Cost
Name
National Human Genome Research Institute
Department
Type
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Oh, Julia; Byrd, Allyson L; Deming, Clay et al. (2014) Biogeography and individuality shape function in the human skin metagenome. Nature 514:59-64
Segre, Julia A (2013) What Does It Take to Satisfy Koch's Postulates Two Centuries Later?: Microbial Genomics and Propionibacteria acnes. J Invest Dermatol 133:2141-2
Scharschmidt, Tiffany C; List, Karin; Grice, Elizabeth A et al. (2009) Matriptase-deficient mice exhibit ichthyotic skin with a selective shift in skin microbiota. J Invest Dermatol 129:2435-42
Grice, Elizabeth A; Kong, Heidi H; Conlan, Sean et al. (2009) Topographical and temporal diversity of the human skin microbiome. Science 324:1190-2
Scharschmidt, Tiffany C; Segre, Julia A (2008) Modeling atopic dermatitis with increasingly complex mouse models. J Invest Dermatol 128:1061-4