The skin microbiome represents the consortium of bacteria, viruses, fungi, and archaea living on our skin that has been shown to play an active and intimate role in shaping cutaneous health. Modulation of the skin milieu, whether host or microbial, provides a unique opportunity for innovative new therapeutics for skin and infectious disease prevention and treatment. Our long-term goal is to create new microbiome-based therapeutics that can integrate into the skin ecosystem and stably and continuously remediate the skin. Yet the integration of exogenous probiotics to an existing community has had little lasting success to date in either skin (or gut) communities, likely due to competitive barriers from other microbes or host exclusion by immune selection. Little is known about how potential probiotic strains integrate into an existing community and whether probiotics can be engineered to improve their entry and retention into an existing microbial community. Yet these are fundamental questions that must be answered to develop effective engineered probiotics. In this proposal, we will use a combination of high-throughput phenotyping, genomics, imaging, CRISPR-mediated genetic screens and computational modeling to define the rules that govern probiotic integration into an existing human skin microbiome in skin organoids and gnotobiotic mouse models. We will use these data to create and validate a predictive algorithm that, given microbial community and clinical data, suggests the best probiotic strain for that individual, skin site, or disease state, and predicts subsequent integration efficacy and impact on the endogenous microbial community. These data will also provide, by far, the deepest investigation to date into the ecology and genetics underlying skin microbial interactions. We will obtain new insights into the biological and genetic factors that may limit a probiotic?s efficacy in the skin. This will inform rational selection and engineering of probiotic strains, and will be applied to predicting community resilience to invading pathogens.
Skin diseases, both genetic and microbial in origin, affect 30-70% of the world?s population during their lifetime and account for an estimated $29 billion in direct costs/year and an additional $10 billion in lost productivity in the US alone. Microbiome-based therapeutics (probiotics) have great potential to provide new avenues to prevent and treat skin disease. The ability to optimize the selection and engineering of probiotic microbes will transform the therapeutic landscape of numerous skin diseases and provide a framework to modulate any microbial community that negatively impacts human health.
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