Integrated Analysis of Clinical and Microbiome Risk Factors Associated with the Development of Oral Candidiasis during Cancer Chemotherapy

Abstract

Oral candidiasis is a common side effect of cancer chemotherapy. To better understand predisposing factors, we followed forty-five subjects who received 5-fluorouracil- or doxorubicin-based treatment, during one chemotherapy cycle. Subjects were evaluated at baseline, prior to the first infusion, and at three additional visits within a two-week window. We assessed the demographic, medical and oral health parameters, neutrophil surveillance, and characterized the salivary bacteriome and mycobiome communities through amplicon high throughput sequencing. Twenty percent of all subjects developed oral candidiasis. Using multivariate statistics, we identified smoking, amount of dental plaque, low bacteriome and mycobiome alpha-diversity, and the proportions of specific bacterial and fungal taxa as baseline predictors of oral candidiasis development during the treatment cycle. All subjects who developed oral candidiasis had baseline microbiome communities dominated by Candida and enriched in aciduric bacteria. Longitudinally, oral candidiasis was associated with a decrease in salivary flow prior to lesion development, and occurred simultaneously or before oral mucositis. Candidiasis was also longitudinally associated with a decrease in peripheral neutrophils but increased the neutrophil killing capacity of Candida albicans. Oral candidiasis was not found to be associated with mycobiome structure shifts during the cycle but was the result of an increase in Candida load, with C. albicans and Candida dubliniensis being the most abundant species comprising the salivary mycobiome of the affected subjects. In conclusion, we identified a set of clinical and microbiome baseline factors associated with susceptibility to oral candidiasis, which might be useful tools in identifying at risk individuals, prior to chemotherapy.

The Dysbiosis and Inter-Kingdom Synergy Model in Oropharyngeal Candidiasis, a New Perspective in Pathogenesis

“…This finding supports the concept that candidiasis occurs in a polymicrobial environment enriched with these bacteria consistent with our mouse tongue infection models [13,[15][16][17]49]. We also conducted the first prospective study of oral microbiome changes in chemotherapy-treated cancer patients who develop oropharyngeal candidiasis [22]. In this cohort, development of oropharyngeal candidiasis was not associated with mycobiome structure shifts but was the result of increased Candida load, with C. albicans being the most abundant species [22].…”

“…Oral microbiome shifts could not be explained by antibiotic intake or by a selective antibacterial action of 5-FU [41]. Interestingly, salivary fungal communities were not disturbed by chemotherapy while antibiotic use was not correlated with the risk for developing oropharyngeal candidiasis [22,41]. A chemotherapy-induced increase in oral commensal bacterial burdens, particularly aciduric bacteria such as Lactobacilli and Streptococci has also been reported in a chemotherapy treated breast cancer cohort [42].…”

“…The oral cavity is home to hundreds of bacterial species and close to one hundred fungal species [19,20]. C. albicans is the most abundant fungal species in the oral microbiome [20][21][22], colonizes the alimentary tract of 30-70% of healthy individuals within the first few weeks of life, and persists without causing disease [23]. The frequency of colonization, number of species, and strains of oral Candida spp.…”

Candida biofilm production is associated with higher mortality in patients with candidaemia

“…30 There is less evidence for an association between fungi and cancer; it was shown that lesions on the oral mucosa have a greater likelihood of undergoing malignant transformation when infected with Candida compared with those that are not infected. [31][32][33] Furthermore, the adherence and biofilm production of Candida cells on patient mucosa is higher following radiotherapy, both in terms of number of cells and total biomass production, which may be associated with the increased frequency of fungal mucosal infections. 34,35 We observed candidaemia with bacteraemia in 34% of all cases consistent with the previously described data ranging from 6% to 34.5%.…”

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

“…We previously found both the mouth and gut to be dominated by Candida albicans and Candida glabrata prior to mucormycosis during induction remission chemotherapy (8). Similarly, patients with a baseline microbiome community dominated by Candida and aciduric bacteria were more likely to develop oral candidiasis during antineoplastic treatment (9). Recently, variation in mycobiome composition was linked to treatment-related toxicities after autologous HSCT for multiple myeloma (10).…”