Determinants of colonization for commensal skin bacteria

Abstract / Project Summary Microbiome-based therapies have untapped potential to prevent infection and treat disease—augmentation of the microbiome might one day promote colonization resistance against pathogens, treat inflammation, and provide therapeutic metabolites. The grand challenge facing microbiome-based therapies is the unpredictability of engraftment after application; the degree to and conditions under which human microbiomes are permissive to colonization of new strains is poorly understood. This application seeks to define rules of on-human bacterial evolution, ecology, and colonization, towards the long-term goal of determining the species and therapeutic design modalities that have the highest potential for long-lasting probiotic therapy. We use healthy human sebaceous skin as a model system because of its tractability, low complexity, and high similarity across humans, and because states of health are optimal for applying probiotics without instigating an immune response. We propose to profile five abundant species which comprise the vast majority of on and across person diversity in this community, at the high genomic resolution necessary to build rules of on-person engraftment. We hypothesize that our high-resolution, culture- based approach will reveal commonalities across species in terms of their on-person ecology and evolution, with differences that inform the niche of each microbe and species-specific therapeutic strategies. We will leverage a growing collection of longitudinally collected facial swabs from children, adolescents, and adults. In Aim 1, we will build on and across-person phylogenies to understand how strain stability and transmission vary across species and life stages. In Aim 2, we will characterize the extent to which each species’ on-person evolution is dominated by adaptive versus neutral evolution, which will inform the degree to which probiotics will need to be personalized. In Aim 3, we will identify the role to which interbacterial antagonism controls colonization by combining genomic data with high-throughput in vitro screening and modeling. This work will identify common and species-specific rules of colonization in the skin microbiome, and microbiomes in general, laying the foundation for probiotic strategies with high potential for stable colonization.