Genetic analysis of mucin utilization by Akkermansia muciniphila and its impact on host physiology

阿克曼氏菌利用粘蛋白的遗传分析及其对宿主生理的影响

• 批准号: 9790938
• 负责人: Raphael H Valdivia
• 金额: $ 51.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790938
• 关键词: Adhesions; Anaerobic Bacteria; Anatomy; Animals; Biological Models; Cell physiology; Cells; Complex; DNA sequencing; Data; Diet; Ecology; Electron Microscopy; Engineering; Epithelial; Epithelial Cell Junction; Epithelial Cells; Fatty acid glycerol esters; Fluorescence Microscopy; Gastrointestinal Contents; Gastrointestinal tract structure; Gene Activation; Gene Expression; Generations; Genes; Genetic; Genetic Screening; Germ-Free; Glucose; Goals; Health; Health Promotion; High Fat Diet; Human; Immunologics; Inflammation; Insertional Mutagenesis; Intestines; Intracellular Membranes; Libraries; Metabolic; Metabolism; Methods; Microbe; Modeling; Molecular; Molecular Genetics; Monitor; Morphology; Mucins; Mucolytics; Mus; Mutagenesis; Nutritional; Obesity; Organoids; Physiological; Physiology; Play; Population; Probiotics; Process; Production; Resistance; Resolution; Role; Surface; System; Testing; Tracer; Weight Gain; Work; base; beneficial microorganism; genetic analysis; gut colonization; gut microbiota; host colonization; host-associated microbial communities; immune health; intestinal epithelium; microbial; microbial community; microbiota; microorganism interaction; mouse model; mutant; next generation; novel; off-label use; preference; programs; reverse genetics; sugar; tool

ABSTRACT Microbes that inhabit the mucin layer that separates epithelial surfaces from the bulk of microbial contents of the gastrointestinal tract (GI) play a critical role in maintaining the metabolic and immunological health of their host. For instance, the mucolytic, gram negative, obligate anaerobic bacterium Akkermansia muciniphila is associated with protection from high-fat induced obesity. Concomitantly, the abundance of this microbe decreases in humans on western style diets. Importantly, in mouse models of diet-induced obesity, experimental colonization with A. mucinophila leads to lower rates of weight gain and glucose resistance. In addition, A. muciniphila contributes to dampening inflammation by enhancing mucin production and promoting intestinal barrier integrity through enhanced formation of epithelial cell junctions. Not surprisingly, A. muciniphila is being considered as a potential commercial probiotic. Unfortunately, the molecular mechanisms underlying the interactions between Akkermansia, its host, and associated microbial communities are largely unknown In this application, we propose to apply genetic methods we recently developed to characterize the process of mucin acquisition and degradation by A. mucinipihila, develop new ex vivo colonization models to test the impact of A. muciniphila exposure on epithelial cell physiology and function, and define the role that mucin metabolism plays in Akkermansia colonization of mice and its impact on GI ecology. The proposed work will generate new genetic tools and host model systems with which to understand the molecular basis of how this emerging beneficial microbe exerts its health-promoting effects on its host, and aid in the engineering of A. muciniphila strains with enhanced probiotic functions.

抽象的 栖息在粘蛋白层的微生物将上皮表面与 胃肠道（GI）的大部分微生物含量在 维持其宿主的代谢和免疫学健康。例如， 粘液溶剂，革兰氏阴性，肌肉厌氧细菌akkermansia 粘膜粘膜与免受高脂诱导肥胖症的保护有关。 随之而来的是，这种微生物的丰度在西方的人类中降低 风格饮食。重要的是，在饮食引起的肥胖症的小鼠模型中，实验性 粘蛋白果仁糖定植会导致体重增加率较低和葡萄糖 反抗。此外，粘曲霉有助于通过 通过增强粘蛋白的产生并通过 增强上皮细胞连接的形成。毫不奇怪，A。Muciniphila是 被认为是潜在的商业益生菌。 不幸的是，在相互作用之间相互作用的分子机制 Akkermansia，其宿主和相关的微生物社区在很大程度上是 在此应用程序中未知，我们建议应用遗传学方法我们最近 开发以表征通过 A. Mucinipihila，开发了新的离体定植模型，以测试A.的影响。 对上皮细胞生理学和功能的粘膜接触，并定义 粘蛋白代谢在小鼠及其的akkermansia定植中起作用的作用 对胃肠道生态学的影响。 拟议的工作将生成新的遗传工具和主机模型系统 这要了解这种新兴微生物的分子基础 对其宿主发挥健康促进作用，并有助于A。 具有增强益生菌功能的粘膜菌株。