Genetic determinants of Bacteroides vulgatus colonization fitness and host inflammatory responses

普通拟杆菌定植适应性和宿主炎症反应的遗传决定因素

• 批准号: 10680228
• 负责人: John F Rawls
• 金额: $ 66.29万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680228
• 关键词: Acceleration; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Bacteroides; Biology; Clinical Management; Communities; Comparative Genomic Analysis; Complex; Development; Diagnostic; Disease; Ecology; Genes; Genetic; Genetic Annotation; Genetic Determinism; Genetic Variation; Genome; Genomics; Gnotobiotic; Goals; Health; Human; Human Microbiome; Immune response; Immunity; Individual; Infant; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Knowledge; Life; Link; Lipids; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Diseases; Mission; Mus; Non-Insulin-Dependent Diabetes Mellitus; Operon; Outcome; Pathway interactions; Phenotype; Physiology; Polycystic Ovary Syndrome; Population; Prognostic Marker; Public Health; Regulation; Research; Rodent; Structure; Testing; Therapeutic; Therapeutic Uses; United States National Institutes of Health; Variant; burden of illness; fitness; genetic information; genetic strain; gut bacteria; gut colonization; gut inflammation; gut microbes; gut microbiome; gut microbiota; human disease; human model; humanized mouse; improved; in vivo; lipid transport; member; microbial; microbiome; microbiome composition; microbiome research; mouse model; non-alcoholic fatty liver disease; novel strategies; personalized therapeutic; prognostic; trait

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.

抽象的 普通拟杆菌 (Bvu) 是不同人类肠道微生物群中最常见的成员之一 人群，并与包括炎症性肠病在内的多种人类疾病密切相关 然而，我们对遗传和表型的理解存在根本差距。 Bvu 物种复合体内的多样性，以及 Bvu 菌株如何对宿主做出机械贡献 我们的长期目标是了解肠道微生物如何影响人类健康和 我们对人源 Bvu 菌株 CL09T03C04 的初步研究确定了假定的遗传。 小鼠肠道中 Bvu 适应性和竞争的决定因素，并将这些基因与代谢物相关 通过使用无菌小鼠，我们还确定了不同的 Bvu 菌株具有 这些结果与其他不同的关联之间存在着不同的影响。 人类和动物模型中的 Bvu 和肠道炎症可以部分通过遗传多样性来解释 然而，与该物种相关的详细注释的遗传信息仍然很少，并且 Bvu 物种复合体中的菌株水平变异几乎完全未被探索。 拟议的研究旨在定义 Bvu 遗传变异与宿主炎症和肠道之间的关系 我们将检验 Bvu 利用不同的遗传和代谢特征来实现微生物生态学的中心假设。 定植肠道并改变宿主炎症，并且 Bvu 菌株中这些特征的存在存在差异 在具体目标 1 中，我们将检验以下工作假设：监管 Bvu 菌株 CL09T03C04 的体内生存和竞争需要不同的脂质代谢物。 目标 2，我们将测试不同 Bvu 菌株促进或限制肠道的能力的工作假设 炎症是由不同的遗传特征介导的，肠道炎症会改变 Bvu 的适应性。 成果将从几个方面垂直推进该领域：首先，它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，包括基因、途径和 负责 Bvu 在肠道定植并影响和适应肠道炎症的能力的代谢物。 他们将鉴定促炎和抗炎 Bvu 菌株以及可能解释之前的相关机制 Bvu 物种复合体与 IBD 相关疾病的恶化和预防的关联 这些结果预计会产生积极影响，因为它们可能导致炎症的发展。 新的 Bvu 导向的预后标记物和治疗方法来改变肠道微生物生态和 炎症，有可能改善 IBD 和其他人类疾病的诊断和治疗管理。