The Role of Syntrophic Bacteria in Methanogenic Metabolism in the Human Gut

合养细菌在人类肠道产甲烷代谢中的作用

基本信息

  • 批准号:
    8214683
  • 负责人:
  • 金额:
    $ 15.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-02-01 至 2015-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The human gut harbors 10-100 trillion microorganisms that enable the harvest of nutrients/energy from otherwise undigestible components of our diet (e.g. complex plant polysaccharides). Syntrophic (cooperative) metabolism, where one microbe produces compounds that the other requires for growth or removes compounds that inhibit the progress of metabolic reactions, has a high impact on the efficiency at which our microbes extract calories from our food. Knowledge of how different human gut bacteria fit within the cascade of metabolic interactions of the anaerobic degradation process will help to relate community composition information to the function and efficiency of the gut bioreactor. The goal of this work is to use both metagenomic (16S ribosomal RNA or shotgun) sequences from human stool samples and genome sequences from cultured gut isolates to predict microbial interactions that can be further explored/verified with laboratory experiments. This work focuses on interactions between bacteria and Methanobrevibacter smithii, the most prominent archaeal methanogen in the human gut. Methanogenic archaea were chosen because 1) they can increase the efficiency of bacterial fermentation by preventing the accumulation of metabolic products such as hydrogen 2) they are thought to be a "keystone" species, (i.e. have a higher influence on community composition and function than their prevalence would suggest) and 3) they closely associate with specific syntrophic bacteria in other environments such as sludge digestors, but whether there is an analog in the gut is not known. The goal of Specific Aim 1 is to use metagenomic sequence data from human stool samples to identify species (phylotypes) and genes whose prevalence are correlated with the presence/absence of M. smithii. The preliminary analysis of 191 samples that were collected through an ongoing longitudinal study of the effects of obesity on the gut microbiota, has identified 27 bacterial phylotypes, representing at least 3 deep bacterial lineages that appear to have conserved the traits that lead to co-occurrence with M. smithii. Specific Aims 2 and 3 pursue a combination of laboratory and computational techniques to determine whether the co- occurrence between these bacteria and M. smithii is driven by syntrophy or by shared environmental preferences. Some of the co-occurring phylotypes are from uncultured lineages whose biological properties are completely unknown. Specific Aim 2 will yield information on these uncultured lineages and determine whether co-occurrence was driven by syntrophy by 1) microscopic determination of whether they form structured complexes with M. smithii using Fluorescence In Situ Hybridization (FISH) and 2) metagenomic sequencing of cell populations that were concentrated using flow cytometry. Specific Aim 3 further explores the underlying cause of co-occurrence patterns by developing and applying metabolic reconstruction-based techniques to predict interactions between microbes, including syntrophy and metabolic niche convergence. Finally, I will use this combined information to design confirmatory experiments in gnotobiotic mice. This work will facilitate the use of the growing collection of human-gut derived sequences to understand whether and how particular microbes interact, and will provide insights as to how to