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Therapeutic Responses to Roseomonas mucosa in Atopic Dermatitis Involve Lipid-Mediated TNF-related Epithelial Repair

ABSTRACT: Dysbiosis is increasingly implicated as a targetable contributor to the pathogenesis of atopic dermatitis (AD). We previously reported first-in-human safety and clinical activity results from topical application of commensal R. mucosa for the treatment of AD in ten adults and five children older than 9 years of age. However, both mechanism of action and impacts on the most common age range for AD patients (less than 7 years of age) remained unexplored. We now show in patients as young as three years, R. mucosa treatment was associated with significant improvements in disease severity, barrier function, S. aureus burden, topical steroid requirements, and quality of life without any related adverse events. Our observed response rates were significantly greater than those seen in the placebo control groups of prior AD studies and similar to responses seen during open-label testing phase for currently approved topical treatments. Improvements and colonization persisted up to 8 months after cessation of treatment. Production of lipids in the sphingolipid pathway, cholinergic signaling, and flagellin expression accounted for modeled therapeutic impacts via induction of TNFR2-related epithelia-to-mesenchymal transition. These results support conduct of a placebo-controlled trial and suggest a role of commensals in maintenance of the epithelial barrier.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146184 | GEO | 2020/09/23

REPOSITORIES: GEO

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Project description:Background: Dupilumab is an IL-4 receptor a mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and 210.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and Th17/Th22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P 5 .001; week 16, P 5 .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen- specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor a blockade significantly and progressively improved disease activity, suppressed cellular/ molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities. (J Allergy Clin Immunol 2019;143:155-72.)

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Therapeutic Responses to Roseomonas mucosa in Atopic Dermatitis Involve Lipid-Mediated TNF-related Epithelial Repair

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