Identifying Microbial, Epithelial and Immune Cell Interactions that Mediate Mucosal Homeostasis and Determine IBD Phenotype

识别介导粘膜稳态并确定 IBD 表型的微生物、上皮细胞和免疫细胞相互作用

• 批准号: 10616986
• 负责人: Ryan B Sartor
• 金额: $ 9.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10616986
• 关键词: Address; Bile Acids; Biochemical; Blinded; Cell Communication; Characteristics; Chronic; Clinical; Clostridium perfringens; Colitis; Communities; Complex; Diet; Dietary Factors; Dietary Sulfur; Dose; Eating; Epithelial; Epithelial Cells; Exposure to; Feces; Fusobacterium; Gene Expression; Gnotobiotic; Goals; Hispanic; Histologic; Homeostasis; Human; Immune; Immunologics; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interleukin-10; Intestinal Diseases; Intestines; LCN2 gene; Measurement; Measures; Mediating; Metagenomics; Mitochondria; Molecular; Mucous Membrane; Mucous body substance; Mus; Nutritional; Pathogenesis; Patients; Pharmacology; Phase; Population; Production; Property; Role; Specimen; Structure; Sulfate; Sulfur; Sulfur Metabolism Pathway; Sulfur-Reducing Bacteria; Systemic disease; Testing; Volatile Fatty Acids; Work; bacterial community; clinically relevant; dietary; dietary manipulation; disease phenotype; dysbiosis; fecal transplantation; gut inflammation; gut microbiota; in vivo; metabolomics; metagenomic sequencing; microbial; microbial community; microbiota; microbiota profiles; murine colitis; protective effect; sodium sulfide; western diet

This Diversity Supplement request (PA21-071) related to P01DK094779 is directly integrated into the goals and aims of P01 Project 2 by exploring the functional activities of clinically relevant sulfur-reducing bacteria (SRB) derived from IBD patients and healthy subjects. Shifts in microbial communities and functions characteristic of many intestinal and systemic diseases are promoted by environmental, pharmacological, nutritional and dietary factors. Several clues place sulfur metabolism at the center of the pathogenesis of inflammatory bowel diseases (IBD), with characteristic increased sulfated bile acid and increased SRB. Healthy gut microbiota contain SRB, which are expanded in IBD patients. These SRB can exploit and metabolize an increased sulfur-rich compound pool in IBD patients eating a Western diet to promote intestinal inflammation through toxic H2S production that permeabilizes the mucosal barrier by dissolving the mucus layer, impairs epithelial cell mitochondrial function and alters SCFA-producing bacterial populations and related microbial imbalances that dysregulate bile acids, as seen in IBD. Our work will establish the roles of SRB in IBD and use the latest scientific approaches and humanized murine colitis models developed in P01 Project 2 to test functional properties of these strains that are derived from IBD patients and healthy controls. Hypothesis: sulfur availability modulates the abundance, function and H2S-production of SRB in complex human fecal bacterial communities and influences aggressiveness of experimental colitis. Specific Aims: 1. Characterize the abilities of identified dietary sulfur substrates and H2S to modulate intestinal sulfur-reducing bacteria numbers and fecal bacterial community structure. 2. Determine the inflammatory vs. protective effects of enriched vs. depleted SRB fecal populations and selected SRB strains from IBD clinical isolates. 3. Characterize the ability of high IL-10-inducing bacterial strains to inhibit in vivo SRB populations, H2S production and colitis in humanized IL-10-/- mice. These clinically relevant molecular, strain level and functional characterizations of clinically relevant SRB and the effects of dietary manipulations will expand our understanding of SRB influences on mucosal homeostasis vs chronic inflammation as well as the scope and impact of P01 Project 2 studies.

与P01 DK 094779相关的多样性补充申请（PA 21 -071）直接纳入目标 P01项目2通过探索临床相关的硫还原菌的功能活性 (SRB)来源于IBD患者和健康受试者。微生物群落和功能的变化 许多肠道和全身性疾病的特征是由环境，药理学， 营养和饮食因素。有几条线索将硫代谢置于 炎症性肠病（IBD），具有特征性硫酸化胆汁酸增加和SRB增加。 健康的肠道微生物群含有SRB，其在IBD患者中扩增。这些SRB可以利用和 代谢增加的富含硫的化合物池IBD患者吃西方饮食，以促进肠道 通过溶解粘液使粘膜屏障透化的有毒H2S产生的炎症 层，损害上皮细胞线粒体功能，并改变SCFA生产细菌种群和相关 微生物失衡导致胆汁酸失调，如IBD中所见。我们的工作将确立工代机构在以下方面的作用： IBD，并使用P01项目2中开发的最新科学方法和人源化小鼠结肠炎模型 以测试来自IBD患者和健康对照的这些菌株的功能特性。 假设：硫的有效性调节复合体中硫酸盐还原菌的丰度、功能和H2S的产生 人粪便细菌群落和影响实验性结肠炎的侵袭性。 具体目标：1。表征已鉴定的膳食硫底物和H2S调节 肠道降硫菌数量和粪便细菌群落结构。2.确定 富集与耗尽SRB粪便群和选定SRB的炎症与保护作用 来自IBD临床分离株的菌株。3.表征高IL-10诱导性细菌菌株的能力， 抑制人源化IL-10-/-小鼠体内SRB群体、H2S产生和结肠炎。 这些临床相关的分子、菌株水平和临床相关SRB的功能特征， 饮食调控的影响将扩大我们对SRB影响粘膜稳态的理解 与慢性炎症以及P01项目2研究的范围和影响。