A Review of the Relationship between Oral Bacteria, Immunity, and Cognitive Function Targeting Drug Discovery

Introduction: The tripartite interaction between oral bacteria, the immune system, and cognitive function (the oral-brain axis) has increasingly garnered attention as a drug discovery target. Advanced biopharmaceutical technologies are used in addition to conventional vaccine technologies for developing preventive drugs. Regarding drug discovery, in addition to conventional improvements in the oral biome, the GAIN trial using gingipain inhibitors released by Porphyromonas gingivalis (Pg bacteria) has also attracted attention, as well as the serious effects of Treponema denticola (Td bacteria). Currently, there are no preventive drugs for these conditions; conventional oral hygiene management such as probiotics and scaling is the mainstay of treatment. Given this situation, developing preventive drugs is extremely important; we conducted this review for accelerating drug discovery. Method: Electronic search of PubMed, CENTRAL, MEDLINE, EMBASE, Google, and CINAHL was performed. This period comprised the most recent five years (2020–2025). Based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement, the screening of selected databases involved evaluating data by titles and abstracts, and the eligibility analysis involved organizing methodologies and key results by reading the full documents, followed by result evaluation and final analysis. Results: Clinical trials of gingipane protease inhibitors have confirmed their efficacy. However, newly discovered hepatotoxicity hinders drug development; moreover, the development of new drugs with improved safety is still in progress. Although probiotics and postbiotics have proven to be effective, antimicrobial resistance associated with conventional antibiotics is problematic. Phage therapy showed superior antimicrobial activity compared with conventional antibiotics, infecting and lysing only the target bacteria without affecting beneficial commensal bacteria. Conclusion: Developing preventive drugs focusing on the tripartite interaction between oral bacteria, the immune system, and cognitive function, new drugs are currently in the development stage and their safety needs to be established. Oral care is evolving from a conventional and uniform approach into a precise one based on individuals’ genetic background, microbiome, and systemic disease status. The use of Artificial Intelligence and induced pluripotent stem cells in regenerative medicine is progressing.