Understanding the molecular mechanisms of Akkermansia glycan-binding adhesins in shaping microbial communities and balancing intestinal inflammation in response to host signals

了解阿克曼氏菌聚糖结合粘附素在塑造微生物群落和平衡肠道炎症以响应宿主信号方面的分子机制

• 批准号: 10723996
• 负责人: Timothy Jarrod Smith
• 金额: $ 9.14万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723996
• 关键词: Aeromonas; Anti-Inflammatory Agents; Bacteria; Bacterial Adhesins; Binding; Biochemical; Butyrates; Cell surface; Cells; Chronic; Clinical; Colorectal Cancer; Communities; Cues; Disease; Engineering; Environment; Epithelium; Evolution; Exhibits; Fermentation; Genetic; Genetic Variation; Goals; Health; Health Promotion; Home; Human; Immune response; Immune system; Immunologics; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Knowledge; Laboratory Research; Learning; Mediating; Membrane; Metabolic Diseases; Microbe; Modeling; Molecular; Mucins; Mucous body substance; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Polysaccharides; Positioning Attribute; Probiotics; Process; Production; Property; Reagent; Regulation; Research; Role; Ruminococcus; Shapes; Signal Transduction; Spatial Distribution; Structure; Surface; Testing; Therapeutic; Vesicle; Work; Zebrafish; chronic inflammatory disease; design; endoplasmic reticulum stress; enteric infection; enteric pathogen; experimental study; gut bacteria; gut health; gut inflammation; gut microbes; gut microbiota; immunoregulation; innate immune pathways; insight; interest; intestinal epithelium; knowledge translation; member; microbial; microbial community; microbiome; microbiota; pathogen; response; skills; sugar; symbiont; therapeutic development; therapy development; trait

PROJECT SUMMARY/ABSTRACT Akkermansia muciniphila is a bacterial resident of the human intestine that is associated with protection from chronic inflammatory diseases such as inflammatory bowel diseases, colorectal cancers, and type-2 diabetes. The molecular mechanisms that determine how A. muciniphila inhabits the intestine and how it promotes host health are not known. A. muciniphila grows in dense aggregates in tight association with the glycan-rich mucin lining of the intestine. When cultured in mucin medium, A. muciniphila produces anti-inflammatory compounds and stimulates other glycan-coated gut microbes like Ruminococcus gnavus to produce butyrate, a fermentation byproduct with therapeutic properties. The board and long-term objective of this project is to learn how the glycan environment of the intestine shapes A. muciniphila’s anti-inflammatory activities and decode species- level mechanisms that drive variability among clinical isolates. This work has wide-reaching implications in fields such as probiotic and therapeutic development aimed at treating inflammatory diseases. The focus of this proposal is to develop a molecular understanding of how A. muciniphila strains regulate a diverse group of glycan-binding cell surface adhesins referred to as PbH1-containing adhesins (PbHAs) to engage with the mucin environment of the intestine, to interact with and manipulate butyrate fermentation in other symbionts, and to modulate innate immune pathways in the host. In Specific Aim 1 I will engineer a zebrafish bacterial symbiont to express each of the seven diverse PbHAs encoded by two A. muciniphila species of interest (MucT and AKK2750) and test how expression shapes their aggregation properties in culture and influences their spatial organization in the larval zebrafish gut. Further, I will use experimental evolution to uncover the genetic pathways that drive MucT and AKK2750 aggregation in mucin medium. Specific Aim 2 will investigate the role of PbHAs in co-aggregation with R. gnavus and determine how MucT and AKK2750 mucin-sensing and co-aggregation with R. gnavus influence butyrate fermentation. Lastly, Specific Aim 3 will use a zebrafish model of microbe- induced intestinal inflammation to identify PbHAs and other species-specific factors that reduce inflammation and promote intestinal health. I will use a pathogen-targeting PbHA to design therapeutic beads that bind and deplete an intestinal pathogen and restores gut health. The molecular insights I will discover, research reagents I will generate, and skills I will acquire through these studies will position me to establish my own independent research laboratory investigating the molecular mechanisms of microbiome-mediated human health.

项目摘要/摘要 Akkermansia Muciniphila是人类肠道的细菌居住，与保护有关 慢性炎症性疾病，例如炎症性肠病，结直肠癌和2型糖尿病。 确定脂肪曲霉如何影响肠道及其如何促进宿主的分子机制 健康尚不清楚。 A.粘膜粘膜在密集的聚集体中生长，与富含聚糖的粘蛋白紧密相关 肠的衬里。当在粘蛋白培养基中培养时，粘膜曲霉会产生抗炎化合物 并刺激其他聚糖涂层的肠道微生物，例如ruminococcus gnavus产生丁酸酯，发酵 具有治疗特性的副产品。该项目的董事会和长期目标是了解 肠道的聚糖环境形成A. Muciniphila的抗炎活性和解码物种 - 促进临床分离株之间变异性的水平机制。这项工作对领域具有广泛的影响 例如旨在治疗炎症性疾病的益生菌和治疗性发育。重点 提案是对A.粘膜菌株如何调节潜水员群的分子理解 聚糖结合细胞表面粘合剂称为含PBH1的粘合剂（PBHA），可与粘蛋白互动 肠的环境，与其他符号相互作用并操纵丁理丁酸酯发酵，并 调节宿主中的先天免疫道路。在特定目标1中，我将设计斑马鱼细菌符号 表达七个潜水员的PBHA中的每一个，由两种感兴趣的A.粘拟性种类（muct和muct和 AKK2750）并测试表达如何塑造其在培养中的聚集特性并影响其空间 幼虫斑马鱼肠道的组织。此外，我将使用实验进化来揭示遗传途径 在粘蛋白培养基中，驱动MUCT和AKK2750聚集。具体目标2将研究PBHA的作用 在与R. gnavus共聚集中，并确定MUCT和AKK2750粘蛋白感应和聚集 Gnavus R. gnavus影响丁酸酯发酵。最后，特定的目标3将使用微生物的斑马鱼模型 诱发肠道炎症，以鉴定PBHA和其他规范特异性因素，以减少炎症 并促进肠道健康。我将使用靶向病原体的PBHA来设计结合和 耗尽肠道病原体并恢复肠道健康。我会发现的分子见解，研究试剂 我将产生，通过这些研究将获得的技能将使我确定自己的独立 研究实验室研究了微生物组介导的人类健康的分子机制。