Project 1 - Determining the contributions of the gut microbiota to the physiologi

项目 1 - 确定肠道微生物群对生理的贡献

• 批准号: 8742500
• 负责人: JEFFREY I GORDON
• 金额: $ 60.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8742500
• 关键词: Adult; Aftercare; Biological Assay; Biological Markers; Body Composition; Calorimetry; Clinical Research; Collection; Communities; Complement; Data; Data Set; Development; Diagnostic; Diet; Dietary Component; Disease; Experimental Designs; Family; Fatty acid glycerol esters; Functional disorder; Future; Genes; Genetic Crossing Over; Germ-Free; Gnotobiotic; Goals; Growth; Health; Home environment; Housing; Human; In Vitro; Individual; Insulin Resistance; Invaded; Lead; Liver; Magnetic Resonance; Mass Spectrum Analysis; Measures; Metabolic; Metagenomics; Microbe; Modification; Mus; National Health and Nutrition Examination Survey; Nature; Nutrient; Obesity; Organism; Outcome; Paired Comparison; Pathogenesis; Pattern; Phenotype; Physiological; Physiology; Preclinical Testing; Prevention; Probiotics; Ribosomal RNA; Role; Sampling; Serum; Skeletal Muscle; Taxon; Testing; Therapeutic; Time; Translational Research; Transplantation; Twin Multiple Birth; Twin Studies; Variant; Work; arm; base; feeding; food consumption; fruits and vegetables; genome sequencing; gut microbiota; insight; member; metabolomics; microbiome; obesity prevention; pre-clinical research; prebiotics; prevent; repaired; research study; sample collection; saturated fat; tool; transmission process

SUMMARY Project 1 will use a translational research pipeline for human gut microbiota-directed diagnostics and therapeutics we developed based on gnotobiotic mice harboring microbiota transplanted from three types of adult twin pairs discordant for obesity and/or its associated metabolic abnormalities [LeanMetabolicallyHealthy-Obese Metabolically Unhealthy (LnMH/ObMUN), LnMH/ObMH, ObMH/ObMUN]. Its goal is to (i) establish a causal role of the gut microbiota in obesity and associated metabolic phenotypes, (ii) obtain mechanistic insights about the interactions between diet and members of the gut microbiota that produce these phenotypes, (iii) conduct tests of the effects of manipulating diet and bacterial taxa on phenotypes transmitted by ObMUN microbiota. Project 1 has 4 aims. (1) Determine the effects of microbiota, collected from twin pairs at the end of the each of their two in-home diet periods, on body composition/metabolic phenotypes of recipient adult gnotobiotic mice given a diet homologous to that consumed at the time the donor's microbiota was collected or the other diet that twins will have consumed (cross-over diet group). Within-pair, between-twin pair comparisons and across discordant pair type comparisons will be performed. (2) Co-house gnotobiotic mice harboring intact uncultured microbiota from discordant pairs to determine if (i) microbiota from the LnMH donor prevents or ameliorates development of obesity- and obesity-associated metabolic dysfunction in mice colonized with the ObMH or ObMUN co-twin's microbiota, and how prevention/amelioration correlates with invasion of bacterial taxa from the microbiota of one cagemate to the other, and later comparable co-housing experiments involving ObMH and ObMUN mice. (3) Determine if bacterial culture collections prepared from microbiota samples characterized in Aim 2 also transfer discordant donor phenotypes to gnotobiotic mice; perform co-housing experiments to identify invasive cultured taxa associated with phenotypic rescue in different diet contexts. (4) Execute a testing matrix in which a culture collection from a representative ObMUN or ObMH co-twin are introduced to separate groups of gnotobiotic mice fed a representative USA diet high in saturated fats and low in fruits and vegetables, alone or with a lead probiotic consortium (invasive taxa identified from aims 2, 3), or a lead prebiotic (identified from in vitro screen), or a combination of the two (synbiotic lead). The therapeutic lead will be administered at the time of colonization with the culture collection (prevention arm) or 2 weeks after initial colonization (treatment arm). Metabolic profiling will be performed with Core A. Multi-omics datasets will be analyzed with existing tools and used to generate new analysis strategies with Project 3 and Core B.

概括 项目 1 将使用转化研究管道进行人类肠道微生物群定向诊断和 我们开发的疗法基于携带三种类型移植微生物群的无菌小鼠 肥胖和/或其相关代谢异常不一致的成年双胞胎 [LeanMetabolicallyHealthy-Obese 代谢不健康 (LnMH/ObMUN)、LnMH/ObMH、ObMH/ObMUN]。其目标是 (i) 确定肠道的因果作用 肥胖中的微生物群和相关代谢表型，(ii) 获得有关肥胖的机制见解 饮食与产生这些表型的肠道微生物群成员之间的相互作用，(iii) 进行测试 控制饮食和细菌分类群对 ObMUN 微生物群传播表型的影响。项目1 有4个目标。 (1) 确定微生物群的影响，这些微生物群是在双胞胎结束时收集的 家庭饮食期间，对接受特定生素的受体成年小鼠的身体成分/代谢表型 饮食与收集捐赠者微生物群时消耗的饮食或双胞胎的其他饮食相同 将食用（交叉饮食组）。配对内、双胞胎间比较以及不一致的比较 将执行配对类型比较。 (2) 具有完整未培养微生物群的共养无菌小鼠 从不一致的配对中确定 (i) 来自 LnMH 供体的微生物群是否可以预防或改善 ObMH 或 ObMUN 双胞胎定植的小鼠中肥胖和肥胖相关的代谢功能障碍 微生物群，以及预防/改善与微生物群入侵细菌类群的关系 一只与另一只笼养在一起，后来又进行了 ObMH 和 ObMUN 小鼠的类似共养实验。 (3) 确定从目标 2 中表征的微生物群样本制备的细菌培养物保藏是否也转移 无菌小鼠的供体表型不一致；进行共同居住实验以识别侵入性培养物 与不同饮食环境中表型拯救相关的分类单元。 (4) 执行测试矩阵，其中文化 来自代表性 ObMUN 或 ObMH 双胞胎的集合被引入不同的无菌小鼠组 喂养具有代表性的美国饮食，饱和脂肪含量高，水果和蔬菜含量低，单独或含铅 益生菌联盟（从目标 2、3 中鉴定出的入侵类群），或主要益生元（从体外筛选中鉴定出）， 或两者的组合（合生素）。治疗先导药物将在 通过培养物收集进行定植（预防组）或初始定植后 2 周（治疗组）。 代谢分析将使用 Core A 进行。多组学数据集将使用现有工具进行分析， 用于通过项目 3 和核心 B 生成新的分析策略。