Altered skin microbiome, inflammation, and JAK/STAT signaling in Southeast Asian ichthyosis patients

Abstract

Background 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. Results 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. Conclusions 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.

The Innate Immune System Surveillance Biomarker p87 in African Americans and Caucasians with Small High-Grade Dysplastic Adenoma [SHiGDA] and Right-Sided JAK3 Colon Mutations May Explain the Presence of Multiple Cancers Revealing an Important Minority of Patients with JAK3 Mutations and Colorectal Neoplasia

“…There are no current JAK3 mutations associated with microbiome studies aside from a solitary paper correlating skin microbiome with the Jak-Stat pathways [23]. In order to elucidate the presence of a JAK3-altered microbiome, we were able to define the microbiome in one APC patient with the seminal JAK3 mutation and one patient with a variant of the Lynch Syndrome, the Muir-Torre Syndrome who did not have a JAK3 mutation.…”

“…There are multiple studies of CRC in the African American population most recently reviewed by Carethers [23] showing that most studies show more proximal neoplasia and more advanced neoplasia on the right-side of the colon with greater lesion aggressiveness and poorer prognosis. Not all studies showed significant genetic changes in AA (African Americans) but more KRAS mutations and MSS CRC tumors were more prevalent [30].…”