Date Published: April 22, 2019
Publisher: Public Library of Science
Author(s): Martinna Bertolini, Amit Ranjan, Angela Thompson, Patricia I. Diaz, Takanori Sobue, Kendra Maas, Anna Dongari-Bagtzoglou, Mairi C. Noverr.
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.
Oropharyngeal (OPC) and gastrointestinal candidiasis are common infections in patients on high dose cancer chemotherapy, mostly attributed to Candida albicans. In these populations prevalence rates of OPC range between 25–40% . Cytotoxic chemotherapy also causes an inflammatory form of oral and gastrointestinal injury known as mucositis . Mucosal injury combined with the myelosuppressive effects of chemotherapy, promote bacterial and fungal translocation through mucosal barriers leading to bloodstream infections, a major cause of morbidity and mortality in this patient population [3,4]. There is some evidence that the oral and intestinal bacterial microbiota in humans may be altered by cytotoxic chemotherapy, although the effects on the fungal microbiota are less clear [5,6].
In this study we investigated the influence of C. albicans infection on the composition of the oral and intestinal mucosa-associated bacteria in the context of cytotoxic chemotherapy. We demonstrated that C. albicans infection led to a profound taxonomic imbalance on the oral mucosa that contributed to pathology. We also discovered that antibiotics that clear the dominant Enterococcus taxon during infection ameliorate invasive candidiasis, further demonstrating that bacterial community changes in OPC represent a dysbiotic shift promoting C. albicans virulence. Importantly, although antibiotics alone significantly increased oral fungal burdens, virulence required a chemotherapy-modulated host environment. Mucosal injury and immunosuppression caused by 5Fu played a major role in increased invasive infection in this model, with dysbiotic communities playing an accessory role. Thus our studies support a novel pathogenesis framework in the oral mucosa which includes the fungus, the resident bacterial microbiota and a host-permissive environment (Fig 9).