Oral Microbiome and Metabolome Changes During Orthodontic Treatments: A Systematic Review of Limited Clinical Evidence

<i>Background and Objectives</i>: Recent advances in dentistry include microbiological and metabolomic analyses, which have the potential to improve the understanding of oral microbiome-host imbalances during orthodontic treatment. Fixed appliances, functional devices and, more recently, clear aligners have been associated with several oral health conditions, including enamel demineralization, dental caries, gingivitis, periodontitis and root and bone resorption. In this context, metabolomic approaches may enable the identification of metabolites in biological samples that could potentially serve as biomarkers and reflect functional biological changes within the oral ecosystem. Investigating orthodontic appliances and associated metabolomic alterations may therefore contribute to advancing current knowledge in orthodontics. This systematic review aimed to describe the available evidence on oral metabolomic changes during orthodontic treatment. <i>Materials and Methods</i>: A systematic literature search was conducted in PubMed, Web of Science, Scopus and the Cochrane Library. A total of 1632 records were identified. After duplicate removal and screening, 18 full-text articles were assessed for eligibility. Of these, 15 studies were excluded, and three studies met the inclusion criteria. Risk of bias was assessed using the ROBINS-I and RoB 2 tools, and the GRADE approach was applied to evaluate the certainty of evidence. The review protocol was registered in PROSPERO (CRD420251141544). <i>Results</i>: Three studies met the inclusion criteria. Overall, the available evidence was limited and heterogeneous. The included studies suggested potential differences in oral microbiome composition and metabolomic profiles between patients treated with fixed appliances and those treated with clear aligners. Reported metabolomic findings were exploratory and involved amino acid-related, immune-associated, and acidic metabolic pathways. Limitations: Only three studies were included, all conducted in a single country. The small sample size and methodological heterogeneity limit the generalizability of the findings. In addition, potential confounding variables highlight the need for further standardized longitudinal studies.