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Large-scale profiling of microbial and metabolic interactions between C. difficile and gut microbiota using ultrahigh-throughput droplet microfluidics

使用超高通量液滴微流体对艰难梭菌和肠道微生物群之间的微生物和代谢相互作用进行大规模分析

基本信息

批准号：
10473701
负责人：
Ophelia Venturelli
金额：
$ 23.33万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-23 至 2023-07-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Clostridium difficile (C. difficile) is a major antibiotic resistant intestinal pathogen that is a leading cause of antibiotic associated diarrhea and colitis which, in severe cases, can lead to death. Treatment with antibiotics frequently leads to recurrence of the infection, which is then treated with fecal microbiota transplantation (FMT). In this case, a fecal sample from a healthy donor is transplanted into a patient with C. difficile infection, which has been shown to prevent recurrence of infections. Notably, FMT can lead to negative health outcomes including death due to the potential transmission of pathogens and uncharacterized factors in the samples. The observed efficacy of FMT suggests that commensal gut bacteria play a critical role in suppressing infection caused by C. difficile. Previous studies have elucidated specific molecular mechanisms that can influence C. difficile colonization including exploitation of key nutrients available in the inflamed gut and secondary bile acids. We postulate that there are diverse classes of ecological and molecular mechanisms mediating protection from C. difficile depending on the ecological and environmental context. Indeed, treatments of C. difficile infection based on defined microbiota have not proven successful. To elucidate the diverse classes of mechanisms, we propose to develop a droplet microfluidic workflow to construct millions of synthetic human gut communities, screen these consortia based on the abundance of C. difficile and determine species composition of the sorted “hits.” Combining this method with exo-metabolomics and machine learning techniques, we will infer microbial interactions and metabolite effectors impacting C. difficile growth. A detailed understanding of the diverse community types and metabolic properties that suppress C. difficile growth will be a major advance towards designing safe and effective treatments for this major intestinal pathogen.

项目总结/摘要艰难梭菌（C.艰难梭菌）是一种主要的抗生素耐药性肠道病原体，其是导致抗生素相关的腹泻和结肠炎，严重时可导致死亡。用抗生素治疗通常会导致感染复发，然后用粪便微生物群移植（FMT）进行治疗。在这种情况下，来自健康供体的粪便样本被移植到患有C的患者体内。艰难梭菌感染已被证明可以防止感染复发。值得注意的是，FMT可能导致负面的健康结果包括由于样品中病原体和未表征因素的潜在传播而导致的死亡。的观察到的FMT的功效表明，肠道细菌在抑制感染方面起着关键作用梭菌所致的很难先前的研究已经阐明了影响C. 艰难的定植，包括利用炎症肠道中的关键营养物质和次级胆汁酸。我们假设，有不同类别的生态和分子机制介导的保护， C.这取决于生态和环境背景。事实上，C.菌感染已经证明是不成功的。为了阐明不同类别的机制，我们建议开发液滴微流体工作流程，以构建数百万个合成人类肠道群落，根据C.并确定分类的物种组成 “命中率”将这种方法与外代谢组学和机器学习技术相结合，我们将推断微生物相互作用和影响C.艰难的成长详细了解各种抑制C.艰难的增长将是一个重大的进步，为这种主要的肠道病原体设计安全有效的治疗方法。