Functional characterization and directed modulation of the skin microbiome in pemphigoid diseases

皮肤微生物区系在免疫和局部炎症反应中发挥着越来越重要的作用，这些微生物群落的变化是在慢性炎症性皮肤病的背景下观察到的。在第一个资助期间，我们实现了对大疱性类天疱疮(BP)背景下皮肤微生物区系的全面描述，并确定了几个可能影响疾病出现和/或严重程度的有趣的候选细菌分类群。在这项提案中，我们的目标是进一步表征和测试候选益生菌及其产品对BP的调节潜力。因此，我们计划实现BP皮肤微生物组的精细分类和功能表征，包括功能猎枪元基因组图谱和在类天疱疮(PD)小鼠模型的背景下对已识别的候选细菌的实验评估。葡萄球菌属和丙酸杆菌属的候选细菌类群是人们特别感兴趣的，其中短链脂肪酸是调控疾病的候选细菌衍生效应分子。我们建议的具体目标包括(I)定义关键候选指示物种的物种水平分类，(Ii)确定候选益生菌在小鼠PD模型中的作用，以及(Iii)识别人类BP皮肤微生物组中的功能基因组差异和菌株水平变异。

The skin microbiota play an increasingly recognized role in immunity and local inflammatory responses, and alternations in these microbial communities are observed in the context of chronic inflammatory skin diseases. During the first funding period we achieved a thorough description of the skin microbiota in the context of bullous pemphigoid (BP) and identified several interesting candidate bacterial taxa that may influence the likelihood of disease emergence and/or severity. In this proposal, we aim to further characterize and test candidate probiotic bacteria and their products for the potential to modulate BP. Accordingly, we plan to achieve a fine-scale taxonomic and functional characterization of the skin microbiome in BP, including functional shotgun metagenomic profiling and experimental evaluation of the identified candidate bacteria in the context of mouse models of pemphigoid disease (PD). Candidate bacterial taxa belonging to the genera Staphylococcus and Propionibacterium are of specific interest, for which short chain fatty acids are candidate bacteria-derived effector molecules modulating disease. The specific aims of our proposal include (i) define species level taxonomy of key candidate indicator species, (ii) determine the effect of candidate probiotic bacteria in a mouse PD model and (iii) identify functional genomic differences and strain level variation in the human BP skin microbiome.