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 P01DK094779 相关的多样性补充请求 (PA21-071) 直接集成到目标中 P01项目2的目标是探索临床相关硫还原菌的功能活动 (SRB) 源自 IBD 患者和健康受试者。微生物群落和功能的变化 许多肠道和全身疾病的特征是由环境、药物、 营养和饮食因素。一些线索将硫代谢置于疾病发病机制的中心 炎症性肠病 (IBD)，其特征是硫酸化胆汁酸增加和 SRB 增加。 健康的肠道微生物群含有 SRB，它在 IBD 患者中扩增。这些 SRB 可以利用并 在吃西方饮食的 IBD 患者中代谢增加的富含硫的化合物库，以促进肠道 通过溶解粘液而渗透粘膜屏障的有毒 H2S 产生而引起炎症 层，损害上皮细胞线粒体功能并改变产生 SCFA 的细菌群体和相关 微生物失衡导致胆汁酸失调，如炎症性肠病 (IBD) 中所见。我们的工作将确立 SRB 在以下方面的作用： IBD 并使用 P01 项目 2 开发的最新科学方法和人源化小鼠结肠炎模型 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物中 SRB 的丰度、功能和 H2S 产量 人类粪便细菌群落并影响实验性结肠炎的侵袭性。 具体目标： 1. 表征已确定的膳食硫底物和 H2S 的调节能力 肠道硫还原菌数量和粪便细菌群落结构。 2. 确定 富集与贫化 SRB 粪便群体和选定 SRB 的炎症与保护作用 IBD 临床分离菌株。 3. 表征高 IL-10 诱导菌株的能力 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SRB和临床相关的分子、菌株水平和功能特征 饮食控制的影响将扩大我们对 SRB 对粘膜稳态影响的理解 与慢性炎症以及 P01 项目 2 研究的范围和影响。