A new paradigm of respiration in the human gut Bacteroides

项目总结/摘要 尽管在过去十年中产生了大量关于 虽然我们对人体肠道微生物的能量产生过程知之甚少， 这个生态系统中丰富的成员。我们对肠道的基本知识 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，以及我们如何适当地改变生态系统的组成，以改善 人体健康类杆菌属是人类肠道菌群中数量最多、最稳定的一个属， 几十年来，微生物群落中的菌株一直在宿主中定居。目前，拟杆菌被预测为 有一个原始的无氧呼吸途径， 细胞过程在这个应用程序中，基于强有力的支持数据，我们将测试我们的前提 类杆菌有更复杂的呼吸途径， 包括直接产生H+和Na+梯度， 流程.这一新范式的核心是我们预测拟杆菌具有完整的 有氧呼吸途径，使他们能够利用氧气在粘液层的结肠 上皮细胞，我们预测这显著有助于它们在肠道中的适应性。另外我们 将检验我们的假设，即拟杆菌属的有氧呼吸具有社区范围的影响， 显著促进结肠的低氧环境，允许氧不耐受 成员殖民肠道，特别是附近的粘液层。本申请的目的 将在三个目标中解决，利用三个共同PI的不同优势。在 目的1，我们将使用遗传学，功能测定和生物化学，以完全阐明这两个 拟杆菌属的需氧和厌氧途径。在目标2中，我们将重点关注离子梯度 以及它们所激发的细胞过程。在目标3中， 将使用无菌小鼠模型来测试呼吸途径中哪些酶是关键的 在体内健身，有氧呼吸的作用，赋予健身优势， 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， 改变了我们对拟杆菌的认识，它们在肠道微生物群中的生态效应， 传统观点认为这些细菌是严格的厌氧菌。

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.