A new paradigm of respiration in the human gut Bacteroides

人类肠道拟杆菌呼吸的新范例

• 批准号: 9366764
• 负责人: Blanca Barquera
• 金额: $ 62.56万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9366764
• 关键词: Address; Aerobic; Affect; Anaerobic Bacteria; Area; Bacteria; Bacteroides; Biochemical; Biochemistry; Biological Assay; Carbon; Cell Respiration; Cell physiology; Colon; Communities; Complex; Consumption; Critical Pathways; Cytoplasm; Data; Development; Dietary Polysaccharide; Disease; Ecology; Ecosystem; Electron Transport Pathway; Energy-Generating Resources; Environment; Enzymatic Biochemistry; Enzymes; Epithelium; Fermentation; Formulation; Generations; Genetic; Gnotobiotic; Goals; Harvest; Health; Human; Immune; Intestines; Ions; Knowledge; Literature; Metabolic; Metabolism; Microbe; Microscopy; Modeling; Monosaccharides; Mucous body substance; Multienzyme Complexes; Nutrient; Oxygen; Pathway interactions; Patients; Physiology; Polysaccharides; Probiotics; Process; Property; Resistance; Respiration; Role; Testing; Thinking; base; design; enteric pathogen; experience; fitness; flexibility; gut microbiota; improved; in vivo; insight; member; microbial; microbial community; microbiota; mouse model; mutant; novel; sugar

Project Summary/Abstract Despite the tremendous amount of data that has been generated over the last decade regarding the human intestinal microbiota, we still know little about energy generation processes of most of the abundant members of this ecosystem. This gap in our fundamental knowledge of the gut microbiota hinders our understanding of how the Bacteroides interact with other community members, the conditions in the gut environment that contribute to microbial compositional changes, and how we may appropriately alter the composition of the ecosystem to improve human health. Bacteroides is the most abundant and stable genus of the human intestinal microbiota with strains colonizing their hosts for decades. Currently, Bacteroides are predicted to have a primitive anaerobic respiration pathway that would produce little energy to power cellular processes. In this application, based on strong supporting data, we will test our premise that Bacteroides have a more complex respiration pathway that creates a much larger amount of energy including the direct generation of both H+ and Na+ gradients to power cellular processes. Central to this new paradigm is our prediction that Bacteroides have a complete aerobic respiration pathway that allows them to utilize oxygen at the mucus layer of the colonic epithelium, which we predict significantly contributes to their fitness in the gut. In addition, we will test our hypothesis that aerobic respiration by the Bacteroides has community-wide effects, significantly contributing to the low oxygen environment of the colon, allowing oxygen intolerant members to colonize the gut, especially near the mucus layer. The objectives of this application will be addressed in three aims, taking advantage of the diverse strengths of three co-PIs. In Aim 1, we will use genetics, functional assays and biochemistry to completely elucidate both the aerobic and anaerobic pathways of Bacteroides. In Aim 2, we will focus on the ion gradients that the respiration pathway creates and the cellular processes that they energize. In Aim 3, we will use gnotobiotic mouse models to test which enzymes of the respiration pathway are critical for in vivo fitness, the role of aerobic respiration in conferring a fitness advantage to the Bacteroides, and the community wide effects of aerobic respiration on the gut microbiota and colonization of enteric pathogens. We predict this project will reveal new paradigms that will alter our thinking about Bacteroides, their ecological effects in the gut microbiota, and the conventional wisdom that these bacteria are strict anaerobes.

项目摘要/摘要 尽管在过去十年中产生了大量关于 对于人体肠道微生物区系，我们仍然知之甚少 这个生态系统中丰富的成员。我们对肠道基本知识的这一缺口 微生物区系阻碍了我们对类杆菌如何与其他群落相互作用的理解 成员们，肠道环境中对微生物组成有贡献的条件 变化，以及我们如何适当地改变生态系统的组成以改善 人类健康。类杆菌是人类肠道中最丰富、最稳定的属 几十年来菌株在宿主上定植的微生物群。目前，类杆菌属预测 有一条原始的无氧呼吸途径，几乎不会产生能量来发电 细胞过程。在这个应用中，基于强大的支持数据，我们将测试我们的前提 类杆菌有一个更复杂的呼吸途径，可以产生更多的 能量，包括直接产生H+和Na+梯度为细胞提供能量 流程。这一新范式的核心是我们的预测，即类杆菌有一个完整的 有氧呼吸途径，使它们能够利用结肠粘液层的氧气 上皮，我们预测这对它们在肠道中的适合性有很大的贡献。此外，我们 将检验我们的假设，即类杆菌的有氧呼吸具有社区范围的影响， 极大地促进了结肠的低氧环境，使人无法耐氧 在肠道内定居，尤其是在粘液层附近。本应用程序的目标是 将分三个目标进行，利用三个共同绩效指标的不同优势。在……里面 目标1，我们将利用遗传学、功能分析和生物化学来完整地阐明 类杆菌的需氧和厌氧途径。在目标2中，我们将重点关注离子梯度 呼吸途径所创造的，以及它们所激发的细胞过程。在目标3中，我们 将使用诺生菌小鼠模型来测试呼吸途径中的哪些酶是关键的 对于活体健身来说，有氧呼吸在赋予身体健康优势方面的作用 类杆菌，以及有氧呼吸对肠道微生物区系和群落的影响 肠道病原体的定植。我们预测这个项目将揭示新的范式，将 改变我们对类杆菌的看法，它们在肠道微生物区系中的生态效应，以及 传统观点认为，这些细菌是严格意义上的厌氧菌。