Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis

Abstract

Background Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. Results Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus , Actinomyces , Gemella , Granulicatella , and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris . Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. Conclusions Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dy...

The salivary microbiota in health and disease

“…Interestingly, strong correlation was observed in salivary levels of Lactobacillus species and fluctuations of saliva flow rates and salivary pH levels during radiotherapy [80]. Another report demonstrated that chemotherapyinduced oral mucositis was associated with a decrease in salivary levels of health-associated bacterial genera, including Streptococcus, Actinomyces and Veillonella in combination with an increase of the periodontitis-associated genera Fusobacterium and Prevotella, and increased transcription of genes related to innate immunity and apoptosis in oral epithelial cells from patients with oral mucositis [81].…”

Observational Cohort Study of Oral Mycobiome and Interkingdom Interactions over the Course of Induction Therapy for Leukemia

“…It has been previously shown that cytotoxic and cisplatin compounds have direct anti-Candida activity and also inhibit filamentation/conidation (12). More recently, investigators demonstrated that the oral microbiome is disrupted by 5-fluorouracil (5-FU) and doxorubicin chemotherapy, but they did not observe major changes in the composition of the mycobiome (13). Moreover, mice receiving both 5-fluorouracil and C. albicans had a loss of bacterial diversity and showed endogenous overgrowth of organisms such as Enterococcus and Stenotrophomonas in the oral mucosa (14).…”

“…To our knowledge, the changes in the oral mycobiome occurring as a result of chemotherapy have been studied only in regard to their role in chemotherapy-induced mucositis in the setting of 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy in mice and humans (13,14). In patients, although the authors expected chemotherapy to affect the oral mycobiome, no major changes in the composition of fungal communities were observed (13). Thus, our study would be the first to show specific changes in the oral mycobiome associated with chemotherapeutic intensity and type.…”

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

“…Chemotherapeutic agents may affect gut microbial communities by disrupting the homeostatic balance among resident microorganisms; meanwhile, they can accelerate the microbe evolution at molecular level [4][5][6]. Many recent studies have explored the interaction between microbiota and anticancer drugs along with interventions aimed at shaping microbiota to optimize drug efficacy and reduce side effects [7].…”