Influence of FLG loss-of-function mutations in host-microbe interactions during atopic skin inflammation

Background: Loss-of-function mutations in the filaggrin (FLG) gene directly alter skin barrier function and critically influence atopic inflammation. While skin barrier dysfunction, Th2-associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the mechanisms interconnecting genotype, transcriptome and microbiome remain largely elusive. Objective: In-depth analysis of FLG genotype-associated skin gene expression alterations and host-microbe interactions in AD. Methods: Multi-omics characterization of a cohort of AD patients carrying heterozygous loss-of-function mutations in the FLG gene (AD(Mut)) (n = 15), along with matched wild-type (AD(Wt)) patients and healthycontrols. Detailed clinical characterization, microarray gene expression and 16 S rRNA-based microbial marker gene data were generated and analyzed. Results: In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis, while the lesional skin of AD(Wt )demonstrated the specific upregulation of pro-inflammatory cytokines and T-cell proliferation. S. aureus dominated the microbiome in both patient groups, however, shifting microbial communities could be observed when comparing healthy with non-lesional AD(Wt) or AD(Mut) skin, offering the opportunity to identify microbe-associated transcriptomic signatures. Moreover, an AD core signature with 28 genes, including CCL13, CCL18, BTC, SCIN, RAB31 and PCLO was identified. Conclusions: Our integrative approach provides molecular insights for the concept that FLG loss-of-function mutations are a genetic shortcut to atopic inflammation and unravels the complex interplay between genotype, transcriptome and microbiome in the human holobiont. Crown Copyright (c) 2022 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology. All rights reserved.

Automated summary

This study investigates the relationship between FLG gene mutations and atopic dermatitis (AD), revealing that FLG mutations lead to skin barrier dysfunction and water imbalance, as well as enhanced inflammatory response and T-cell proliferation. Staphylococcus aureus dominates the microbial communities in AD patients, and changes in microbial composition can be observed when comparing healthy individuals or non-lesional skin.