Antifungal defense of probiotic Lactobacillus rhamnosus GG is mediated by blocking adhesion and nutrient depletion. Candida albicans

Candida albicans is an inhabitant of mucosal surfaces in healthy humans but also the most common cause of fungal nosocomial blood stream infections, associated with high morbidity and mortality. As such life-threatening infections often disseminate from superficial mucosal infections we aimed to study the use of probiotic Lactobacillus rhamnosus GG (LGG) in prevention of mucosal C. albicans infections. Here, we demonstrate that LGG protects oral epithelial tissue from damage caused by C. albicans in our in vitro model of oral candidiasis. Furthermore, we provide insights into the mechanisms behind this protection and dissect direct and indirect effects of LGG on C. albicans pathogenicity. C. albicans viability was not affected by LGG. Instead, transcriptional profiling using RNA-Seq indicated dramatic metabolic reprogramming of C. albicans. Additionally, LGG had a significant impact on major virulence attributes, including adhesion, invasion, and hyphal extension, whose reduction, consequently, prevented epithelial damage. This was accompanied by glucose depletion and repression of ergosterol synthesis, caused by LGG, but also due to blocked adhesion sites. Therefore, LGG protects oral epithelia against C. albicans infection by preventing fungal adhesion, invasion and damage, driven, at least in parts, by metabolic reprogramming due to nutrient limitation caused by LGG. Overall design: Host pathogen interaction study with probiotic strain

白色念珠菌（Candida albicans）是健康人体黏膜表面的定植菌，同时也是引发真菌性医院获得性血流感染最常见的病原体，该类感染常伴随较高的发病率与死亡率。鉴于此类危及生命的感染常由浅表黏膜感染播散而来，本研究旨在探讨益生菌鼠李糖乳杆菌GG株（Lactobacillus rhamnosus GG，LGG）在预防黏膜白色念珠菌感染中的应用价值。本研究通过口腔念珠菌病体外模型证实，LGG可保护口腔上皮组织免受白色念珠菌所致的损伤。此外，本研究还阐明了该保护作用背后的潜在机制，并剖析了LGG对白色念珠菌致病性的直接与间接影响。LGG并不会影响白色念珠菌的生存活力。与之相反，通过RNA测序（RNA-Seq）开展的转录组分析显示，白色念珠菌发生了显著的代谢重编程。此外，LGG对白色念珠菌的主要毒力特性（包括黏附、侵袭及菌丝延伸）具有显著影响；上述毒力特性的削弱，进而阻止了上皮组织的损伤。该现象伴随LGG介导的葡萄糖耗竭与麦角固醇合成抑制，同时也与黏附位点被阻断有关。因此，LGG可通过抑制真菌黏附、侵袭及组织损伤，从而保护口腔上皮免受白色念珠菌感染，该保护作用至少部分源于LGG引发的营养限制所导致的代谢重编程。整体实验设计：采用益生菌菌株开展的宿主-病原体互作研究。