Genetic determinants of Bacteroides vulgatus colonization fitness and host inflammatory responses

摘要 创伤类杆菌是人类肠道微生物区系中最常见的成员之一。 它与包括炎症性肠炎在内的多种人类疾病密切相关 疾病(IBD)。然而，在我们对遗传和表型的理解上存在着根本的差距 BVU物种复合体内的多样性，以及BVU菌株如何机械地对宿主做出贡献 炎症表型。我们的长期目标是了解肠道微生物如何影响人类健康和 疾病。我们对人源性BVU株CL09T03C04的初步研究确定了可能的基因 小鼠肠道中BVU适合性和竞争的决定因素，并将这些基因与代谢产物相关联 通过质谱学鉴定。利用灵知生菌小鼠，我们还证实了不同的BVU菌株具有 对肠道炎症和免疫的不同影响。这些结果与其他不同的联系之间 人类和动物模型中的BVU和肠道炎症可以部分解释为 BVU菌株。然而，与这一物种相关的经过良好注释的遗传信息仍然很少，而且 跨BVU物种复合体的应变水平差异几乎完全没有被探索过。该计划的目标是 建议的研究是确定BVU基因变异与宿主炎症和肠道之间的关系 微生物生态学。我们将测试核心假设，即BVU使用不同的遗传和代谢特征来 定植肠道和改善宿主炎症，以及在BVU菌株中这些特征的可变存在 解释了它们不同的宿主反应。在具体目标1中，我们将检验监管的工作假设 Bvu菌株CL09T03C04体内生存和竞争需要不同的脂代谢产物。具体而言 目的2，我们将检验不同BVU菌株促进或限制肠道功能的工作假说 炎症是由不同的遗传特征介导的，肠道炎症改变了BVU的健康状况。预期中的 结果将在几个方面垂直推动该领域的发展。首先，他们将提供第一个深入的理解 Bvu物种复合体的遗传和表型多样性，包括识别基因、途径和 负责BVU定植肠道并影响和适应肠道炎症的代谢物。第二, 他们将识别促炎和抗炎的BVU菌株以及可能解释先前 BVU物种复合体与IBD相关疾病的加重和保护的关系 发炎。这些结果预计将产生积极影响，因为它们可能导致 以BVU为导向的新的预后标志物和治疗方法以改变肠道微生物生态和 炎症，有可能改善对IBD和其他人类疾病的诊断和治疗管理。

ABSTRACT Bacteroides vulgatus (Bvu) is one of the most common members of the gut microbiota across diverse human populations and has been strongly associated with multiple human diseases including the inflammatory bowel diseases (IBD). However, there exist fundamental gaps in our understanding of the genetic and phenotypic diversity within the Bvu species complex, as well as how Bvu strains mechanistically contribute to host inflammatory phenotypes. Our long-term goal is to understand how gut microbes impact human health and disease. Our preliminary studies in the human-derived Bvu strain CL09T03C04 identified putative genetic determinants for Bvu fitness and competition in the mouse gut and also associated these genes with metabolites identified by mass spectrometry. Using gnotobiotic mice, we have also established that different Bvu strains have variable impacts on intestinal inflammation and immunity. These results and other diverse associations between Bvu and gut inflammation in humans and animal models could be explained in part by genetic diversity among Bvu strains. Yet, there remains a paucity of well-annotated genetic information associated with this species, and strain-level variation across the Bvu species complex is almost completely unexplored. The objective of the proposed research is to define the relationships between Bvu genetic variation with host inflammation and gut microbial ecology. We will test the central hypothesis that Bvu uses distinct genetic and metabolic traits to colonize the gut and modify host inflammation, and that the variable presence of those traits in Bvu strains explains their divergent host responses. In Specific Aim 1, we will test the working hypothesis that regulation of distinct lipid metabolites is required for in vivo survival and competition in Bvu strain CL09T03C04. In Specific Aim 2, we will test the working hypotheses that the ability of different Bvu strains to promote or restrict gut inflammation is mediated by distinct genetic traits, and that gut inflammation alters Bvu fitness. The expected outcomes will vertically advance the field in several ways. First, they will provide the first in-depth understanding of genetic and phenotypic diversity in the Bvu species complex, including identification of genes, pathways, and metabolites responsible for Bvu’s ability to colonize the gut and to impact and adapt to gut inflammation. Second, they will identify pro- and anti-inflammatory Bvu strains and affiliated mechanisms that may explain prior association of the Bvu species complex with both exacerbation of and protection against IBD-associated inflammation. These results are expected to have a positive impact because they could lead to the development of new Bvu-directed prognostic markers and therapeutic approaches to modify gut microbial ecology and inflammation, potentially improving diagnostic and therapeutic management of IBD and other human diseases.