Department of Oral Health Sciences, University of Connecticut Health Center, Farmington, Connecticut, United States of America.
Microbial Analysis, Resources, and Services Core, University of Connecticut, Storrs, Connecticut, United States of America.
PLoS Pathog. 2019 Apr 22;15(4):e1007717. doi: 10.1371/journal.ppat.1007717. eCollection 2019 Apr.
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.
感染性并发症是癌症患者接受化疗后发病率和死亡率升高的常见原因，这是由于口腔和胃肠道念珠菌病、念珠菌血症和败血症的风险增加所致。白念珠菌与内源性黏膜细菌之间的相互作用对于理解侵袭性感染的机制非常重要。我们发表了一种小鼠静脉内化疗模型，该模型可重现接受氟尿嘧啶治疗的患者的口腔和肠道黏膜炎以及骨髓抑制。我们使用该模型研究了白念珠菌对黏膜细菌微生物组的影响，并比较了同一小鼠口腔和肠道黏膜的全球群落变化。我们通过 qPCR、原位杂交和培养方法验证了 16S rRNA 基因测序数据。接受 5-氟尿嘧啶和白念珠菌的小鼠在口腔而不是小肠黏膜上出现内源性细菌过度生长。白念珠菌感染与口腔和肠道黏膜的细菌多样性丧失有关，在这些部位，土著的 Stenotrophomonas、α-变形菌门和肠球菌属占主导地位，而肠球菌属在口腔黏膜中占主导地位。免疫抑制和念珠菌感染都导致了口腔微生物组的变化。从患有口咽念珠菌病的小鼠中分离出的肠球菌被认为可降解上皮连接蛋白 E-钙黏蛋白，并增加体外口腔上皮屏障的通透性。重要的是，体内用抗生素耗尽这些生物体可减弱口腔黏膜 E-钙黏蛋白降解和白念珠菌侵袭，而不影响真菌负荷，表明细菌群落变化代表明显的生态失调。我们的研究表明，白念珠菌、常驻黏膜细菌微生物群和发病机制中的宿主环境之间存在复杂的相互作用。我们为白念珠菌在塑造常驻细菌群落和驱动黏膜生态失调方面的作用提供了重要的新见解。
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