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.

项目总结/摘要 嗜粘蛋白阿克曼氏菌是人类肠道的细菌居民，其与保护免受 慢性炎性疾病如炎性肠病、结肠直肠癌和2型糖尿病。 决定A.嗜粘蛋白菌栖息于肠道及其如何促进宿主 健康状况不明。A.嗜粘蛋白菌以与富含聚糖的粘蛋白紧密结合的致密聚集体生长 肠内壁在粘蛋白培养基中培养时，A.嗜粘蛋白菌产生抗炎化合物 并刺激其他聚糖包被的肠道微生物，如活泼瘤胃球菌，产生丁酸， 具有治疗作用的副产品。该项目的董事会和长期目标是了解如何 肠的聚糖环境形状为A。muciniphila的抗炎活性和解码物种- 导致临床分离株之间变异性的水平机制。这项工作具有广泛的影响，在领域 例如益生菌和旨在治疗炎性疾病的治疗开发。的重点 该计划旨在从分子水平上了解A.嗜粘蛋白菌株调节一组不同的 与粘蛋白结合的聚糖结合细胞表面粘附素，称为含PbH 1的粘附素（PbHAs 肠道环境，与其他共生体相互作用并操纵丁酸发酵，以及 调节宿主的先天免疫途径。在具体目标1中，我将设计一种斑马鱼细菌共生体， 表达由两个A.感兴趣的嗜粘蛋白物种（MucT和 AKK 2750），并测试表达如何在培养中塑造它们的聚集特性，以及如何影响它们的空间分布。 组织在幼斑马鱼肠道。此外，我将使用实验进化来揭示遗传途径 其驱动MucT和AKK 2750在粘蛋白培养基中聚集。具体目标2将研究PbHAs的作用 与R. gannavus并确定MucT和AKK 2750粘蛋白传感和共聚集的方式 与R. gavus影响丁酸发酵。最后，具体目标3将使用斑马鱼模型的微生物- 诱导肠道炎症，以确定PbHAs和其他减少炎症的物种特异性因子 促进肠道健康。我将使用病原体靶向PbHA设计治疗珠， 消除肠道病原体并恢复肠道健康。我将发现的分子见解，研究试剂 我将产生，我将通过这些研究获得的技能将使我能够建立自己的独立 该研究实验室研究微生物组介导的人类健康的分子机制。