Pathological microbial niches in diabetic foot ulcers: a host-microbe framework for impaired repair and niche-based...

Diabetic foot ulcers (DFUs) are commonly described through the clinical triad of hyperglycaemia, ischaemia and infection. That language is useful for bedside decision-making, but it does not fully explain why some wounds remain inflamed and open despite debridement, offloading, antimicrobial therapy, vascular assessment and modern wound care. Here we develop a conceptual review framework in which many non-healing DFUs are interpreted as pathological microbial niches: local tissue regions where microbial persistence and host repair failure reinforce each other. Hyperglycaemia, impaired perfusion, hypoxia, neuropathic pressure injury, necrotic material and extracellular matrix degradation generate ecological space for microbial survival. Microbial products, biofilm-like spatial organisation, strain-level traits, fungi and polymicrobial interactions then amplify neutrophil extracellular traps, inflammasome signalling, protease release, fibroblast dysfunction, endothelial impairment and defective re-epithelialisation. The result is not a linear sequence from colonisation to infection to inflammation, but a self-reinforcing loop in which microbial adaptation and host non-healing programs become difficult to separate. We summarise evidence from chronic wound microbiome studies, biofilm histology, strain-level and fungal analyses, host transcriptomics, single-cell data and emerging spatial omics, while emphasising the boundaries of each evidence type. The central question is not whether microbes can be detected in DFU tissue, but whether they are viable, metabolically active, spatially organised and positioned close enough to host cells to alter repair behaviour. We propose an operational definition of the pathological microbial niche and a translational scheme for biofilm-dominant, ischaemia-dominant, protease-dominant, senescence-dominant and immune-resolution-failure wound patterns. This framing may help move DFU microbiome research from descriptive association toward mechanism-based stratification and more rational combinations of source control, vascular optimisation, antimicrobial therapy and repair-directed treatment.