Abstract
Diabetic foot ulcers (DFU) and venous leg ulcers (VLU) are prevalent chronic wounds with a debilitating impact on patient morbidity and mortality. Effective treatments for chronic wounds are limited and the absence of valid chronic wound animal models has driven the use of bioinformatics to gain new insights into dysregulated mechanisms shared in chronic wound healing. Because chronic wounds share features such as a hyperproliferative, non-migratory epidermis, fibrosis, decreased angiogenesis, and a de-regulated inflammatory response, it was predicted that a bioinformatic comparison of DFUs and VLUs would identify a core chronic wound transcriptome. Analysis of the newly identified core chronic wound transcriptome highlighted shared mechanisms, including a host response pathway modulated by the microbiome: the aryl hydrocarbon receptor signaling pathway. Aryl hydrocarbon receptor signaling was found to be suppressed in chronic wounds which contributes to wound healing inhibition. Additionally, comparisons of prototypical skin commensal bacteria strains isolated from chronic wounds found that increased antimicrobial resistance was a driver of bacterial fitness, pathogenicity, and wound healing impairment in chronic wounds. Further studies of the chronic wound microbiome identified an intracellular niche of S. aureus present which contributes to inflammatory cell death, pyroptosis. A postbiotic derived from Lactobacillus was found to effectively reduce the intracellular niche of S. aureus in keratinocytes while simultaneously promoting wound healing and strengthening the skin barrier. To validate the core chronic wound transcriptome and impacts of the microbiome, an integrative approach that included patients’ wound samples, primary human cells, and human skin ex vivo infection models were used. The results herein characterize mechanisms important for chronic wound healing and for future development of targeted therapeutics.