Harnessing Microbiome-Mediated and Macrophage-Driven Mechanisms for Oral Wound Healing

Oral mucosa healing is a complex process that involves the innate wound healing system, including the coagulation cascade, extracellular matrix remodeling, immune cell responses, and fibroblast and epithelial responses, within the context of a dynamic resident microbiome. Unlike cutaneous wounds, oral wounds heal rapidly with minimal scarring despite constant exposure to diverse microbial communities, saliva, and mechanical stress. Emerging evidence highlights the critical interplay between microbiome-mediated signaling and macrophage plasticity in shaping wound outcomes, suggesting that similar mechanisms operate within the oral cavity. Inflammation is an essential component of wound repair, and its resolution is necessary to promote tissue remodeling and functional regeneration. Macrophages play a central role in this transition through phenotype switching from a pro-inflammatory (M1) to a pro-resolving, anti-inflammatory (M2) state. This review synthesizes current understanding of the oral microbiome's influence on macrophage polarization across distinct stages of oral wound healing and examines microbial-based strategies that modulate the immune response to enhance repair. Significant knowledge gaps remain, including limited clinical translation, inter-individual variability in microbiome composition, and complete mechanistic insight into host-microbe immune interaction. Addressing these challenges enables the development of precision microbiome-based therapeutics that restore microbial balance, direct macrophage-driven regeneration, and improve outcomes in oral wounds and chronic inflammatory conditions.