P33: Influencers in epidermolysis bullosa: the cutaneous microbiome

Ajoy Bardhan,^1,2 Dario Balacco,² Melissa Grant,² Sarah Kuehne,² Iain Chapple^2,3 and Adrian Heagerty^1,2

¹Adult EB Unit, University Hospitals Birmingham NHS Foundation Trust, Solihull, UK; ²Dermatology Research Group, University of Birmingham, Birmingham, UK; and ³Birmingham Dental Hospital, Birmingham Community Health NHS Trust, Birmingham, UK

Epidermolysis bullosa (EB) is a heterogeneous group of rare intractable inherited skin fragility disorders characterized by blister formation inducible by minimal-to-no trauma. Frustrated wound healing accounts for the major burden of disease. Microbial colonization and local infection is common. Moreover, recurrent and chronic wounds are painful, necessitate expensive dressings, generate increased metabolic demands and are a portal for disseminated life-threatening infection. Microbiological culture is typically employed in clinical practice to identify bacterial species and their sensitivities to antimicrobial treatments. However, the cutaneous microbiome – the total combined genetic material of the microbiota present on the skin – is thought to influence cutaneous homeostasis (including modulation of inflammation) in both health and disease. The advent of unbiased culture-independent molecular techniques to define the skin microbiome has enabled accurate surveys of microbial composition and structure, including fastidious organisms and those present in low abundance during ‘healthy’ conditions. Resident commensal microflora contribute to immune education, regulate innate and adaptive immunity, as well as competing with and inhibiting pathogens. Chronic wounds states, including diabetic foot ulcers and recessive dystrophic EB, have been shown to be associated with a persistent reduction in microbial diversity, termed ‘dysbiosis’. However, comprehensive assessments of the cutaneous microbiome have yet to be undertaken across EB subtypes. Initial studies used sequencing of highly conserved bacterial 16S rRNA to determine bacterial diversity and abundance. However, whole metagenome shotgun sequencing forgoes the need for marker genes and therefore offers a more comprehensive assessment of a microbial community, including fungi and viruses. While acute inflammation is a critical early stage during wound healing, chronic nonresolving inflammation in the setting of EB contributes to a stalled wound healing environment and an elevated risk of malignant transformation to highly aggressive squamous cell carcinoma. It is not yet known whether dysbiosis in EB wounds contributes to downstream signalling that results in a subsequent failure to resolve acute inflammation. To our knowledge, we have, for the first time, applied a shotgun metagenomic sequencing approach to characterize the cutaneous microbiome at the sites of acute blister formation across three major EB subtypes: EB simplex, junctional EB and dystrophic EB, identifying distinct shifts in microbial profiles vs. healthy controls. Further work is currently being undertaken to elucidate the significance of these unique microbial fingerprints and their impact on the acute inflammatory response in the setting of wound healing across EB subtypes. This may generate new insights into pathomechanisms underlying delayed wound healing, and unmask novel therapeutic targets that may be leveraged to improve wound healing, and consequently quality of life for affected individuals.