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.

摘要 普通拟杆菌（Bacteroides vulgatus，Bvu）是人类肠道菌群中最常见的成员之一，其致病菌主要为普通拟杆菌（Bacteroides vulgatus，Bvu 并且与多种人类疾病（包括炎症性肠病）密切相关 疾病（IBD）。然而，我们对遗传和表型的理解存在根本性的差距， Bvu物种复合体内的多样性，以及Bvu菌株如何机械地促进宿主 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， 疾病我们对人源性Bvu菌株CL09T03C04的初步研究确定了推定的遗传学特征。 Bvu适应性和小鼠肠道竞争的决定因素，并将这些基因与代谢物相关联 通过质谱鉴定。使用gnotobiotic小鼠，我们还建立了不同的Bvu菌株， 对肠道炎症和免疫力的可变影响。这些结果和其他不同的关联之间 人类和动物模型中的Bvu和肠道炎症可以部分解释为遗传多样性， Bvu菌株。然而，仍然缺乏与该物种相关的注释良好的遗传信息， 跨Bvu物种复合体的菌株水平变化几乎完全未被探索。的目的 拟议的研究是确定Bvu遗传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中心假设，即Bvu使用不同的遗传和代谢特征， 定殖肠道和修改宿主炎症，这些特征在Bvu菌株中的可变存在 解释了它们不同的宿主反应在具体目标1中，我们将测试工作假设，即 Bvu菌株CL09T03C04的体内存活和竞争需要不同的脂质代谢物。在特定 目的2，我们将测试不同Bvu菌株促进或限制肠道功能的能力， 炎症是由不同的遗传特征介导的，肠道炎症改变了Bvu适应性。预期 成果将以几种方式纵向推进该领域。首先，他们将提供第一次深入了解 Bvu物种复合体的遗传和表型多样性，包括识别基因，途径， 代谢物负责Bvu的能力，殖民肠道和影响和适应肠道炎症。第二、 他们将确定促炎和抗炎Bvu菌株及其相关机制， Bvu物种复合体与IBD相关疾病的加重和预防的相关性 炎症这些结果预计将产生积极影响，因为它们可能导致发展 新的Bvu导向的预后标志物和治疗方法，以改变肠道微生物生态， 炎症，潜在地改善IBD和其他人类疾病的诊断和治疗管理。