Connection between drug-mediated neurotransmission and salivary microbiome

Salivary microbiome alterations associated with cognitive function have been reported in patients with neurodegenerative diseases1-3. Gut microorganisms can modulate therapeutic efficacy via drug metabolism4-7. Additionally, several drugs against diabetes and inflammatory bowel disease can lead to microbial dysbiosis8-10. However, the effect of central nervous system (CNS) drug use on the microbiome remains unknown. Here, we show that the usage of anti-dementia drugs, including donepezil and memantine, more largely affects the salivary microbiome composition than the gut microbiome composition. We observed salivary microbiome diversity reduction in patients with neurodegenerative diseases who received N-methyl-D-aspartate receptor inhibitor drugs. Furthermore, the use of acetylcholine-modulating drugs contributed to the salivary microbiome composition, suggesting that the salivary microbiome responds to changes in CNS drug-induced cerebral acetylcholine and glutamate levels. Multivariate analysis adjusted with or without the use of anti-dementia drugs demonstrated that the difference in the salivary microbiome correlated with cognitive function. We show the unique salivary microbiome structure of CNS drug users, suggesting the possibility of monitoring pharmacokinetics using the salivary microbiome. Our results also provide evidence of the presence of the microbiome-oral-brain axis and will accelerate the elucidation of the interplay between the salivary microbiome and neurodegeneration.