PROJECT SUMMARY
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.