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 Bacteroides Vulgatus（BVU）是潜水员人类肠道菌群中最常见的成员之一 种群，与多种人类疾病（包括炎症性肠）密切相关 疾病（IBD）。但是，我们对遗传和表型的理解存在根本差距 BVU物种复合物中的多样性以及BVU菌株如何机械贡献宿主 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和 疾病。我们在人类衍生的BVU菌株CL09T03C04中的初步研究确定了推定的通用 确定小鼠肠道中的BVU适应性和竞争，并将这些基因与代谢产物相关联 通过质谱法确定。使用gnotobiotic小鼠，我们还确定不同的BVU菌株具有 对肠道感染和免疫力的可变影响。这些结果和其他潜水员之间的关联 人类和动物模型中的BVU和肠道注射可以部分通过遗传多样性来解释 BVU条纹。然而，与该物种相关的通知遗传信息仍然很少， BVU物种复合物之间的应变水平变化几乎是完全出乎意料的。目的 拟议的研究是定义BVU遗传变异与宿主注射与肠道的关系 微生物生态学。我们将检验中心假设，即BVU使用不同的遗传和代谢特征 殖民肠道并修改宿主注入，并且这些特征在BVU菌株中的可变存在 解释了他们不同的宿主反应。在特定目标1中，我们将检验以下假设 在BVU菌株CL09T03C04中，需要独特的脂质代谢物。具体 AIM 2，我们将测试工作假设，即不同BVU菌株促进或限制肠道的能力 炎症是由不同的遗传特征介导的，肠道注射会改变BVU的适应性。预期 成果将以几种方式垂直地推进该领域。首先，他们将提供第一个深入的理解 BVU物种复合物中的遗传和表型多样性，包括鉴定基因，途径和 代谢物负责BVU殖民肠道并影响和适应肠道注射的能力。第二， 他们将识别可能解释先验的促和抗炎的BVU菌株和关联机制 BVU物种复合物与IBD相关的加重和保护 炎。预计这些结果将产生积极的影响，因为它们可能导致发展 新的BVU指导的预后标记和治疗方法，以修改肠道微生物生态学和 炎症，有可能改善IBD和其他人类疾病的诊断和治疗管理。