From prebiotics to engineered microbes: microbe-inspired therapies for atopic dermatitis

Abstract Atopic dermatitis (AD) is a common chronic inflammatory skin disease with diverse clinical and histological features. While primarily immune-mediated, genetic studies have also highlighted the role of epithelium-expressed gene abnormalities (e.g., filaggrin mutations) as a key factor. The approaches to treat AD are multifaceted, involving barrier restoration, local anti-inflammatory treatment, and, if needed, systemic immunosuppressive therapy. Genetic variations in the stratum corneum and the immune system are linked to an unbalance between the host and its microbiota, known as dysbiosis. An impaired skin barrier and immune responses can alter the microbial composition, while the skin microbiota itself can influence skin immunity and barrier formation. A hallmark of AD is increased bacterial colonization with Staphylococcus aureus (S. aureus), which is found on lesional skin in over 90% of patients. It contributes to disease severity driving further breakdown of the skin barrier and immune stimulation. The most common treatment for S. aureus infections in AD is topical or systemic antibiotic administration. While these treatments are typically reserved for active infections, they are sometimes prescribed to AD patients without clear skin infection. However, these treatments can disrupt commensal skin and gut microbiota, which play a critical role in maintaining skin and gut health. In this review we describe various therapies targeting the skin microbiome to reduce infection and inflammation in AD, including transplantation of microbiota, and the use of prebiotics, probiotics, and postbiotics. In addition, we provide a perspective to engineer and to harness bacteria of the skin microbiome as next-generation probiotics, also known as engineered live biotherapeutic products (eLBPs), using synthetic biology to create strains that can sense skin signals, such as immune signals, and environmental factors, and produce therapeutic treatments for AD on demand.