Uncovering the modes and genetics of gut bacterial transmission

揭示肠道细菌传播的模式和遗传学

• 批准号: 10028457
• 负责人: Andrew Moeller
• 金额: $ 39.21万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028457
• 关键词: Animal Experiments; Bacteria; Bacterial Genome; Birth; Communities; Complement; Development; Environment; Evolution; Family; Generations; Genes; Genetic; Genetic Materials; Germ-Free; Gnotobiotic; Horizontal Disease Transmission; Human; Immune system; Individual; Inherited; Knowledge; Life; Mammals; Metabolic; Methods; Microbiology; Mothers; Mus; Neurosecretory Systems; Phenotype; Population; Public Health; Social Interaction; Source; Symbiosis; System; Work; bacterial community; bacterial genetics; base; enteric pathogen; functional genomics; genomic tools; gut bacteria; gut microbiota; innovation; insight; member; metagenome; novel strategies; social; trait; transmission process; transposon sequencing

Mammals harbor hundreds of bacterial species in the gut that are deeply integrated with their hosts’ metabolic, immune, and neuroendocrine systems. Before birth, mammals lack a defined gut microbiota, which must be assembled anew in each host generation. Individuals acquire their first inoculum from the mother during birth and are subsequently colonized throughout life by bacteria from the external environment, including social contacts. However, the modes by which specific gut bacterial lineages are transmitted between hosts remain poorly understood. It currently remains unknown which, if any, gut bacterial lineages are faithfully inherited within mammalian host lineages over multiple generations. Similarly, the relative contributions of horizontal transmission through social interactions and shared environments are unclear. Furthermore, the underlying genetic bases of bacterial transmission phenotypes have not been discovered. Resolving these knowledge gaps is of critical significance for understanding the full complement of genetic material inherited within mammalian lineages, the evolution of symbiosis between gut bacteria and mammalian species, the community assembly of the gut microbiota within individual mammals, and the spread of bacterial enteropathogens within mammalian populations. Here, we propose to identify vertically and horizontally transmitted members of the mouse gut microbiota (Aim 1) and to discover the genetic bases of gut bacterial transmission phenotypes (Aim 2). In Aim 1, we will employ an innovative experimental system that utilizes wild-derived outbred populations of mice reared in outdoor enclosures to disentangle the modes of transmission within the gut microbiota. As part of this work, we will also develop new approaches for assembling high-quality bacterial genomes from metagenomes that will provide unprecedented opportunities to study dispersal of bacteria. In Aim 2, we will employ transposon- insertion sequencing of gut bacterial lineages that disperse within and between germ-free mouse lines reared in gnotobiotic isolators in order to identify the specific genes that underlie gut bacterial transmission phenotypes. This work will focus on both vertically and horizontally transmitted bacterial lineages identified by our previous work as well as by results of Aim 1. Determining the genetic basis of gut bacterial transmission within and between mammalian lineages has the potential to reshape understanding of the mechanisms and evolution of bacterial dispersal strategies. In addition, Aim 2 will contribute substantially to the development of functional genomics tools in mammalian gut bacteria. Cumulatively, the proposed work will yield fundamental insights into the modes of gut bacterial transmission in mammals.

哺乳动物的肠道中有数百种细菌，它们与它们的 宿主的代谢、免疫和神经内分泌系统。在出生之前，哺乳动物缺乏一个明确的 肠道微生物群，必须在每一代宿主中重新组装。个人获得 它们在出生时从母体获得第一次接种物，随后在整个生命过程中定植 包括社会接触在内的外部环境中的细菌。然而，模式由 哪些特定的肠道细菌谱系在宿主之间传播仍然知之甚少。它 目前仍不清楚，如果有的话，肠道细菌谱系忠实地继承了 哺乳动物宿主谱系在多个世代。同样， 通过社会互动和共享环境的横向传播尚不清楚。 此外，细菌传播表型的潜在遗传基础尚未被阐明。 发现了解决这些知识差距对于全面了解 在哺乳动物谱系内遗传的遗传物质的补充，共生的进化 在肠道细菌和哺乳动物物种之间，肠道微生物群的群落组装 以及细菌性肠道病原体在哺乳动物体内的传播 人口。在这里，我们建议确定垂直和水平传输的成员， 小鼠肠道微生物群（目标1），并发现肠道细菌传播的遗传基础 表型（目标2）。在目标1中，我们将采用创新的实验系统， 在户外围栏中饲养的野生远系小鼠种群， 在肠道菌群中传播。作为这项工作的一部分，我们还将开发新的 从宏基因组组装高质量细菌基因组的方法， 研究细菌传播的前所未有的机会。在目标2中，我们将使用转座子- 无菌内和无菌间肠道细菌谱系的插入测序 在无菌隔离器中饲养的小鼠品系，以鉴定 肠道细菌传播表型。这项工作将侧重于纵向和横向 通过我们以前的工作以及目标1的结果确定的传播细菌谱系。 确定肠道细菌在哺乳动物内和哺乳动物间传播的遗传基础 谱系有可能重塑对人类遗传机制和进化的理解， 细菌扩散策略。此外，目标2将大大有助于发展 在哺乳动物肠道细菌中的功能基因组学工具。拟议的工作将累积起来， 产生对哺乳动物肠道细菌传播模式的基本见解。