Topical Propionate Accelerates Skin Wound Healing in Diabetic Mice Through an FFAR2-Independent Pathway

Wound healing is a complex physiological process divided into inflammatory, proliferative, and remodeling phases. In diabetes mellitus, this process is impaired, leading to chronic wounds with slow healing, high infection risk and limited efficacy by conventional therapies. Short-chain fatty acids (SCFAs), microbiota-derived metabolites, exhibit immunomodulatory actions via G-protein-coupled receptor activation or histone deacetylase (HDAC) inhibition, representing an attractive therapeutic strategy. This study evaluated the therapeutic role of propionate in wound healing using a type 1 diabetic murine model. Male C57BL/6 mice (8–12 weeks) were rendered diabetic with Alloxan (65 mg/kg i.v.;blood glucose >350 mg/dL after 7 days). An excisional dorsal skin wound (1 cm) was treated topically once daily with saline or propinoate (30 mM) for 14 days. Lesion area was quantified on days 0, 3, 7, 10, and 14. On day 7, cytokines, remodeling enzymes, and the expression of free fatty acid receptor 2 (FFAR2) and HDACs were assessed. Propionate accelerated wound closure in diabetic mice (p<0.05), but not in euglycemic controls. In FFAR2-deficient mice, the pro-healing effect of propionate was maintained, suggesting an FFAR2-independent mechanism. On day 7, no differences were detected in inflammatory cytokines, neutrophil or macrophage infiltration, or the expression of FFAR2 and HDACs 3, 4, 8, and 9. However, propionate treatment significantly reduced MMP-3 and TIMP-1 levels (p<0.05). In vitro, propionate (0.1 mM, 24 h) stimulated human keratinocyte (HaCaT) migration under basal conditions, with a discrete effect under pro-inflammatory challenge. In conclusion, topical propionate promotes diabetic wound closure independent of FFAR2 without major alterations in local inflammation or HDAC expression, but with a direct impact on tissue remodeling enzymes and keratinocyte re-epithelialization, standing out as a promising candidate for chronic diabetic wound management