Molecular recognition of vitamin B12 and related compounds in human gut microbial

本项目的长期目标是了解微生物之间的合作和竞争如何塑造人类肠道微生物群落（微生物群）的组成。这些动态在微生物群落组成中产生了人际差异，远远超过了我们基因组中的人际差异。这种微生物变异与肠道内外的疾病易感性有关， 个人对治疗方法的反应。虽然在记录人类肠道微生物群的多样性方面取得了重大进展，但对解释这些群落如何形成和变化的基本原理知之甚少。这种知识的缺乏意味着我们无法确定哪些微生物途径代表了治疗干预的适当目标，如何改变肠道中的物种平衡，或者如何成功地将新物种引入这些社区。因此，了解人类肠道微生物之间如何交换代谢物以及这些网络中的哪些代表了决定群落结构的基本机制是一个重要目标。为了应对这一挑战，该资助申请描述了一些实验，以剖析与维生素B12（类可丽素）相关的大部分未被重视的小分子决定人类肠道微生物群落组成的发现。目标1将研究人类肠道微生物组中类可啉转运蛋白的独特功能如何影响这些系统的组装和功能。目的2将检验以下假设：人类肠道微生物组中超过30种不同类型的类可丽素利用系统专门用于获得不同的类可丽素。目的3研究不同的类可啉（以及产生这些分子的微生物）是否在主要的人类共生体中诱导共享或不同的反应。这些研究的完成将产生一个机制的理解，如何从饮食和微生物来源的corrinoids确定在人类肠道的社区组成。了解这些群落相互作用的机制为改变肠道微生物群落组成的治疗应用提供了基础。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how cooperation and competition between microbes shapes the composition of human gut microbial communities (microbiota). These dynamics produce interpersonal differences in microbial community composition that far exceed the interpersonal differences in our genomes. This microbial variation is linked to disease predisposition inside and outside of the gut and also to individual response to therapeutics. Although significant progress has been made documenting the diversity of the human gut microbiota, much less is known about the underlying principles that explain how these communities form and change. This lack of knowledge means that we cannot identify which microbial pathways represent appropriate targets for therapeutic intervention, how to shift the balance of species in the gut, or how to successfully introduce new species into these communities. Thus, understanding how metabolites are exchanged between human gut microbes and which of these networks represent the fundamental mechanisms that determine community structure is an important goal. To address this challenge, this grant application describes experiments to dissect the discovery that largely unappreciated small molecules related to vitamin B12 (corrinoids) determine human gut microbial community composition. Aim 1 will examine how the unique features of corrinoid transporters in the human gut microbiome impact the assembly and function of these systems. Aim 2 will test the hypothesis that the greater than 30 different types of corrinoid utilization systems in the human gut microbiome are specialized for acquisition of distinct corrinoids. Aim 3 examines whether different corrinoids (and by extension, the microbes that produce these molecules) induce shared or distinct responses in prominent human symbionts. Completion of these studies will produce a mechanistic understanding of how corrinoids from diet and microbial sources determine community composition in the human gut. Understanding these mechanisms of community interaction provides a basis for therapeutic applications to alter the composition of gut microbial communities.