Progressive microbiome dysregulation with predominance of Staphylococcus correlates with wound burden and disease activity in recessive dystrophic epidermolysis bullosa: a prospective case-control study

BackgroundRecessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis characterised by skin fragility, with blistering, wounds and inflammation. Bacterial wound colonisation and infection, mainly caused by Staphylococcus aureus, are common, but the interplay of microbiome dysregulation and RDEB disease activity, severity, systemic inflammation, and age were so far unknown.ObjectivesBy analysing the microbiome of skin, wounds, oral mucosa, and stool in a well-characterised RDEB cohort, we aimed to uncover the natural history and dynamics of skin and mucosal microbiome and its impact on clinical and inflammatory laboratory parameters.MethodsMicrobiome swabs from wounded and unwounded skin, oral mucosa and stool samples of children and adolescents (0-20 years) with RDEB were prospectively collected, subjected to 16S-sequencing, and compared to age- and sex-matched healthy controls. Blood samples were analysed for blood count, CRP, immunoglobulins, and selected cytokines. Taxonomy, alpha diversity, and abundances were correlated with wound burden, disease activity and inflammatory parameters in statistical models.Results28 children (mean age 9.6 years), 18 with severe and 10 with intermediate RDEB, and 28 healthy age-matched controls were included. Skin microbiome showed significantly reduced alpha diversity compared to healthy controls and early, age-progressive predominance of Staphylococcus first in wounds, then in unwounded skin. Changes in oral mucosal and gut microbiome in RDEB were less pronounced with no significant differences in alpha diversity. Patients with severe disease showed reduced alpha diversity and higher abundances of Staphylococcus on both wounded and unwounded skin. Staphylococcus abundance correlated significantly with both acute (P < 0.01) and chronic (P < 0.05) wound burden. High CRP correlated with higher abundance of Staphylococcus on unwounded skin (P < 0.05) and of Bifidobacterium on both unwounded skin (P < 0.01) and wounds (P < 0.05). No significant correlations were found with IL-6, INF-gamma, TGF-beta, or TNF-alpha levels. Stepwise linear regression modelling for Staphylococcus aureus abundance on wounds included total wound burden, chronic wound burden, total EBDASI, CRP, leukocyte count, IL-6, TGF-beta and TNF-alpha.ConclusionsChildren with RDEB experience early and progressive skin microbiome dysregulation starting on wounds and later extending to unwounded skin. The predominance of Staphylococcus significantly correlates with wound burden and disease activity, and to some extent with systemic inflammation. While the immune system seems capable to cope with the bacterial load to a certain extent, this study emphasises the need to target Staphylococcus early not only on wounds, but on the entire skin surface.