Oral mucosal microbiome alterations in recurrent aphthous stomatitis: a systematic review of 16 S rRNA gene sequencing studies

Recurrent aphthous stomatitis (RAS) is a prevalent inflammatory disorder of the oral mucosa characterized by recurrent painful ulcerations in otherwise healthy individuals. This systematic review aimed to evaluate alterations in the oral mucosal microbiome of patients with RAS based on studies using 16 S rRNA sequencing. A systematic search of PubMed, Scopus, and Web of Science was conducted on April 14, 2026. Eligible studies included human case-control investigations evaluating oral mucosal swab samples from patients with clinically diagnosed RAS and healthy controls using 16 S rRNA sequencing. Studies based solely on saliva, culture methods, PCR-only analyses, or lacking controls were excluded. Joanna Briggs Institute Critical Appraisal Checklist for Case-Control Studies was used for the evaluation of selected articles. Six studies met the inclusion criteria. Considerable heterogeneity was observed in alpha and beta diversity outcomes. Most studies reported reduced microbial richness in RAS lesions, whereas others found increased or unchanged diversity. Ulcerated sites frequently demonstrated reduced abundance of health-associated taxa such as Streptococcus and Firmicutes, with increased levels of Proteobacteria and inflammation-associated genera including Neisseria, Haemophilus, Prevotella, and Fusobacterium. Microbial alterations were most pronounced at active ulcer sites, while non-ulcerated or healed mucosa more closely resembled healthy controls. Current evidence suggests that RAS is associated with localized, site-specific microbial dysbiosis rather than generalized oral microbiome disruption. However, methodological heterogeneity and small sample sizes limit definitive conclusions. Future standardized longitudinal studies integrating functional metagenomics are warranted to clarify the role of the microbiome in RAS pathogenesis.