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.

项目概要/摘要 尽管在过去十年中产生了大量关于 对于人类肠道微生物群，我们对大多数微生物的能量产生过程仍然知之甚少 这个生态系统的丰富成员。我们对肠道的基础知识存在差距 微生物群阻碍了我们对拟杆菌如何与其他群落相互作用的理解 成员，肠道环境中有助于微生物组成的条件 变化，以及我们如何适当改变生态系统的组成以改善 人类健康。拟杆菌是人类肠道中最丰富、最稳定的属 微生物群及其在宿主上定植数十年的菌株。目前，预计拟杆菌 具有原始的无氧呼吸途径，产生很少的能量来提供动力 细胞过程。在此应用程序中，基于强有力的支持数据，我们将测试我们的前提 拟杆菌有更复杂的呼吸途径，产生的量要大得多 能量，包括直接产生 H+ 和 Na+ 梯度来为细胞供电 流程。这个新范式的核心是我们的预测，即拟杆菌具有完整的 有氧呼吸途径，使它们能够利用结肠粘液层的氧气 我们预测，上皮细胞对它们在肠道中的适应性有显着贡献。此外，我们 将检验我们的假设，即拟杆菌的有氧呼吸对整个社区有影响， 显着促进结肠的低氧环境，导致氧不耐受 成员定植于肠道，尤其是粘液层附近。此应用程序的目标 将利用三位共同PI的不同优势，通过三个目标来实现这一目标。在 目标 1，我们将使用遗传学、功能分析和生物化学来彻底阐明 拟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 呼吸途径所产生的以及它们所激发的细胞过程。在目标 3 中，我们 将使用无菌小鼠模型来测试呼吸途径中哪些酶是至关重要的 对于体内健身，有氧呼吸在赋予身体健身优势方面的作用 拟杆菌以及有氧呼吸对肠道微生物群的社区广泛影响 肠道病原体的定植。我们预测这个项目将揭示新的范式 改变我们对拟杆菌、它们对肠道微生物群的生态影响以及 传统观点认为这些细菌是严格厌氧菌。