Impact of the repurposed drug thonzonium bromide on host oral-gut microbiomes

Drug repurposing has become a feasible strategy for the development of novel therapeutic applications, including as antimicrobials. However, in vivo studies investigating its alternative antimicrobial use for oral treatments and their influence on the local and distant gut microbiota remain sparse. Here, we assessed the impact of topical oral applications of a repurposed FDA-approved drug, thonzonium bromide, on the gastrointestinal microbiome and host tissues in a rat model of dental caries. To investigate the oral and gut microbiota from the same animals, we employed suspended cages designed to reduce cross-contamination associated with coprophagy. Using this model, we recapitulated the distinctive body-site microbiota that mirror the human microbiome profile as determined by 16S amplicon sequence variant and compositional analyses. Oral microbiota was perturbed by the treatments with specific disruption of Rothia and Veillonella (associated with dental caries), whereas no global impact in the fecal microbial community was observed. However, specific disturbances in the oral-gut microbial interactions were identified using nestedness and machine-learning approaches, showing increased sharing of oral taxon Sutterella in the gut microbiota. Host-tissue analyses revealed dental caries reduction on teeth by topical thonzonium bromide without deleterious effects on the oral or intestinal soft tissues, indicating bioactivity and biocompatibility when used orally. Altogether, we demonstrate how an oral treatment using a repurposed drug caused localized microbial disturbances and therapeutic effects while promoting turnover of specific oral species in the lower gut in vivo.