Congenital ichthyosis (CI) is a collective group of rare hereditary skin disorders. Patients present with epidermal scaling, fissuring, chronic inflammation, and increased susceptibility to infections. Recently, there is increased interest in the skin microbiome; therefore, we hypothesized that CI patients likely exhibit an abnormal profile of epidermal microbes because of their various underlying skin barrier defects. Among recruited individuals of Southeast Asian ethnicity, we performed skin meta-genomics (i.e., whole-exome sequencing to capture the entire multi-kingdom profile, including fungi, protists, archaea, bacteria, and viruses), comparing 36 CI patients (representing seven subtypes) with that of 15 CI age-and gender-matched controls who had no family history of CI. This case–control study revealed 20 novel and 31 recurrent pathogenic variants. Microbiome meta-analysis showed distinct microbial populations, decreases in commensal microbiota, and higher colonization by pathogenic species associated with CI; these were correlated with increased production of inflammatory cytokines and Th17- and JAK/STAT-signaling pathways in peripheral blood mononuclear cells. In the wounds of CI patients, we identified specific changes in microbiota and alterations in inflammatory pathways, which are likely responsible for impaired wound healing. Together, this research enhances our understanding of the microbiological, immunological, and molecular properties of CI and should provide critical information for improving therapeutic management of CI patients.

中文翻译：

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东南亚鱼鳞病患者皮肤微生物组、炎症和 JAK/STAT 信号的改变

先天性鱼鳞病（CI）是一组罕见的遗传性皮肤病。患者出现表皮脱屑、龟裂、慢性炎症和感染易感性增加。最近，人们对皮肤微生物组的兴趣日益浓厚。因此，我们假设 CI 患者可能由于其各种潜在的皮肤屏障缺陷而表现出异常的表皮微生物特征。在招募的东南亚种族个体中，我们进行了皮肤宏基因组学（即全外显子组测序，以捕获整个多界谱，包括真菌、原生生物、古细菌、细菌和病毒），比较了 36 名 CI 患者（代表 7 名亚型）与 15 名无 CI 家族史的年龄和性别匹配的 CI 对照。这项病例对照研究揭示了 20 种新的致病变异和 31 种复发致病变异。微生物组荟萃分析显示不同的微生物种群、共生微生物群的减少以及与 CI 相关的致病菌的定植增加；这些与外周血单核细胞中炎症细胞因子以及 Th17 和 JAK/STAT 信号通路的产生增加相关。在 CI 患者的伤口中，我们发现了微生物群的特定变化和炎症途径的改变，这可能是导致伤口愈合受损的原因。总之，这项研究增强了我们对 CI 的微生物学、免疫学和分子特性的理解，并为改善 CI 患者的治疗管理提供了关键信息。