5-Fluorouracil sensitivity varies among oral micro-organisms

Abstract

5-Fluorouracil (5-FU), a commonly used chemotherapeutic agent, often causes oral mucositis, an inflammation and ulceration of the oral mucosa. Micro-organisms in the oral cavity are thought to play an important role in the aggravation and severity of mucositis, but the mechanisms behind this remain unclear. Although 5-FU has been shown to elicit antibacterial effects at high concentrations (>100 µM), its antibacterial effect at physiologically relevant concentrations in the oral cavity is unknown. This study reports the effect of different concentrations of 5-FU (range 0.1-50 µM) on the growth and viability of bacterial monocultures that are present in the oral cavity and the possible role in the activity of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in 5-FU resistance. Our data showed a differential sensitivity among the tested oral species towards physiological concentrations of 5-FU. Klebsiella oxytoca, Streptococcus salivarius, Streptococcus mitis, Streptococcus oralis, Pseudomonas aeruginosa and Lactobacillus salivarius appeared to be highly resistant to all tested concentrations. In contrast, Lactobacillus oris, Lactobacillus plantarum, Streptococcus pyogenes, Fusobacterium nucleatum and Neisseria mucosa showed a significant reduction in growth and viability starting from very low concentrations (0.2-3.1 µM). We can also provide evidence that DPD is not involved in the 5-FU resistance of the selected species. The observed variability in response to physiological 5-FU concentrations may explain why certain microbiota lead to a community dysbiosis and/or an overgrowth of certain resistant micro-organisms in the oral cavity following cancer treatment.

Antibacterial activity of chemotherapeutic drugs against Escherichia coli and Staphylococcus pseudintermedius

“…These findings are consistent with the conclusion of Cohen et al () who found that 5‐FU is primarily bacteriostatic and Vanlancker et al () who reported a decreased growth rate of Streptococcus salivarius and Pseudomonas aeruginosa exposed to 5‐FU. Others have reported more profound effects including the complete inhibition of E. coli and S. aureus at concentrations as low as 0·5 mg l −1 and 1 mg l −1 respectively (Bodet et al ).…”

“…Cytotoxic chemotherapeutic agents used to treat malignant neoplasms have been shown to have off target effects on prokaryotic organisms; similarly some antimicrobials have anti‐tumour activity (Soo et al ; Markowska et al ). Antibacterial effects have been reported for bleomycin (Bodet et al ; Xu et al ), gemcitabine (Sandrini et al ; Jordheim et al ), 5‐fluorouracil (5‐FU) (Cohen et al ; Rogers and Perkins ; Hamilton‐Miller ; Bodet et al ; Vanlancker et al ), doxorubicin (Hamilton‐Miller ; Bodet et al ; Peiris and Oppenheim ; Panda et al ; Feng et al ) and methotrexate (Hamilton‐Miller ; Kruszewska et al ). Unsurprisingly, the spectrum of antibacterial effect for each drug varies between bacterial species (Bodet et al ).…”

The pathogenesis of mucositis: updated perspectives and emerging targets

“…Recent patient studies have looked at overall diversity of oral flora and shifts during chemotherapy [6] to determine relationships with oral mucositis. In vitro models of oral keratinocytes have also been used to demonstrate how microbes impact healing [7,8], as well as the functional changes to the microbes themselves during exposure to irradiation [9,10]. The field has also been advancing rapidly in the area of intestinal mucositis, where microbial dysbiosis, measured in easily accessible fecal samples, has led researchers to postulate that gut microbiome composition can be used as a surrogate marker for changes leading to diarrhea [11].…”

Mutational signatures shift induced by chemotherapeutic agents, 5-Fluorouracil and Oxaliplatin, in the gut microbiome

“…Two commensal species including S. salivarius and L. salivarius were significant enriched after the chemotherapy. According to the previous studies, these two species appeared to be highly resistant to 5-FU [36], which maybe the main driver for a community dysbiosis. We hypothesized that if 5-FU was responsible for the dysbiosis changes seen during chemotherapy, then depleted taxa should be susceptible to the drug while the enriched species would be resistant to 5-FU.…”