promote or discourage the activity M. smithii in the gut. This proposal is a natural extension of my Ph.D. and post-doctoral studies of the human microbiome. The proposed research will further develop the skills needed to achieve my goal of developing an independent research group with both computational and laboratory components. The bioinformatics work integrates my experience with analysis of 16S rRNA and genomic sequence data from the human gut, and extends my expertise into new areas, such as metabolic network modeling. The laboratory component draws upon my experience in performing culture-independent analysis of microbes in soil, and extends my training in FISH and flow-cytometry, for the generation of genomic information from uncultured microbial lineages. Extended training in working with human subjects will also help me to continue to perform human microbiome research. My current position as a post-doc with Dr. Rob Knight at the University of Colorado at Boulder, and the co-mentoring that I receive from Dr. Jeff Gordon from the Center for Genome Sciences at Washington University provide an excellent environment in which to reach these goals. The Knight lab is on the forefront of generating the computational tools required to utilize advances in high-throughput sequencing for the analysis of microbial communities, and is an environment where I can interact with a diverse collection of students, post-docs, and collaborators including individuals with backgrounds in biology (with computational and/or laboratory expertise), computer science (including high performance computing and database design), and applied math. The Gordon lab performs ground-breaking research on the association of the gut microbial community with diseases of nutrition (obesity and malnutrition) and the application of gnotobiotic mouse models to understanding microbial interactions in the gut. They produce massive amounts of sequence information from human gut samples that is central to the work proposed in this grant.
描述(由申请人提供):人类肠道含有10-100万亿微生物,这些微生物能够从我们饮食中其他不可消化的成分(例如复杂的植物多糖)中收获营养素/能量。互养(合作)代谢,即一种微生物产生另一种微生物生长所需的化合物或去除抑制代谢反应进展的化合物,对我们的微生物从食物中提取热量的效率有很大影响。了解不同的人类肠道细菌如何适应厌氧降解过程的级联代谢相互作用,将有助于将群落组成信息与肠道生物反应器的功能和效率联系起来。这项工作的目标是使用来自人类粪便样本的宏基因组(16 S核糖体RNA或鸟枪)序列和来自培养的肠道分离株的基因组序列来预测微生物相互作用,这些相互作用可以通过实验室实验进一步探索/验证。这项工作的重点是细菌和史氏甲烷短杆菌(Methanobrevibacter smithii)之间的相互作用,史氏甲烷短杆菌是人类肠道中最重要的古生产甲烷菌。选择产甲烷古菌是因为1)它们可以通过防止代谢产物如氢的积累来提高细菌发酵的效率2)它们被认为是“关键”物种,(即对群落组成和功能的影响比它们的普遍性所暗示的更大)和3)它们与其他环境中的特定互养细菌密切相关,但肠道中是否存在类似物尚不清楚。具体目标1的目标是使用来自人类粪便样本的宏基因组序列数据来鉴定其流行率与M的存在/不存在相关的物种(MSTs类型)和基因。史密斯。通过正在进行的肥胖对肠道微生物群影响的纵向研究收集的191个样本的初步分析,已经确定了27种细菌类型,代表至少3种深层细菌谱系,这些细菌谱系似乎保留了导致与M共同出现的特征。史密斯。具体目标2和3追求实验室和计算技术的组合,以确定这些细菌和M之间的共存是否是可能的。Smithii是由合成营养或共同的环境偏好驱动的。一些共同出现的基因型来自未培养的谱系,其生物学特性完全未知。具体目标2将产生关于这些未培养谱系的信息,并通过1)显微镜测定它们是否与M形成结构化复合物来确定共现是否由共养驱动。smithii使用荧光原位杂交(FISH)和2)使用流式细胞术浓缩的细胞群的宏基因组测序。具体目标3通过开发和应用基于代谢重建的技术来预测微生物之间的相互作用,包括合成营养和代谢生态位收敛,进一步探索了共生模式的根本原因。最后,我将使用这些综合信息来设计在gnotobiotic小鼠中的验证性实验。这项工作将有助于使用越来越多的人类肠道衍生序列来了解特定微生物是否以及如何相互作用,并将提供有关如何促进或抑制活性M的见解。史密西在肠道。这个建议是我博士学位的自然延伸。以及对人体微生物组的博士后研究拟议的研究将进一步发展所需的技能,以实现我的目标,即发展一个独立的研究小组,同时具有计算和实验室组成部分。生物信息学工作将我的经验与16 S rRNA和人类肠道基因组序列数据的分析相结合,并将我的专业知识扩展到新的领域,如代谢网络建模。实验室部分借鉴了我在土壤中微生物的非培养分析方面的经验,并扩展了我在FISH和流式细胞术方面的培训,用于从未培养的微生物谱系中生成基因组信息。与人类受试者一起工作的扩展培训也将帮助我继续进行人类微生物组研究。我目前在博尔德的科罗拉多大学担任Rob Knight博士的博士后,我从华盛顿大学基因组科学中心的Jeff Gordon博士那里获得了共同指导,这为实现这些目标提供了一个极好的环境。骑士实验室是在产生所需的计算工具,利用高通量测序的微生物群落的分析进展的最前沿,是一个环境,我可以与学生,博士后和合作者,包括具有生物学背景的个人的不同集合互动(具有计算和/或实验室专业知识),计算机科学(包括高性能计算和数据库设计),戈登实验室对肠道微生物群落与营养疾病的关系进行了开创性的研究。(肥胖和营养不良)和应用gnotobiotic小鼠模型来理解肠道中的微生物相互作用。他们从人类肠道样本中产生了大量的序列信息,这是这项资助中提出的工作的核心。

