Regulation of carbon utilization in gut-resident bacteria

项目概要- R35项目补助金 哺乳动物肠道的微生物群是一个复杂的个体菌株群落，部分由微生物形成。 竞争饮食成分。尽管计算分析预测了不同的酶的能力， 但是，这些知识不足以确定饮食如何影响肠道中的细菌丰度。在 特别是，对肠道细菌中碳利用酶的调节知之甚少。他们有 机制与E.大肠杆菌碳分解代谢物抑制顺序消耗首选营养素？还是 它们同时消耗所有可用的营养物质这些不同的策略如何有助于微生物 肠道中的丰富？我们已经确定了一种类似于科林塞拉碳分解代谢物阻遏的机制 当肠道中有丰富的次级碳源时，产气杆菌可能是一个缺点。 我们的实验室旨在描述科林塞拉碳消耗的监管机制 种，在文化和小鼠肠道。Collinsella物种是研究很少的放线菌， 慢性人类疾病，包括2型糖尿病和动脉粥样硬化。我们仔细研究了一组 相关物种和菌株在碳消耗的调节方面有所不同。我们将利用现有的 变异性和实验进展，以确定在这些碳分解代谢物阻遏的共同途径， 细菌我们将使用单细胞免疫荧光技术测量该途径的异质性和相关的代谢功能。 RNA测序最后，我们将描述这种调节对细菌生长和竞争的影响， 老鼠内脏 总之，这项研究将确定有助于在治疗中采取有利策略的调控途径。 哺乳动物肠道的复杂营养环境。尽管有大量的相关研究 暗示了肠道微生物组在人类疾病中的作用，在确定 控制肠道中细菌丰度和功能的细菌代谢途径。这一差距限制了我们双方的 了解这些社区相互作用的基本生物学，以及设计有效的 用于以复杂微生物生态失调为特征的人类疾病的微生物治疗剂。

PROJECT SUMMARY - R35 PARENT GRANT The microbiota of the mammalian gut is a complex community of individual strains shaped in part by microbial competition over diet components. Despite computational analyses predicting enzymatic capacity of diverse bacteria, this knowledge is not sufficient to determine how diet influences bacterial abundance in the gut. In particular, little is known about regulation of carbon utilization enzymes in gut bacteria. Do they have mechanisms similar to E. coli carbon catabolite repression to consume preferred nutrients sequentially? Or do they consume all available nutrients simultaneously? How do these different strategies contribute to microbial abundance in the gut? We have identified a mechanism resembling carbon catabolite repression in Collinsella aerofaciens that may be a disadvantage when there is an abundance of secondary carbon source in the gut. Our laboratory seeks to characterize regulatory mechanisms governing carbon consumption in Collinsella species, in culture and in the mouse gut. Collinsella species are poorly studied Actinobacteria that are linked to chronic human diseases including type 2 diabetes and atherosclerosis. We have studied a group of closely related species and strains that vary in their regulation of carbon consumption. We will use this existing variability and experimental evolution to identify a common pathway of carbon catabolite repression in these bacteria. We will measure the heterogeneity of this pathway and related metabolic functions using single-cell RNA-seq. Finally, we will characterize the impact of this regulation on bacterial growth and competition in the mouse gut. Together, this research will define regulatory pathways that contribute to advantageous strategies in the complex nutrient environment of the mammalian intestine. Despite the vast number of correlative studies implicating a role for the gut microbiome in human disease, there remains much to explore in identifying bacterial metabolic pathways governing bacterial abundance and function in the gut. This gap limits both our understanding of the basic biology of these community interactions as well as the ability to design effective microbial therapeutics for human diseases characterized by complex microbial dysbiosis.