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

通过共生细菌产生抗真菌代谢物来调节真菌群和肠道炎症

• 批准号: 10087924
• 负责人: William D Fiers
• 金额: $ 7.05万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-25 至 2022-01-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087924
• 关键词: 16S ribosomal RNA sequencing; Adaptive Immune System; Anaerobic Bacteria; Antibiotics; Antibodies; Antifungal Agents; Area; Automobile Driving; Bacteria; Butyrates; C Type Lectin Receptors; Candida albicans; Cells; Chemicals; Colon; Communities; Complex; Consensus; Crohn' s disease; Data; Diagnostic; Disease; Disease Progression; Ecosystem; Environment; Environmental Impact; Environmental Risk Factor; Etiology; Evaluation; Flow Cytometry; Fungal Components; Gastrointestinal Diseases; Gastrointestinal tract structure; Generations; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Germ-Free; Growth; Health; Human; Immune response; Immune system; Immunologics; Impairment; In Vitro; Incidence; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune System; Intestines; Investigation; Knockout Mice; Laboratories; Libraries; Literature; Mediator of activation protein; Modeling; Mononuclear; Mus; Natural Products; Onset of illness; Oral; Organism; Pathway interactions; Phagocytes; Pharmaceutical Preparations; Physiological; Play; Population; Prevalence; Prevention; Probiotics; Production; Property; Protozoa; Regulation; Regulatory T-Lymphocyte; Reproducibility; Research; Ribosomes; Role; Small Intestines; Stains; Stream; Structure; Systemic infection; Testing; Twin Multiple Birth; Ulcerative Colitis; Valerates; Virus; Volatile Fatty Acids; Work; adaptive immune response; base; colonization resistance; commensal bacteria; cost; dectin 1; dysbiosis; fungal microbiota; fungus; gastrointestinal; gastrointestinal infection; germ free condition; gut bacteria; gut microbiota; immune activation; in vivo; inflammatory disease of the intestine; insight; member; microbial; microbiome sequencing; microbiota; mouse model; mycobiome; neutrophil; new therapeutic target; novel; opportunistic pathogen; pathogenic fungus; pressure; prevent; response; small molecule; therapy design; tool; treatment strategy

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.

项目摘要 人体肠道支持由细菌（或真菌）组成的复杂的微生物环境。 微生物群）和真菌（或真菌生物群）成分。虽然这些生物体在诱导 肠道中的免疫激活和炎症已经开始被研究， 科学界认为，它们在胃肠道内的种间相互作用仍然是一个问题。 研究领域不足。这种相互作用的化学基础，对于合理设计 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 与陆地和海洋次级代谢物结构测定的活跃领域形成鲜明对比 和生物活性，其中生物合成的天然产物和效应途径似乎源源不断 真菌和细菌之间的区别我们初步的核糖体16 S测序数据显示， 厌氧细菌的特定群落以可再生的方式急剧增加， 抗真菌药物这一分析表明，细菌和真菌可能占据着类似的竞争优势， 肠道生态系统中的生态位。为了阐明细菌代谢物影响 我们开发了一个已知肠道代谢物库， 在体外生理相关条件下筛选抗真菌活性。这导致了识别 两种细菌来源的具有抗真菌活性的代谢产物。此外，我们实验室和其他人的工作 表明，在炎症性肠病（IBD）期间， 人肠道和条件性真菌病原体白色念珠菌（C.白色念珠菌）。我们 因此，假设机会致病真菌是由细菌代谢产物控制的 并且该机制由肠道真菌刺激并影响胃肠炎症。此外 为了在前所未有的小分子水平上揭示真菌-细菌相互作用的新机制， 这项研究的结果将阐明真菌生态失调如何影响病原学和进展 肠道炎症，照亮潜在的新战略，治疗胃肠道疾病。