项目成果

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Catherine Lozupone其他文献

Catherine Lozupone的其他文献

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{{ truncateString('Catherine Lozupone', 18)}}的其他基金

Dietary and synbiotic strategy to limit gut microbiome dysbiosis and protect against Clostridioides difficile infection
限制肠道微生物群失调并预防艰难梭菌感染的饮食和合生策略
  • 批准号:
    10592305
  • 财政年份:
    2021
  • 资助金额:
    $ 15.11万
  • 项目类别:
Core 2 - Mucosal Immunobiology Core (MIC)
核心 2 - 粘膜免疫生物学核心 (MIC)
  • 批准号:
    10277293
  • 财政年份:
    2021
  • 资助金额:
    $ 15.11万
  • 项目类别:
Core 2 - Mucosal Immunobiology Core (MIC)
核心 2 - 粘膜免疫生物学核心 (MIC)
  • 批准号:
    10700081
  • 财政年份:
    2021
  • 资助金额:
    $ 15.11万
  • 项目类别:
Dietary and synbiotic strategy to limit gut microbiome dysbiosis and protect against Clostridioides difficile infection
限制肠道微生物群失调并预防艰难梭菌感染的饮食和合生策略
  • 批准号:
    10396969
  • 财政年份:
    2021
  • 资助金额:
    $ 15.11万
  • 项目类别:
Factors mediating gut microbiota dysbiosis and metabolic disease in HIV patients
HIV患者肠道菌群失调和代谢性疾病的介导因素
  • 批准号:
    9117527
  • 财政年份:
    2014
  • 资助金额:
    $ 15.11万
  • 项目类别:
Factors mediating gut microbiota dysbiosis and metabolic disease in HIV patients
HIV患者肠道菌群失调和代谢性疾病的介导因素
  • 批准号:
    8926414
  • 财政年份:
    2014
  • 资助金额:
    $ 15.11万
  • 项目类别:
Factors mediating gut microbiota dysbiosis and metabolic disease in HIV patients
HIV患者肠道菌群失调和代谢性疾病的介导因素
  • 批准号:
    8799703
  • 财政年份:
    2014
  • 资助金额:
    $ 15.11万
  • 项目类别:
The Role of Syntrophic Bacteria in Methanogenic Metabolism in the Human Gut
合养细菌在人类肠道产甲烷代谢中的作用
  • 批准号:
    8655670
  • 财政年份:
    2011
  • 资助金额:
    $ 15.11万
  • 项目类别:
The Role of Syntrophic Bacteria in Methanogenic Metabolism in the Human Gut
合养细菌在人类肠道产甲烷代谢中的作用
  • 批准号:
    8586882
  • 财政年份:
    2011
  • 资助金额:
    $ 15.11万
  • 项目类别:
The Role of Syntrophic Bacteria in Methanogenic Metabolism in the Human Gut
合养细菌在人类肠道产甲烷代谢中的作用
  • 批准号:
    8029419
  • 财政年份:
    2011
  • 资助金额:
    $ 15.11万
  • 项目类别:

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