Bacterial adaptions in host-microbe interactions.

项目总结/摘要 炎症性肠病（IBD）长期以来与肠道中的组成和代谢变化有关， 肠道微生物群，但广泛的研究工作未能确定单一的病原微生物作为肠道微生物群 病原体在这项研究中，我们调查了一个替代假设，其中肠道炎症驱动 肠道细菌的适应，进一步加剧IBD疾病。尽管细菌的适应性 必要的肠道生存和持续发炎的肠道，我们目前还不明白如何这些 适应性策略改变了肠道微生物的功能。这些包括代谢和免疫调节 调节健康和疾病中粘膜免疫稳态的肠道细菌的活性。因此 是了解发炎的肠道环境如何塑造肠道细菌代谢， 进一步加剧IBD中的炎症。这项研究的长期目标是了解肠道细菌如何直接 免疫反应，以开发合理的微生物疗法的炎症性疾病。我们的中央 一种假说认为，发炎肠道的氧合环境驱动了肠道的代谢适应， 细菌，导致加剧肠道炎症的细菌菌株的扩张。中央 假设将通过追求三个具体目标进行测试：1）定义遗传和功能变异， IBD肠道中的脆弱类杆菌; 2）确定肠道细菌的代谢适应 在实验性结肠炎;和3）确定氧气对厌氧菌代谢和免疫的影响 调变我们将研究B的遗传变异。来自健康和IBD群组的脆弱菌株。这 这些信息将使得能够构建菌株特异性B。fragilis基因组规模的模型，以阐明 IBD相关菌株的代谢输出和表型状态。接下来，我们将确定基因 B的改编。脆弱的小鼠结肠炎模型，并测试肠道炎症对细菌的影响， 代谢和免疫调节。最后，我们将研究如何氧适应菌株的B。脆弱的可能 对肠道内环境稳定有代谢和免疫影响。拟议的研究是 重要的是，确定肠道细菌对肠道炎症早期阶段的适应将是一个重要的研究方向。 检测和治疗IBD早期阶段并预防进展为衰弱的有效策略 IBD的慢性期。

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) has long been associated with compositional and metabolic changes in the gut microbiota, yet extensive research efforts have failed to identify a single pathogenic microorganism as the causative agent. In this grant, we investigate an alternative hypothesis in which gut inflammation drives adaptations in commensal bacteria that further exacerbates disease in IBD. Though bacterial adaptations are necessary for commensal survival and persistence in the inflamed gut, we currently do not understand how these adaptive strategies alter the function of commensal microbes. These include metabolic and immunomodulatory activities of commensal bacteria that regulate mucosal immune homeostasis in health and disease. Thus, there is a critical need to understand how the inflamed gut environment shapes commensal bacteria metabolism to further exacerbate inflammation in IBD. The long-term goal of this study is to understand how gut bacteria direct immune responses in order to develop rational microbial therapies for inflammatory diseases. Our central hypothesis is that the oxygenated environment of the inflamed gut drives metabolic adaptations in commensal bacteria, resulting in expansion of bacterial strains that exacerbate intestinal inflammation. The central hypothesis will be tested by pursuing three specific aims: 1) define the genetic and functional variation of commensal Bacteroides fragilis in the IBD gut; 2) determine the metabolic adaptations of commensal bacteria during experimental colitis; and 3) identify the impact of oxygen on anaerobic bacterial metabolism and immune modulation. We will examine the genetic variation of B. fragilis strains from healthy and IBD cohorts. This information will enable the construction of strain-specific B. fragilis genome-scale models to elucidate the metabolic output and phenotypic states of IBD-associated strains. Next, we will determine the genetic adaptations of B. fragilis in mouse models of colitis and test the impact of intestinal inflammation on bacterial metabolism and immune modulation. Finally, we will examine how oxygen-adapted strains of B. fragilis may have metabolic and immunological consequences on intestinal homeostasis. The proposed research is significant because defining commensal bacteria adaptations to early stages of gut inflammation will be a powerful strategy for detecting and treating early stages of IBD and preventing progression into the debilitating chronic phase of IBD.