Bacterial adaptions in host-microbe interactions.

项目摘要/摘要 炎症性肠病(IBD)长期以来一直与机体的成分和代谢改变有关。 肠道微生物区系，然而广泛的研究工作未能确定单一的致病微生物是 致病因素。在这项授权中，我们研究了肠道炎症驱动的另一种假说。 共生细菌的适应性进一步加剧了IBD的疾病。尽管细菌的适应能力 对于在发炎的肠道中共生生存和持续存在是必要的，我们目前还不清楚这些 适应性策略改变了共生微生物的功能。这些包括代谢和免疫调节。 在健康和疾病中调节粘膜免疫动态平衡的共生细菌的活性。因此，在那里 迫切需要了解发炎的肠道环境如何塑造共生细菌的新陈代谢 进一步加重IBD的炎症。这项研究的长期目标是了解肠道细菌如何引导 免疫反应，以开发合理的炎症性疾病的微生物疗法。我们的中央 假说是发炎肠道的氧合环境共同驱动新陈代谢适应。 细菌，导致细菌菌株的扩张，从而加剧肠道炎症。中环 假设将通过追求三个具体目标来检验：1)定义基因和功能变异 IBD肠道中脆弱类杆菌的共生；2)确定共生细菌的代谢适应 在实验性结肠炎期间；以及3)确定氧气对厌氧菌代谢和免疫的影响 调制。我们将研究来自健康人群和IBD人群的脆弱芽孢杆菌菌株的遗传变异。这 信息将使构建特定菌株脆弱芽孢杆菌基因组规模的模型能够阐明 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 脆弱芽孢杆菌在小鼠结肠炎模型中的适应性及肠道炎症对细菌的影响 新陈代谢和免疫调节。最后，我们将研究适应氧气的脆弱芽孢杆菌菌株 对肠道内环境平衡有代谢和免疫学影响。拟议的研究是 意义重大，因为定义共生细菌对肠道炎症早期阶段的适应将是一种 发现和治疗早期IBD并防止进展为衰弱的强有力的策略 IBD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.