Candida albicans induces mucosal bacterial dysbiosis that promotes invasive infection

Abstract

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.

Role of glucosyltransferase R in biofilm interactions between Streptococcus oralis and Candida albicans

“…It is possible that, like lactobacilli, endogenous streptococcal species have antagonistic relationships with C. albicans. Of note, S. oralis and other human streptococcal species with symbiotic relationships with this fungus are not part of the mouse microbiome [18,33,40]. However, we have reported a symbiotic relationship between oral endogenous enterococci and C. albicans in mice [33], consistent with the reduction in the abundance of these organisms in mice receiving sucrose that have reduced C. albicans burdens.…”

“…Tongue bacterial DNA and sequencing was performed using a lysis protocol and sequencing analysis pipeline optimized for mucosal microbiome characterization in murine tongue tissues [33]. The V4 region was amplified using 515F and 806R primers with Illumina adapters and bar codes on the 3′ end.…”

The Role of Candida albicans Secreted Polysaccharides in Augmenting Streptococcus mutans Adherence and Mixed Biofilm Formation: In vitro and in vivo Studies

“…The oral microbiome is one of the most complex environments harboring diverse microbiota that co-exist in equilibrium (Wade, 2013;Krom et al, 2014;Xu and Dongari-Bagtzoglou, 2015;Sultan et al, 2018). This equilibrium is crucial for maintaining oral health as an imbalance potentiates the dominance of pathogenic species, which may lead to the development of disease (Jenkinson and Lamont, 2005;Duran-Pinedo and Frias-Lopez, 2015;Bertolini et al, 2019). In the oral cavity, microorganisms exist within highly organized and structured microbial communities referred to as biofilms, where microbial cells are embedded within a self-produced extracellular polymeric substance (Jenkinson et al, 1990;Kolenbrander et al, 2002;Rickard et al, 2003;Vu et al, 2009).…”

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

“…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). In addition to chemotherapy, antimicrobial therapy, a very common practice in this patient population, impacts mycobiome composition.…”

“…This effect was not seen in other taxa analyzed (data not shown). 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).…”