Gut microbiome communication with the bone marrow regulates intestinal inflammation

项目摘要 意义：迫切需要新的方法来治疗或预防溶组织内阿米巴，因为它是一种 这是低收入国家婴儿腹泻的重要原因。没有疫苗，只有一类 抗寄生虫药对侵袭性阿米巴病有效。 假设：这个项目将测试肠道微生物组的代谢产物能够 表观遗传学改变骨髓以增加肠道中性粒细胞炎症并提供抗原- 在随后的阿米巴感染期间的非特异性保护。 方法：这个项目将确定肠道微生物群如何与骨髓沟通以调节 肠道炎症导致随后的感染。初步数据表明，骨骼中的表观遗传变化 骨髓，由肠道细菌斯氏梭菌引起，足以赋予粘膜 预防随后的溶组织内阿米巴感染。这一发现导致了一种假设，即内脏 辛辛德氏菌的定植增加了一种血清介质(脱氧胆酸盐)，然后作用于骨髓。 (JMJD3)，以帮助支持粒细胞单核细胞祖细胞(GMP)的扩增和更强大的肠道中性粒细胞 回应。目标1将确定华支睾吸虫如何从肠道传递到骨髓。目标2和目标3将 确定骨髓在银屑病定植过程中的表观遗传学改变及其保护作用 内阿米巴。这些研究的成功完成将确定肠道梭菌是如何与 骨髓诱导表观遗传变化，从而诱导抗原非特异性的“训练有素的天然免疫”。另外， 我们的方法的影响超越了阿米巴病和传染病，延伸到 造血和先天训练的免疫力。成功完成这些研究将有助于发展 下一代疗法利用微生物群和经过训练的免疫力来帮助清除 病原体或有助于调节炎症的严重程度。 创新：这项工作将提供对基础培训基础流程的更好理解 由宿主微生物区系诱导的免疫。从这项工作中衍生出的新概念将确定 在微生物区系介导的预防感染方面很重要，可作为转化医学的靶点。 这项工作的环境是一个研究小组和司致力于研究的发病机制 传染性结肠炎，包括阿米巴病，在过去的25年里。在表观遗传学、生物信息学、 此外，还包括梭状芽胞杆菌生物学(见支持函)。伯吉斯博士，圆周率项目，在 训练有素的免疫领域和微生物组调节阿米巴结肠炎易感性的开创性研究。

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.