Highly simplified model of a mammalian intestinal community

高度简化的哺乳动物肠道群落模型

• 批准号: 8598909
• 负责人: James Gregory PHILLIPS
• 金额: $ 25.08万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-17 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598909
• 关键词: Address; Affect; Aging; Antibiotics; Bacteria; Biological Markers; Biological Process; Biomedical Research; Cell physiology; Characteristics; Colitis; Colorectal Cancer; Communicable Diseases; Communities; Complex; Crohn' s disease; Development; Diet; Dietary Practices; Disease; Early Diagnosis; Enteral; Environment; Escherichia coli; Event; Exhibits; Experimental Models; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genomics; Goals; Growth; Health; Home environment; Human; Immune; Immune system; In Vitro; Individual; Inflammatory; Intestines; Knowledge; Lead; Maintenance; Malignant Neoplasms; Measures; Mediating; Medicine; Metabolic; Metabolism; Microbial Genetics; Modeling; Monitor; Mus; Mutation; Natural Immunity; Nutrient; Nutritional Requirements; Physiological; Physiology; Play; Predisposition; Prevention; Prevention strategy; Relative (related person); Research; Role; Severity of illness; Stress; System; Systems Development; Testing; Ulcerative Colitis; Work; adaptive immunity; cost; deep sequencing; direct application; experience; gastrointestinal; gastrointestinal function; gastrointestinal system; gut microbiota; human disease; immune function; improved; innovation; member; microbial; microbial community; microorganism; mouse model; pathogen; response; transcriptome sequencing; ward

The human gastrointestinal (GI) tract is home to an extremely complex bacterial community that plays essential roles for the host, including conversion and breakdown of metabolites, immune system development and protection against microbial pathogens. These communities are highly dynamic-their composition and metabolic activity can be altered dramatically by changes in their mammalian host, including diet, antibiotics, disease and aging. Significantly, changes in the GI microbiota (dysbiosis) are often associated with human inflammatory diseases, including Crohn's disease and ulcerative colitis, infectious diseases and colorectal cancer. These disorders affect millions of people and cost the US economy nearly $40 billion each year. The sheer complexity of the GI microbial community greatly complicates its study and makes it difficult to assign biological function(s) to specific bacterial genera, much less species. Consequently, there is a lack of sensitive biomarkers for early detection and monitoring of GI diseases. To address these gaps in knowledge, we propose to employ a highly simplified mouse model whose GI tract is colonized with only eight bacterial species, the altered Schaedler flora (ASF). Collectively, the ASF facilitates normal physiological function and health of the mouse GI system. In contrast to most bacteria comprising a conventional microbiota, each ASF member can be cultured in vitro. We are one of the few research teams in the US experienced in using this host-microbial community model to evaluate GI mucosal health and disease. Our central hypothesis is that perturbations mediated by host genetics and microbial provocateurs drive metabolic adaptations that are unique signatures of health and disease. We will use deep transcriptome sequencing along with quantitative PCR to profile changes in gene expression and abundance of the entire GI community to assess the metabolic states of the individual species in response to disease states. The ASF model will allow us to identify adaptations important for maintenance of the community through changes in the GI environment at a level not possible with a conventional mouse models, or by using mice colonized with a single bacterial species. The successful completion of these studies will yield a detailed "documentary" of how individual members of the GI community respond to immune- (i.e., intrinsic) and bacterial-driven (i.e., extrinsic) perturbations. This research will contribute to the future of personalized medicine, including identification of new biomarkers that predict predisposition and severity of disease, as well as new strategies to mitigate the consequences of dysbiosis on the host.

人类胃肠道 (GI) 是极其复杂的细菌群落的家园，它发挥着重要作用 对宿主的重要作用，包括代谢物的转化和分解、免疫系统的发育 和针对微生物病原体的保护。这些社区是高度动态的——它们的组成和 代谢活动可以通过哺乳动物宿主的变化而显着改变，包括饮食、抗生素、 疾病和衰老。值得注意的是，胃肠道微生物群的变化（生态失调）通常与人类 炎症性疾病，包括克罗恩病和溃疡性结肠炎、传染病和结直肠病 癌症。这些疾病影响数百万人，每年给美国经济造成近 400 亿美元的损失。这 胃肠道微生物群落的绝对复杂性使其研究变得非常复杂，并且难以分配 特定细菌属的生物学功能，更不用说物种了。因此，缺乏敏感的 用于早期检测和监测胃肠道疾病的生物标志物。为了解决这些知识差距，我们 提议采​​用高度简化的小鼠模型，其胃肠道仅定植有八种细菌 种，改变的谢德勒菌群（ASF）。总的来说，ASF 促进正常的生理功能和 小鼠胃肠道系统的健康。与大多数包含传统微生物群的细菌相比，每种 ASF 成员可以在体外培养。我们是美国少数有使用此技术经验的研究团队之一 评估胃肠道粘膜健康和疾病的宿主-微生物群落模型。我们的中心假设是 由宿主遗传学和微生物刺激物介导的扰动驱动代谢适应， 是健康和疾病的独特特征。我们将使用深度转录组测序 定量 PCR 分析整个 GI 群落基因表达和丰度的变化，以评估 各个物种对疾病状态的代谢状态。 ASF 模型将使我们能够 通过地理标志环境的变化，确定对维持群落重要的适应措施 传统小鼠模型或使用单一细菌定植的小鼠不可能达到这一水平 物种。这些研究的成功完成将产生一部详细的“纪录片”，讲述个人如何 胃肠道群体的成员对免疫（即内在）和细菌驱动（即外在）做出反应 扰动。这项研究将为个性化医疗的未来做出贡献，包括识别 预测疾病易感性和严重程度的新生物标志物，以及减轻疾病影响的新策略 生态失调对宿主的后果。