The microbiome determines organ damage development in sickle cell disease

微生物组决定镰状细胞病的器官损伤发展

• 批准号: 10525715
• 负责人: Huihui Li
• 金额: $ 15.6万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525715
• 关键词: Address; Affect; Africa South of the Sahara; American; Antibiotics; Antibodies; Area; Autoimmune; Bacteria; Bacterial Toxins; Bacterial Translocation; Belief; Blood Circulation; Blood Vessels; Bypass; Cause of Death; Cell Adhesion; Cell membrane; Cells; Cessation of life; Chronic; Complex; Data; Deposition; Development; Development Plans; Diet; Dietary Iron; Disease Progression; Distant; Enterococcus gallinarum; Erythrocytes; Exhibits; Functional disorder; Genes; Germ-Free; Goals; Hematological Disease; Hemolysis; Hospitalization; Immune system; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Inherited; Interleukin-17; Intestinal permeability; Intestines; Iron; Iron Overload; Lead; Leaky Gut; Life; Liver; Mediating; Microbe; Mucous body substance; Mus; Mutation; Organ; Oxidative Stress; Pain; Pathogenicity; Patients; Permeability; Portal vein structure; Probiotics; Renal function; Reporting; Research; Resources; Ribosomal DNA; Role; Sampling; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Specificity; Stress; Sum; Testing; Therapeutic; Tight Junctions; Training; Travel; United States; Up-Regulation; Vaccines; Work; base; beta Globin; biological adaptation to stress; career development; cost; cost effective; dietary control; dietary restriction; germ free condition; gut bacteria; gut microbiome; gut microbiota; improved; inflammatory marker; insight; iron metabolism; liver function; liver injury; microbial; microbial composition; microbiome; microbiome composition; microbiota; mouse model; murine colitis; novel; organ growth; pathogen; pathogenic bacteria; premature; prevent; recruit; treatment group

Project Summary: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States, affecting 70,000- 100,000 Americans. SCD is caused by a mutation in the β-globin gene that leads to significant deformation of the red blood cell (RBC) membrane and promotes RBC adhesion to other cells, inducing vaso-occlusive episodes (VOE). Chronic SCD is accompanied by progressive, systemic multi-organ dysfunction and costs over $475 million annually in hospital admissions. Our recent work demonstrates that the depletion of microbiota in SCD mice by antibiotics reduces organ damage and iron overload. Our preliminary data show that organ damage is significantly improved in germ-free SCD mice compared to specific-pathogen-free SCD mice, confirming the importance of microbiota in organ damage development. Analysis by 16S rDNA sequencing uncovered a candidate bacterium—Enterococcus gallinarum (E. gallinarum)—that may promote organ damage in SCD mice. Additionally, we demonstrate that SCD mice fed an iron-restricted diet exhibit significant reversal of organ damage compared with SCD mice fed a control diet. In the current application, we propose a 5-year experimental plan to advance our understanding of the microbiota-mediated effects on SCD disease progression and to test the manipulation of microbiota as a potential novel SCD treatment. In Specific Aim 1, we will confirm whether E. gallinarum functions as a pathogenic bacterium to influence the progression of organ damage in SCD mice. Additionally, we will investigate whether an E. gallinarum–specific vaccine reduces organ damage burden in SCD mice. We will explore the microbiota- related mechanisms that induce organ damage in SCD mice. Specifically, we will study how microbiota can bypass the gut barrier by analyzing relevant gut permeability parameters such as tight junction and mucus layer integrity. We hypothesize that once E. gallinarum translocates from the portal vein to the liver, it upregulates T helper 17 (Th17) cells that recruit other inflammatory cells to induce the organ damage seen in SCD mice. In Specific Aim 2, we will explore the role of dietary iron in gut microbiota survival and whether dietary iron is involved in disrupting gut barrier integrity in SCD mice. These proposed studies, focused on strategies of microbiota manipulation in SCD, will allow us to identify the key microbial species that contribute to SCD pathophysiology and potentially provide novel, cost-effective approaches for managing SCD’s life-long complications.

项目概要： 镰状细胞病（SCD）是美国最常见的遗传性血液疾病，影响70，000- 十万美国人。SCD是由β-珠蛋白基因突变引起的，该突变导致 红细胞（RBC）膜，并促进RBC粘附到其他细胞，诱导血管闭塞 事件（VOE）。慢性SCD伴有进行性、全身性多器官功能障碍， 每年4.75亿美元的住院费用。 我们最近的工作表明，抗生素对SCD小鼠微生物群的消耗降低了器官功能。 损伤和铁超载。我们的初步数据显示，在无菌条件下， SCD小鼠与无特定病原体的SCD小鼠相比，证实了微生物群在器官中的重要性 损害发展。16 S rDNA序列分析发现一株候选菌--肠球菌 gallinarum（E. gallinarum）-其可促进SCD小鼠中的器官损伤。此外，我们证明， 与喂食铁限制饮食的SCD小鼠相比，喂食铁限制饮食的SCD小鼠表现出显著的器官损伤逆转。 控制饮食。 在当前的应用中，我们提出了一个5年的实验计划，以促进我们对 微生物群介导的对SCD疾病进展的影响，并测试微生物群的操作作为一种潜在的 新的SCD治疗。在具体目标1中，我们将确认E.鸡胚是一种病原体， 细菌影响SCD小鼠器官损伤的进展。此外，我们还将调查 大肠鸡特异性疫苗降低SCD小鼠的器官损伤负担。我们将探索微生物群- 相关机制诱导SCD小鼠器官损伤。具体来说，我们将研究微生物群如何 通过分析相关的肠道通透性参数，如紧密连接和粘液层，绕过肠道屏障 完整我们假设一旦E.鸡胚从门静脉移位到肝脏，它上调T 辅助17（Th 17）细胞，其募集其他炎性细胞以诱导SCD小鼠中所见的器官损伤。在 具体目标2，我们将探讨膳食铁在肠道微生物群存活中的作用，以及膳食铁是否 参与破坏SCD小鼠的肠道屏障完整性。这些拟议的研究，侧重于战略， SCD中的微生物群操作，将使我们能够识别有助于SCD的关键微生物物种 病理生理学，并可能提供新的，具有成本效益的方法来管理SCD的终身 并发症