Loss-of-function mutations in the filaggrin gene have been indicated to directly alter skin barrier function and critically influence atopic inflammation. While skin barrier disruption, Th2 associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the interconnecting mechanisms between genotype, transcriptome and microbiome remain largely elusive. In the present study we addressed these questions using a cohort of atopic dermatitis patients carrying heterozygous loss-of-function mutations in the filaggrin gene (ADMut) (n=15), along with age, sex, body site and severity (SCORAD)-matched wild-type (ADWt) patients and healthy controls from a large-cohort study. In the context of atopic inflammation, lesional skin of ADWt demonstrated significantly increased transcriptomic dysregulation when compared to ADMut, with the specific upregulation of pro-inflammatory cytokines and T-cell proliferation being most prominent. In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis. As expected, S. aureus dominated the microbiome in both ADWt and ADMut patients, however, shifting microbial communities could be observed when comparing healthy with non-lesional ADWt or ADMut skin. Taken together, our integrative approach provides further insight into the "holobiont", and the complex interplay between genotype, transcriptome and microbiome.

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