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）是一个非常复杂的细菌社区的家园 宿主的基本作用，包括代谢物的转化和分解，免疫系统开发 并保护微生物病原体。这些社区是高度动态的构图， 代谢活性可以通过其哺乳动物宿主的变化（包括饮食，抗生素， 疾病和衰老。值得注意的是，胃肠道菌群的变化（营养不良）通常与人类有关 炎症性疾病，包括克罗恩病和溃疡性结肠炎，传染病和结直肠癌 癌症。这些疾病会影响数百万的人，并使美国经济损失近400亿美元。这 胃肠道微生物群落的纯粹复杂性极大地复杂化，使得很难分配 特定细菌属的生物功能，物种要少得多。因此，缺乏敏感的 生物标志物用于早期检测和监测GI疾病。为了解决这些知识的差距，我们 提议采​​用高度简化的小鼠模型，该模型仅用八个细菌定植 物种，改变的Schaedler Flora（ASF）。总体而言，ASF促进了正常的生理功能和 小鼠胃肠道系统的健康。与大多数包含常规微生物群的细菌相反，每个细菌 可以在体外培养成员。我们是美国少数使用此的研究团队之一 宿主微生物社区模型，以评估胃肠道粘膜健康和疾病。我们的中心假设是 宿主遗传学和微生物挑衅者介导的扰动驱动代谢适应 是健康和疾病的独特签名。我们将使用深层转录组测序以及 定量PCR概述了整个GI社区基因表达和丰度的变化，以评估 响应疾病状态的个别物种的代谢状态。 ASF模型将使我们能够 通过改变GI环境的改变，确定对维持社区重要的适应 传统的小鼠模型或使用与单个细菌定殖的小鼠无法保持水平 物种。这些研究的成功完成将产生有关个人如何的详细“纪录片” GI社区的成员对免疫（即内在）和细菌驱动（即外部）做出反应 扰动。这项研究将有助于个性化医学的未来，包括识别 预测疾病的易感性和严重性的新生物标志物，以及减轻新的策略 宿主的营养不良的后果。