Gut microbiome communication with the bone marrow regulates intestinal inflammation

肠道微生物组与骨髓的通讯调节肠道炎症

• 批准号: 10350653
• 负责人: Stacey L Burgess
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-16 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350653
• 关键词: Adoptive Transfer; Amebiasis; Amebic colitis; Amoeba genus; Antigens; Antiparasitic Agents; Bacteria; Bile Acids; Bioinformatics; Biological Assay; Biology; Bone Marrow; ChIP-seq; Chemicals; Child; Cholates; Clostridium; Colitis; Communicable Diseases; Communication; Data; Deoxycholic Acid; Development; Diarrhea; Disease; Entamoeba; Entamoeba histolytica; Epigenetic Process; Exposure to; Future; Gene Expression; Granulopoiesis; Hematopoiesis; Immune system; Immunity; Immunologic Memory; In Vitro; Infant; Infection; Infectious colitis; Inflammation; Inflammatory; Intestines; Knockout Mice; Letters; Marrow; Measures; Mediating; Mediator of activation protein; Metabolic; Modeling; Monoclonal Antibodies; Mucous Membrane; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Phenotype; Population; Predisposition; Process; Production; Research; Serum; Severities; Signal Transduction; Testing; Training; Vaccines; Work; bile salts; chromatin immunoprecipitation; deoxycholate; enteric pathogen; granulocyte; granulocyte-monocyte progenitors; gut colonization; gut inflammation; gut microbiome; gut microbiota; host microbiota; innovation; low income country; microbial; microbiome; microbiome research; microbiota; monocyte; neutrophil; next generation; next generation sequencing; novel; novel strategies; pathogen; prevent; professional atmosphere; progenitor; receptor; response; therapy development; trafficking; transcriptome sequencing; translational medicine; whole genome

Project Summary Significance: There is an urgent need for novel approaches to treat or prevent Entamoeba histolytica as it is an important cause of diarrhea in infants in low income countries. There is no vaccine and only a single class of antiparasitics is effective for invasive amebiasis. Hypothesis: This project will test the hypothesis that metabolic products of the gut microbiome are capable of epigenetically altering the bone marrow to increase intestinal neutrophilic inflammation and provide antigen- nonspecific protection during subsequent ameba infection. Approach: This project will determine how the gut microbiome communicates with the bone marrow to regulate intestinal inflammation to subsequent infection. Preliminary data suggest that epigenetic changes in the bone marrow, caused by exposure to the intestinal bacteria Clostridium scindens, are sufficient to confer mucosal protection from subsequent Entamoeba histolytica infection. This finding led to the hypothesis that gut colonization with C. scindens increases a serum mediator (deoxycholate) that then acts on the marrow (JMJD3) to help support granulocyte monocyte progenitor (GMP) expansion and a more robust gut neutrophil response. Aim 1 will determine how C. scindens communicates from the gut to the marrow. Aim 2 and 3 will determine how the bone marrow is epigenetically altered during C. scindens colonization and protects from Entamoeba. Successful completion of these studies will identify how intestinal Clostridia communicate with the marrow to induce epigenetic changes that induce antigen-nonspecific “trained innate immunity”. Additionally, the impact of our approach extends beyond amebiasis and infectious diseases to basic mechanisms of hematopoiesis and innate trained immunity. Successful completion of these studies will aid in development of next generation treatments that leverage the microbiome and trained immunity to help in clearance of pathogens or help modulate the severity of inflammation. Innovation: This work will provide a greater understanding of fundamental processes underlying trained immunity induced by the host microbiota. Novel concepts derived from this work will identify pathways important in microbiota-mediated protection from infection that can be targeted by translational medicine. The environment for this work is a research group and Division dedicated to the study of the pathogenesis of infectious colitis, including amebiasis, for the past 25 years. Extensive expertise in Epigenetics, Bioinformatics, and Clostridia biology is also included (see letters of support). Dr. Burgess, the project PI, is well cited in the field of trained immunity and pioneered study of the microbiome in regulating susceptibility to amebic colitis.

项目概要 意义：迫切需要治疗或预防溶组织内阿米巴的新方法，因为它是一种 低收入国家婴儿腹泻的重要原因没有疫苗，而且只有单一类别的疫苗。 抗寄生虫药对侵袭性阿米巴病有效。 假设：该项目将检验肠道微生物组的代谢产物能够 表观遗传改变骨髓以增加肠道中性粒细胞炎症并提供抗原 随后阿米巴感染期间的非特异性保护。 方法：该项目将确定肠道微生物组如何与骨髓通讯以调节 初步数据表明，骨骼的表观遗传变化。 由于暴露于肠道细菌梭状芽胞杆菌（Clostridium scindens）而引起的骨髓足以赋予粘膜 这一发现导致了肠道的假设。 C. scindens 的定植会增加血清介质（脱氧胆酸盐），然后作用于骨髓 (JMJD3) 帮助支持粒细胞单核细胞祖细胞 (GMP) 扩增和更强大的肠道中性粒细胞 目标 1 将决定 C. scindens 如何从肠道到骨髓进行通讯。 确定骨髓在 C. scindens 定植过程中如何发生表观遗传改变并防止 成功完成这些研究将确定肠道梭状芽胞杆菌如何与肠道菌沟通。 骨髓诱导表观遗传变化，从而诱导抗原非特异性“训练有素的先天免疫”。 我们的方法的影响超出了阿米巴病和传染病的基本机制 成功完成这些研究将有助于造血和先天免疫力的发展。 下一代治疗方法利用微生物组和经过训练的免疫力来帮助清除 病原体或帮助调节炎症的严重程度。 创新：这项工作将提供对训练背后的基本流程的更好理解 从这项工作中得出的新概念将确定宿主微生物群诱导的免疫途径。 对于微生物介导的感染保护非常重要，可以通过转化医学来靶向。 这项工作的环境是一个致力于研究发病机制的研究小组和部门 过去 25 年，我们在表观遗传学、生物信息学、 梭状芽胞杆菌生物学也包括在内（参见支持信），该项目的 PI 伯吉斯博士在该项目中被广泛引用。 训练有素的免疫领域，并开创了调节阿米巴结肠炎易感性的微生物组研究。