Regulation of the mycobiota and intestinal inflammation via production of antifungal metabolites by commensal bacteria

项目摘要 人类肠道支持复杂的微生物环境，包括细菌(或 微生物区系)和真菌(或真菌生物区系)成分。尽管这些生物中的每一个在引诱 肠道中的免疫激活和炎症已经开始被更大的 科学界，它们在胃肠道背景下的物种间相互作用仍然是 代表性不足的研究领域。这种相互作用的化学基础，对合理设计 胃肠道感染和疾病的治疗，在文献中仍然是完全未知的领域。这 与陆地和海洋次生代谢物结构测定的活跃领域形成鲜明对比 和生物活性，在那里似乎源源不断的生物合成的天然产物和效应器途径 阐明了真菌和细菌之间的关系。我们的初步核糖体16S测序数据显示 厌氧细菌的特定群落以一种可重复的方式急剧增加， 抗真菌药物。这一分析表明，细菌和真菌可能占据着相似的、竞争的 肠道生态系统中的生态位。阐明细菌代谢物可能会影响 菌群，从而建立了竞争优势，我们开发了一个已知肠道代谢物和 在体外生理相关条件下筛选抗真菌活性。这导致了身份的确认 两种细菌来源的具有抗真菌活性的代谢物。此外，我们实验室和其他实验室的工作已经 研究表明，在炎症性肠病(IBD)期间，真菌生物群的物种水平多样性丢失 人体肠道和生长的机会真菌病原体白色念珠菌(白色念珠菌)。我们 因此，假设条件致病真菌受到细菌代谢产物的抑制 这一机制受到肠道真菌的刺激，并影响胃肠道炎症。此外 为了在前所未有的小分子水平上揭示真菌和细菌相互作用的新机制， 这项拟议的调查结果将阐明真菌失调是如何影响病因和进展的。 治疗肠道炎症，为胃肠道疾病的治疗提供了潜在的新策略。

Project Summary The human intestinal tract supports a complex microbial environment consisting of bacterial (or microbiota) and fungal (or mycobiota) constituents. Although the role of each of these organisms in eliciting immune activation and inflammation in the gut has begun to be investigated and appreciated by the larger scientific community, their interspecies interactions within the context of the gastrointestinal tract remains an underrepresented area of research. The chemical basis for such interactions, critical for the rational design of treatments in gastrointestinal infection and disease, remain completely uncharted territory in the literature. This lies in stark contrast to the vibrant fields of terrestrial and marine secondary metabolite structural determination and bioactivity, where a seemingly endless stream of biosynthesized natural products and effector pathways been elucidated between fungi and bacteria. Our preliminary ribosomal 16S sequencing data show that specific communities of anaerobic bacteria are drastically increased in a reproducible way with a variety of antifungal medications. This analysis indicates that bacteria and fungi may occupy a similar, competitive ecological niche within the gut ecosystem. To illuminate the potential for bacterial metabolites to influence the mycobiota, thereby establishing a competitive advantage, we developed a library of known gut metabolites and screened for antifungal activity at physiologically relevant conditions in vitro. This resulted in the identification of two metabolites of bacterial origin with antifungal activity. Additionally, the work of our lab and others has shown that species-level diversity in the mycobiota is lost during inflammatory bowel disease (IBD) in the human gut and outgrowth of the opportunistic fungal pathogen Candida albicans (C. albicans) is observed. We therefore hypothesize that opportunistic pathogenic fungi are held in check by bacterial metabolite production and that this mechanism is stimulated by intestinal fungi and impacts gastrointestinal inflammation. In addition to revealing novel mechanisms of fungal-bacterial interaction at an unprecedented small molecule level, the results of this proposed investigation will illuminate how fungal dysbiosis impacts the etiology and progression of intestinal inflammation, illuminating potential new strategies for the treatment of gastrointestinal diseases.