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: 8412916
• 负责人: James Gregory PHILLIPS
• 金额: $ 26.54万
• 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/8412916
• 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）是一个极其复杂的细菌群落的家园