Understanding the beneficial role and antimicrobial potential of novel human gut bacteria

人体肠道微生物组的研究已成为生物医学研究的新前沿。随着高通量DNA测序的出现，人们越来越认识到人体肠道微生物组组成与人类健康的各个方面之间的密切联系。然而，人类肠道微生物群中的数千种细菌仍然不愿培养(也就是说，它们还没有被分离出来，也没有在实验室条件下生长)。这一技术限制是理解人类肠道细菌在宿主健康中的生物学机制和有益作用的主要障碍。一个如此庞大的未培养群体中最引人注目的例子是被称为克里斯滕斯目的细菌目。Christensenellales是一种高度流行的全球分布的支系，作为一种在维护人类健康方面有希望的参与者而受到越来越多的关注。多项独立观察表明，克里斯滕斯氏细菌对新陈代谢健康、炎症性肠病甚至长寿都有有益的作用。事实上，我的初步数据还表明，Christensenellales物种可能低估了抗菌特性，特别是对迫切需要新治疗方法的机会性病原体。在我最近的工作中，我已经将可用的Christensenellales基因组的数量扩大了近100倍(从89个基因组序列到8,585个基因组序列)，同时表明至少98%属于这一分支的细菌物种仍然没有培养。来自我自己的初步分析和之前的研究的大量证据提出了这样一个假设，即克里斯滕森杆菌具有良好的抗菌特性，对人类健康具有多方面的作用。因此，这打开了一些重要的问题：-哪些功能使Christensenellales能够成功地在人类肠道中定植？-Christensenellales在维持或促进健康方面的作用是什么？-我们如何在体外选择性地培养Christensenellales细菌，以测试它们的机械作用？-Christensenellales细菌对肠道病原体具有抗菌作用吗？考虑到这一点，我将利用我独特的专业知识、数据集和方法，采用一种全面的、跨学科的方法来了解Christensenellales细菌的生物学作用，并探索它们的抗微生物特性。我将：(I)以前所未有的细节和分辨率在基因组水平上研究Christensenellales的功能潜力、与健康相关的特征和肠道适应；(Ii)开发新的方法来培养Christensenellales细菌并进行机械学研究；(Iii)评估Christensenellales的抗菌活性，并测试具有潜在抗生素潜力的新化合物。通过提供Christensenellales的生理和功能的综合观点，我将提高我们对肠道微生物群在人类健康中的作用的理解，并开辟新的研究途径，以开发创新的治疗应用。这里确立的核心原则和方法将为探索与健康和疾病相关的其他未培养细菌提供机会。

The study of the human gut microbiome has emerged as a new frontier of biomedical research. With the advent of high-throughput DNA sequencing, a strong link between the human gut microbiome composition and various aspects of human health is being increasingly recognized. However, thousands of bacterial species in the human gut microbiome remain recalcitrant to cultivation (that is, they have not yet been isolated nor grown under laboratory conditions). This technical limitation represents a major hurdle to understanding the biological mechanisms and beneficial role of human gut bacteria in host health. The most remarkable example of one such large uncultured group is the bacterial order referred to as Christensenellales. Christensenellales is a highly prevalent and globally distributed clade that is gaining increasing attention as a promising player in the maintenance of human health. Multiple independent observations suggest Christensenellales bacteria have a beneficial role in metabolic health, inflammatory bowel disease and even longevity. In fact, my preliminary data also indicates Christensenellales species may have underappreciated antimicrobial properties, particularly against opportunistic pathogens in urgent need of new treatments. In my recent work, I have expanded by almost 100-fold the number of Christensenellales genomes available (from 89 to 8,585 genome sequences), while showing that at least 98% of the bacterial species belonging to this clade remain uncultured. The vast body of evidence from both my own preliminary analyses and previous studies raises the hypothesis that Christensenellales bacteria have a multifaceted role in human health with promising antimicrobial properties. Therefore, this opens a number of important questions:- Which functions enable Christensenellales to successfully colonize the human gut?- What is the role of Christensenellales in maintaining or promoting health?- How can we selectively culture Christensenellales bacteria in vitro to test their mechanistic roles?- Do Christensenellales bacteria have an antimicrobial effect against intestinal pathogens?With this in mind, I will apply a holistic, cross-disciplinary approach leveraging my unique expertise, datasets and methods to understand the biological role of Christensenellales bacteria and explore their antimicrobial properties. I will: (i) investigate the functional potential, health-associated features and gut adaptation of Christensenellales at a genomic level with an unprecedented detail and resolution; (ii) develop new methods to culture Christensenellales bacteria and enable mechanistic investigations; and (iii) evaluate the antimicrobial activity of Christensenellales and test new compounds with promising antibiotic potential. By providing an integrated view of the physiology and functions of Christensenellales, I will improve our understanding of the role of the gut microbiome in human health and open new avenues of research to develop innovative therapeutic applications. The core principles and methodologies here established will open opportunities to explore other uncultured bacteria of relevance to health and disease.