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

J Dermatol Sci. 2022 Jun;106(3):132-140. doi: 10.1016/j.jdermsci.2022.04.007. Epub 2022 Apr 15.


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 (ADMut) (n = 15), along with matched wild-type (ADWt) patients and healthy controls. 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 ADWt 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 ADWt or ADMut 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.

Keywords: Atopic dermatitis; Barrier function; Filaggrin; Microbiome; Multi-omics; Transcriptome.

MeSH terms

  • Dermatitis, Atopic* / metabolism
  • Filaggrin Proteins / metabolism*
  • Host Microbial Interactions / genetics
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism
  • Mutation
  • Skin / metabolism
  • Staphylococcus aureus


  • FLG protein, human
  • Filaggrin Proteins
  • Intermediate Filament Proteins