Oral microbiome dysbiosis and innate immune dysregulation as determinants of oronasal fistula after primary cleft palate repair.

Oronasal fistula complicates 15-55% of primary cleft palate repairs, with recurrence rates approaching 43% after secondary closure, and global fistula rates have risen despite decades of iterative technical refinement, a trend that mechanical closure quality alone cannot explain. This narrative review synthesizes evidence from PubMed/MEDLINE, Scopus, and Web of Science from inception through April 2026 to argue that ONF is increasingly recognizable as a biologically mediated complication in which oral microbiome dysbiosis and innate immune dysregulation are primary, historically underrecognized determinants of palatal wound failure that act in synergy with, rather than independently of, mechanical and technical factors. Children with cleft lip and palate harbor a preoperative dysbiotic oral microbiome characterized by reduced alpha diversity, enrichment of Gram-negative anaerobes, and elevated proportions of pathobionts, including Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella spp., establishing an unfavorable immunological baseline before the first surgical incision. Perioperative broad-spectrum antibiotic prophylaxis compounds this trajectory by depleting commensal communities, while suture-associated polymicrobial biofilms sustain a persistent antigenic depot at the healing flap margin. Unremitting pathogen-associated molecular pattern exposure drives sustained TLR4-NF-κB signaling, NLRP3 inflammasome activation, macrophage M1 polarization arrest, neutrophil extracellular trap-mediated matrix degradation, and complement-coagulation amplification at the wound interface. Failure of the specialized pro-resolving mediator class switch leaves the wound frozen in a self-sustaining inflammatory state, precluding re-epithelialization and adequate collagen deposition. Direct human biopsy evidence for these pathways at palatoplasty wound margins remains limited; the causal temporal relationship between dysbiosis and wound breakdown remains unresolved; and all translational proposals require prospective validation in cleft-specific cohorts. Reducing ONF burden demands a conceptual shift from purely mechanical closure paradigms toward precision perioperative strategies that pair preoperative microbiome profiling, targeted immune modulation, and resolution-phase biomarker monitoring with sound surgical fundamentals.