Candida albicans induces mucosal bacterial dysbiosis that promotes invasive infection

Infectious complications are a common cause of morbidity and mortality in cancer patients undergoing chemotherapy due to increased risk of oral and gastrointestinal candidiasis, candidemia and septicemia. Interactions between C. albicans and endogenous mucosal bacteria are important in understanding the mechanisms of invasive infection. We published a mouse intravenous chemotherapy model that recapitulates oral and intestinal mucositis, and myelosuppression in patients receiving 5-fluorouracil. We used this model to study the influence of C. albicans on the mucosal bacterial microbiome and compared global community changes in the oral and intestinal mucosa of the same mice. We validated 16S rRNA gene sequencing data by qPCR, in situ hybridization and culture approaches. Mice receiving both 5Fu and C. albicans had an endogenous bacterial overgrowth on the oral but not the small intestinal mucosa. C. albicans infection was associated with loss of mucosal bacterial diversity in both sites with indigenous Stenotrophomonas, Alphaproteobacteria and Enterococcus species dominating the small intestinal, and Enterococcus species dominating the oral mucosa. Both immunosuppression and Candida infection contributed to changes in the oral microbiota. Enterococci isolated from mice with oropharyngeal candidiasis were implicated in degrading the epithelial junction protein E-cadherin and increasing the permeability of the oral epithelial barrier in vitro. Importantly, depletion of these organisms with antibiotics in vivo attenuated oral mucosal E-cadherin degradation and C. albicans invasion without affecting fungal burdens, indicating that bacterial community changes represent overt dysbiosis. Our studies demonstrate a complex interaction between C. albicans, the resident mucosal bacterial microbiota and the host environment in pathogenesis. We shed significant new light on the role of C. albicans in shaping resident bacterial communities and driving mucosal dysbiosis. Author summary In cancer patients receiving high dose chemotherapy mucosal candidiasis is common and can lead to invasive, systemic fungal infection with mortality ranging 25-30%. We showed that in chemotherapy-immunosuppressed mice C. albicans induces a dysbiotic switch that favors growth of enterococci on mucosal surfaces, particularly on the oral mucosa. Overgrowth of these organisms led to enhanced oral mucosal barrier breach by C. albicans. Like C. albicans, Enterococcus species are a major concern in critical care patients due to their involvement in sepsis and resistance to multiple antibiotics. There is mounting evidence that C. albicans and Enterococci co-exist in human disease samples. Our discoveries provide the first experimental evidence of pathogenic synergy between these microorganisms in the context of dysbiosis.