Cutaneous Nod2 Expression Regulates the Skin Microbiome and Wound Healing in a Murine Model

The skin microbiome exists in dynamic equilibrium with the host but when the skin is compromised, bacteria can colonise the wound and impair wound healing. Thus the interplay between normal skin-microbial interactions versus pathogenic-microbial interactions in wound repair is important. Bacteria are recognised by innate host pattern recognition receptors (PRRs) and we previously demonstrated an important role for the PRR NOD2 (nucleotide-binding oligomerisation domains-containing protein 2) in skin wound repair. NOD2 is implicated in changes in the composition of the intestinal microbiota in Crohn’s disease but its role on skin microbiota is unknown. Nod2-deficient (Nod2-/-) mice had an inherently altered skin microbiome compared with wild-type (WT) controls. Furthermore, we found Nod2-/- skin microbiome dominated and caused impaired healing, revealed in cross-fostering experiments of WT with Nod2-/- pups which then acquired altered cutaneous bacteria and delayed healing. High-throughput sequencing and qPCR revealed a significant compositional shift, specifically in the genus Pseudomonas in Nod2-/- mice. To confirm whether Pseudomonas directly impairs wound healing, WT mice were infected with P. aeruginosa biofilms and akin to Nod2-/- mice, were found to exhibit a significant delay in wound repair. Collectively, these studies demonstrate the importance of the microbial communities in skin wound healing outcome.