Regulation of carbon utilization in gut-resident bacteria

项目摘要-R35家长赠款 哺乳动物肠道的微生物区系是由部分由微生物形成的单个菌株组成的复杂群落。 饮食成分的竞争。尽管计算分析预测了不同种类的酶活力 对于细菌，这些知识不足以确定饮食如何影响肠道中的细菌丰度。在……里面 特别是，对肠道细菌中碳利用酶的调节知之甚少。他们有吗？ 类似于大肠杆菌碳分解代谢抑制顺序消耗首选营养的机制？或做 它们同时消耗所有可用的营养物质吗？这些不同的策略对微生物有何贡献 肠子里的富足？我们已经确定了一种类似于柯林塞拉体内碳分解代谢抑制的机制 当肠道中有大量的次生碳源时，这可能是一个劣势。 我们的实验室试图描述柯林塞拉碳消费的调控机制 物种，在培养和小鼠的肠道中。Collinsella物种是研究较少的放线杆菌，与 人类慢性疾病，包括2型糖尿病和动脉粥样硬化。我们仔细研究了一组 相关物种和菌株在其对碳消耗的调节方面存在差异。我们将使用现有的 可变性和实验进化以确定在这些细胞中碳分解代谢抑制的共同途径 细菌。我们将使用单细胞来测量这一途径和相关代谢功能的异质性。 RNA序列最后，我们将描述这一规定对细菌生长和竞争的影响。 老鼠的内脏。 总之，这项研究将定义有助于制定有利战略的监管途径 哺乳动物肠道的复杂营养环境。尽管有大量的相关研究 肠道微生物群在人类疾病中的作用，在识别方面仍有许多有待探索的地方 控制肠道细菌丰度和功能的细菌代谢途径。这一差距限制了我们的 了解这些群落相互作用的基本生物学，以及设计有效的 以复杂的微生物失调为特征的人类疾病的微生物疗法。

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.