Investigation of commensal bacteria-produced metabolites with activity towards mycobiota.

研究共生细菌产生的对分枝菌群具有活性的代谢物。

基本信息

批准号：
9808950
负责人：
ILIYAN Dimitrov ILIEV
金额：
$ 25.43万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-10 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808950
关键词：
16S ribosomal RNA sequencing Anaerobic Bacteria Antibiotics Antifungal Agents Area Automobile Driving Bacteria Biological Blood Body Surface Butyrates CX3CR1 gene Candida Candida albicans Cells Chemicals Chemotherapy-Oncologic Procedure Communities Complex DNA Sequence Alteration Data Diagnostic Ecosystem Environment Environmental Impact Evaluation Flow Cytometry Fungal Components Gastrointestinal Diseases Gastrointestinal tract structure Generations Genes Genetic Genetic Polymorphism Germ-Free Growth Health Human Immune system Immunity Immunologics In Vitro Individual Infection Infectious Agent Inflammation Inflammatory Bowel Diseases Intestinal Diseases Intestines Investigation Knowledge Laboratories Libraries Link Literature Marines Mucosal Immunity Mucous Membrane Mus Mycoses Natural Products Oral Organism Pathology Pathway interactions Patients Pharmaceutical Preparations Physiological Population Prevalence Prevention Production Property Regulatory T-Lymphocyte Reproducibility Research Ribosomes Role Sampling Shapes Stains Stream Structure Systemic infection Testing Therapeutic immunosuppression Transplantation Valerates Volatile Fatty Acids Yeasts base colonization resistance commensal bacteria dectin 1 deep sequencing dysbiosis fungal microbiota fungus gastrointestinal infection germ free condition gut microbiome gut microbiota immune activation in vivo in vivo Model insight member microbial microbiota monocyte mouse model mycobiome neutrophil new therapeutic target novel pathogenic fungus pressure receptor response small molecule therapy design tool treatment strategy

项目摘要

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 as well as their ability to initiate systemic infection 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 have 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 activity towards opportunistic members of the mycobiota. We therefore hypothesize that opportunistic pathogenic fungi in the gut are held in check by bacterial metabolite production and that this mechanism is stimulated by intestinal fungi to impact infectious states. In addition to revealing novel mechanisms of fungal-bacterial interaction at an unprecedented small molecule level, the results of this proposed investigation will illuminate potential new strategies for targeting of fungal pathogens.

项目概要人类肠道支持一个复杂的微生物环境，其中包括细菌（或微生物群）和真菌（或分枝菌群）成分。尽管这些生物体在引发肠道内的免疫激活和炎症以及引发全身感染的能力已开始受到更大的科学界的调查和赞赏，它们在物种间的相互作用胃肠道的背景仍然是一个代表性不足的研究领域。化学基础为这种相互作用对于胃肠道感染和疾病治疗的合理设计至关重要，仍然存在文学中完全未知的领域。这与陆地和地球的生机勃勃的领域形成鲜明对比。海洋次生代谢物的结构决定和生物活性，其中看似源源不断的真菌和细菌之间的生物合成天然产物和效应途径已被阐明。我们的初步核糖体 16S 测序数据表明，厌氧菌的特定群落使用各种抗真菌药物以可重复的方式急剧增加。这一分析表明细菌和真菌可能在肠道生态系统中占据相似的、竞争性的生态位。照亮细菌代谢物影响真菌群的潜力，从而建立竞争优势，我们开发了一个已知肠道代谢物库，并在生理相关的条件下筛选抗真菌活性体外条件。这导致鉴定出两种细菌来源的代谢物，其具有以下活性：真菌群的机会主义成员。因此，我们假设机会致病真菌肠道受到细菌代谢物产生的控制，并且这种机制受到肠道的刺激真菌影响传染状态。除了揭示真菌-细菌相互作用的新机制之外前所未有的小分子水平，这项拟议的研究结果将阐明潜在的新针对真菌病原体的策略。