Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair

Abstract

Dysbiosis of the skin microbiota is increasingly implicated as a contributor to the pathogenesis of atopic dermatitis (AD). We previously reported first-in-human safety and clinical activity results from topical application of the commensal skin bacterium Roseomonas mucosa for the treatment of AD in 10 adults and 5 children older than 9 years of age. Here, we examined the potential mechanism of action of R. mucosa treatment and its impact on children with AD less than 7 years of age, the most common age group for children with AD. In 15 children with AD, R. mucosa treatment was associated with amelioration of disease severity, improvement in epithelial barrier function, reduced Staphylococcus aureus burden on the skin, and a reduction in topical steroid requirements without severe adverse events. Our observed response rates to R. mucosa treatment were greater than those seen in historical placebo control groups in prior AD studies. Skin improvements and colonization by R. mucosa persisted for up to 8 months after cessation of treatment. Analyses of cellular scratch assays and the MC903 mouse model of AD suggested that production of sphingolipids by R. mucosa, cholinergic signaling, and flagellin expression may have contributed to therapeutic impact through induction of a TNFR2-mediated epithelial-to-mesenchymal transition. These results suggest that a randomized, placebo-controlled trial of R. mucosa treatment in individuals with AD is warranted and implicate commensals in the maintenance of the skin epithelial barrier.

Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3

“…We previously demonstrated the importance of STAT3 in the scratch assay, an in vitro model of epithelial to mesenchymal transition (EMT; a central process of proliferation and migration of epithelial cells) mediated wound healing in patients with autosomal dominant hyper IgE syndrome due to STAT3 loss of function (STAT3LOF) [14]. We additionally demonstrated a role for STAT3 in the therapeutic response to the commensal flora Roseomonas mucosa in atopic dermatitis [15]. The influence of STAT3 on Warburg physiology as well as on cell proliferation and migration require concurrent activation of JAK2 [5,12,16].…”

Epithelial-Mesenchymal Transition in Atopy: A Mini-Review

“…A recent publication from our group identified therapeutic benefit of topical microbiome transplantation of Roseomonas mucosa from healthy volunteers to the lesions of patients with AD (129). Subsequent research found that lipid mediators from R. mucosa stimulate EMT through potentiation of tumor necrosis factor receptor 2 and nicotinic acetylcholine activation; an additional role for flagella interactions with Toll-Like Receptor 5 was identified (113). This finding was consistent with our prior results in autosomal-dominant hyper IgE syndrome, a primary immune deficiency with an eczematous phenotype.…”

Targeting Innate Immunity to Combat Cutaneous Stress: The Vitiligo Perspective

“…Modulating the skin or gut microbiome appears as an appealing approach. Recent data conducted in atopic dermatitis skin, demonstrated that topical formulation containing specific strains of probiotics could improve skin lesions (62). Additional studies are urgently needed, especially those in vitiligo, but modulation of microbiome, using prebiotics, probiotics, postbiotics, or fecal microbiota transplantation, could be an alternative approach for secondary prevention in vitiligo.…”