Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Elizabeth A. Grice

Second Advisor

Frederic D. Bushman

Abstract

The skin is colonized by communities of bacteria, fungi, and viruses, collectively referred to as the skin microbiome. These microbial communities are shaped by the topology and diseases of the skin. Dysbiosis of the cutaneous microbiome has been associated with several ailments of the skin including atopic dermatitis, acne, rosacea, psoriasis, and chronic wounds. However, our understandings of the processes by which these microbes initiate, maintain, or modulate skin diseases is lacking. Moreover, previous research on the topic has largely been limited by cross-sectional study designs, neglecting the natural dynamism of microbial communities. Here we present a comprehensive analysis of the temporal dynamics of the skin microbiome in various diseases. In the first section, we characterize the diversity and dynamics of both bacterial and fungal communities colonizing chronic wounds and its associations with clinical outcomes. In a study of 100 subjects with diabetic foot ulcers, we sampled the wound microbiota in 2-week intervals until healing, amputation of 26 weeks of follow-up. We demonstrate the high levels of community instability in chronic wounds and expose the positive association between wound healing community instability. We also reveal the effect of antibiotic perturbation on the microbiota. The fungal component was found to have associations with various bacteria and clinical outcomes. Our results should inform the design of future studies and provides evidence that microbial dynamics may be an effective biomarker for identifying high-risk ulcers. The second section investigates the body-site specific effects of psoriasis on the skin microbiome and how it responds to therapy. We reveal these patterns in a study of 114 subjects, across 6 body sites, and over 112 weeks of follow-up. The effect of psoriatic lesions was found to be mild and body-site specific. In contrast, ustekinumab treatment was found to induce moderate shifts in microbial composition, including an increase in atypical skin bacteria and inter-individual heterogeneity. These results suggest that the effect of psoriasis lesions is secondary to the effect the broad effects of the immune environment. Together the work presented in this thesis represents a significant advancement in our understanding of the microbial dynamics of the skin and their associations with human health.

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