白色念珠菌通过肠道微生态真菌-细菌跨界交互作用影响粪菌移植治疗艰难梭菌感染的机制研究

艰难梭菌感染（CDI）是以伪膜性肠炎等消化道症状为发病特点的细菌性感染疾病。粪菌移植（FMT）是通过粪便细菌群移植的方式实现CDI治疗的重要手段，但肠道真菌的定植在此过程是否扮演一定的角色尚不明确。申请人前期研究发现：白色念珠菌（一种真菌）在供体或受体中任何一方肠道中存在时，FMT治疗CDI的效果均会显著降低。申请人前期还发现：白色念珠菌可以影响艰难梭菌生长；并与人体肠道多种益生共生菌丰度显著负相关。因此，申请人科学猜想：白色念珠菌可通过肠道真菌-细菌互作来促进艰难梭菌持续定植、拮抗FMT治疗。本项目拟应用宏基因组学、代谢组学等手段寻找可能的关键相关菌/分子，然后通过体外（真菌-细菌-关键参与菌/参与分子-宿主细胞四元递进、梯度共培养）和体内（动物）实验，逐步定位寻找白色念珠菌促进艰难梭菌持续定植的关键中间细菌和分子，并揭示真菌-细菌互作机制在FMT治疗中的重要作用。

Clostridium difficile infection (CDI) is a debilitating disease featured by pseudomembranous colitis and diarrhea, caused by a single bacterial pathogen C. difficile. Fecal microbiota transplantation (FMT) is an efficacious treatment for clearing CDI through fecal bacterial transfer, however the engagement of gut fungi in this process is unclear. The applicant previously found that the presence of Candida albicans (a fungus) in the intestine of either FMT donor or recipient nullified FMT efficacy. The applicant’s subsequent pilot study showed that C. albicans could promote C. difficile growth and was inversely correlated with the abundances of multiple beneficial bacterial commensals in the gut. The applicant therefore hypothesizes that C. albicans may counteract FMT in treating CDI by synergistically influencing the growth of C. difficile and the fungal-bacterial interactions in the gut. To test this hypothesis, the applicant will adopt multidisciplinary approaches, including metagenomic and metabolomic profiling to pinpoint candidate keystone bacteria and/or metabolite molecules; subsequently by employing in vitro (step-wise co-culture of C. albicans, C. difficile, keystone bacteria and/or metabolite molecules, and host cells) and in vivo (animal) models, the applicant will pinpoint the key intermediating bacteria and molecules in C. albicans facilitating constant colonization of C. difficile, as well as unveil the mechanistic importance of fungal-bacterial interaction underlying FMT treatment.