Regulation of diabetic wound healing by the gut–liver axis via immunometabolic reprogramming of macrophages: from systemic pre-programming to targeted therapy

Diabetic wounds, particularly diabetic foot ulcers, remain a major clinical challenge due to their recalcitrance to healing and limited response to conventional therapies. Successful wound healing critically depends on timely macrophage phenotypic switching from a pro-inflammatory M1-like to a reparative M2-like state; however, the diabetic milieu—characterized by hyperglycemia and advanced glycation end products (AGEs)—impedes this transition, establishing macrophage dysfunction as a hallmark of chronic non-healing wounds. We propose a conceptual framework in which gut–liver axis dysfunction in diabetes does not merely act through direct delivery of metabolites to the wound bed, but may contribute to a state of systemic immunometabolic dysregulation that “pre-programs” bone-marrow-derived monocytes toward a pro-inflammatory M1-like bias before they reach the wound site. We discuss three potential components of this pre-programming: (i) the cellular targets—hematopoietic stem and progenitor cells and circulating monocyte precursors; (ii) the candidate signaling mediators—gut-derived lipopolysaccharide (LPS), inflammatory cytokines, and exosomes acting via the toll-like receptor 4 (TLR4)/NF-κB pathway; and (iii) the proposed molecular imprint—persistent modifications of histone marks such as H3K4me3 and H3K27ac at promoters of pro-inflammatory genes, accompanied by a metabolic shift toward aerobic glycolysis. Importantly, direct evidence that gut–liver-derived exosomes epigenetically remodel hematopoietic progenitors in diabetic wound healing is currently lacking, and this remains a hypothesis generated by integrating separate lines of evidence. Reduced gut-derived short-chain fatty acids (SCFAs) and disrupted hepatic bile acid metabolism may further exacerbate immune dysregulation within the wound microenvironment. On this basis, targeting the gut–liver axis to restore macrophage homeostasis has emerged as a promising therapeutic strategy. We summarize current evidence on probiotics, fecal microbiota transplantation, bile acid modulation, exosome-based delivery, and metabolic interventions, and discuss how these approaches may restore gut–liver axis homeostasis and reprogram macrophage phenotypes to promote wound healing. We clearly indicate the evidence level of each proposed intervention—human clinical trial, animal model, in vitro , or not yet tested. Looking ahead, the integration of multi-omics technologies with smart nanodelivery systems and personalized medicine strategies is expected to accelerate the translation of this regulatory network from basic research to clinical application, providing new conceptual and therapeutic avenues for the management of diabetic wounds.