Summary Mammals have formed an evolutionary alliance with the commensal microbes that inhabit our epithelial boundaries. This lifelong relationship is forged at birth when microbes first colonize our surfaces. Alterations in neonatal microbial communities are associated with several prevalent epithelial inflammatory diseases, including atopic dermatitis. Atopic dermatitis is a devastating skin disease affecting about 20% of children in the western world and is rooted in epidermal barrier dysfunction and commensal dysbiosis. Yet, surprisingly little is known about the functional interactions between colonizing commensals and epithelial populations in neonatal skin. Epidermal stem and progenitor cells (ESPCs) maintain the epidermis throughout our lifetime by taking cues from the microenvironment or “niche”. We recently uncovered a remarkable capacity for ESPCs to sense, respond to, and remember inflammatory stimuli. Whether and how commensal signals similarly influence ESPCs and shape epidermal tissue fitness is an open question. Here we address the tantalizing possibility that commensal microbes are a heretofore unappreciated ESPC niche component. Thus, we aim to illuminate their roles in directing ESPC differentiation, innate immune activation and, consequently, epithelial barrier function and fitness in neonates, when microbes first colonize the skin. We also seek to functionally examine how the early-in-life epithelial–microbe dialogue impacts atopic disease susceptibility. Our proposed use of genetically tractable commensal strains and epidermal-specific deletion of defined microbial sensors with a state-of-the art in vivo tissue-specific gene modulation system to systematically manipulate both host and microbe allows for a comprehensive and mechanistic understanding of the microbe–ESPC dialogue and its impact on epidermal health and disease. The findings the generated from these studies will lay the groundwork for developing microbiota-based therapies to boost the epidermal barrier and mitigate atopic disease.

PROJECT NARRATIVE By taking cues from their microenvironment or “niche”, epidermal stem and progenitor cells (ESPCs) balance proliferation and differentiation to continually generate the epidermis throughout our lifetime. Remarkably little is understood about how signals derived from the commensal microbiota, which harmoniously reside on and in the epidermis, influence ESPCs and consequently epidermal barrier function. This proposal seeks to determine how microbial signals direct ESPC behavior and impact of this cross-talk on skin barrier function and susceptibility to atopic skin disease.