Modulating Host-Microbial Pathways to Prevent Diabetic Foot Ulcer-Related Amputations

Diabetic foot ulcers (DFUs) are a severe complication of diabetes, costing the NHS over £1Bn per year and leading to life-threatening amputations. Current treatments are inadequate, thus there is an urgent clinical need to develop effective therapies that will prevent amputation and restore patient quality of life. We have shown that the microbiome and cellular senescence are two crucial factors linked to poor healing in diabetes. We demonstrated that the bacterial profile of a DFU upon presentation predicts whether it will heal, while our research in mice showed a fundamental link between cellular senescence and poor diabetic wound repair. In this proposal, we will bring together these two important concepts, determining whether the microbiome is a critical driver of senescence in DFU pathology. We will utilise cutting-edge long-read sequencing to identify DFU-isolated pathogens and elucidate their role on host healing and senescence (Aim 1). We will then undertake mechanistic studies to modulate putative microbial pathways driving wound cell senescence (Aim 2). Finally, we will determine whether microbial modulation via postbiotics dampens senescence and reverses diabetic wound pathology (Aim 3). These studies will demonstrate the exciting potential of microbiome modulation to restore healing, which could revolutionise DFU treatment and prevent amputations.