Megakaryocyte regulation by the gut microbiome

肠道微生物组对巨核细胞的调节

• 批准号: 10720081
• 负责人: Melody Y Zeng
• 金额: $ 67.8万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720081
• 关键词: 2019-nCoV; ACE2; Antibiotics; Autoimmune Diseases; Bacteria; Biological Markers; Blood Platelets; Blood coagulation; Blood flow; Bone Marrow; Bone Marrow Cells; COVID-19 pandemic; COVID-19 patient; Cancer Patient; Coagulation Process; Data; Diet; Disease; Fermentation; Fiber; Germ-Free; Goals; Hamsters; Heterogeneity; Histone Deacetylase; Homeostasis; Human; Impairment; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Knowledge; Life; Ligands; Link; Long COVID; Lung; Mediating; Megakaryocytes; Megakaryocytopoieses; Microscopic; Middle East Respiratory Syndrome; Morbidity - disease rate; Mus; Oxygen; Pathway interactions; Patients; Pectins; Predisposition; Probiotics; Regulation; Reporting; Rheumatoid Arthritis; Risk Reduction; Role; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Shapes; Signal Transduction; Systemic Lupus Erythematosus; Testing; Thrombosis; Tissues; Viral Load result; Virus Diseases; Volatile Fatty Acids; Work; commensal bacteria; gut bacteria; gut microbiome; gut microbiota; influenza infection; interest; microbial; mortality; mouse model; neutrophil; novel; progenitor; receptor; response; risk prediction; severe COVID-19; single-cell RNA sequencing; therapeutic development; transcriptomics; transmission process

Abnormal and potentially life-threatening blood clotting is seen in other severe infections, such as SARS- CoV-2, MERS, and H1N1 influenza. Platelets are produced by megakaryocytes. Enhanced megakaryopoiesis is found in severe COVID-19. Increased megakaryopoiesis is commonly found in autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE). Hypercoagulation also accounts for a significant percentage of mortality and morbidity in cancer patients. However, the regulation of megakaryocyte differentiation and function, however, remains poorly understood. The gut microbiome shapes tissue homeostasis beyond the gut through release of metabolites or microbial ligands. The link between the gut microbiome and megakaryocyte function is poorly understood. Our preliminary data demonstrate that fiber-fermenting gut bacteria that generate short-chain fatty acids (SCFAs) downregulate the ACE2 receptor, the entry receptor for SARS-CoV-2 infection and transmission; SCFA treatment led to reduced viral burdens in both mice and hamsters following infection with SARS-CoV-2 or a pseudovirus expressing the spike protein of SARS-CoV-2. In addition, our work uncovered a potentially novel function of SCFAs in limiting the coagulation response via the Sh2b3-Mpl axis to modulate megakaryopoiesis and platelet turnover. This proposal aims to define the role of the gut microbiome in the regulation of megakaryocyte maturation and function at steady state and in viral infection. This goal will be accomplished with the following 3 Specific Aims: 1. Define the role of the gut bacteria in steady-state maturation and function of megakaryocytes; 2. Interrogate the role of the gut microbiome in megakaryocyte maturation and function in viral infection; 3. Define the role of SCFAs in megakaryocyte maturation and function in homeostasis and viral infection. We will decipher the SCFA-Sh2b3-Mpl axis in the regulation of megakaryopoiesis and platelet turnover at steady state in viral infection, and explore the benefit of using SCFA-producing gut bacteria or pectin fiber to control megakaryocyte response in viral infection. This work will uncover a link between the gut microbiome and megakaryocyte response at steady state and in viral infection. Our findings will potentially identify specific gut commensal bacteria or metabolites that, either directly or indirectly, modulate the maturation of megakaryocytes and function; this knowledge can be leveraged in the development of therapeutics to treat uncontrolled megakaryopoiesis in various disease settings. These bacteria and metabolites of interest, including SCFAs as our data supported, could be additionally used as biomarkers to predict the risk of excessive megakaryopoiesis.

其他严重感染（例如 SARS）中也会出现异常且可能危及生命的凝血现象。 CoV-2、MERS 和 H1N1 流感。血小板由巨核细胞产生。增强型 在严重的 COVID-19 中发现了巨核细胞生成。巨核细胞生成增加常见于 自身免疫性疾病，包括类风湿性关节炎、系统性红斑狼疮（SLE）。 高凝状态也是癌症患者死亡率和发病率的很大一部分原因。 然而，巨核细胞分化和功能的调节仍然很差。 明白了。肠道微生物组通过释放肠道微生物来塑造肠道外的组织稳态 代谢物或微生物配体。肠道微生物组和巨核细胞功能之间的联系是 不太了解。我们的初步数据表明，纤维发酵肠道细菌可产生 短链脂肪酸 (SCFA) 下调 ACE2 受体，即 SARS-CoV-2 的进入受体 感染和传播； SCFA 治疗降低了小鼠和仓鼠的病毒负荷 感染 SARS-CoV-2 或表达 SARS-CoV-2 刺突蛋白的假病毒后。在 此外，我们的工作发现了 SCFA 在限制凝血反应方面的潜在新功能 通过 Sh2b3-Mpl 轴调节巨核细胞生成和血小板周转。该提案旨在定义 肠道微生物组在调节巨核细胞成熟和稳态功能中的作用 以及病毒感染中。这一目标将通过以下 3 个具体目标来实现： 1. 定义角色 肠道细菌稳态成熟和巨核细胞功能的影响； 2. 询问角色 巨核细胞成熟中的肠道微生物组和病毒感染中的功能； 3. 定义角色 SCFA 在巨核细胞成熟中的作用以及在体内平衡和病毒感染中的作用。我们将破译 SCFA-Sh2b3-Mpl 轴在稳定状态下调节巨核细胞生成和血小板周转 病毒感染，并探索使用产生 SCFA 的肠道细菌或果胶纤维来控制的益处 病毒感染中的巨核细胞反应。 这项工作将揭示稳态下肠道微生物组和巨核细胞反应之间的联系 以及病毒感染中。我们的研究结果将有可能识别特定的肠道共生细菌或代谢物 直接或间接调节巨核细胞的成熟和功能；这些知识 可用于治疗各种疾病中不受控制的巨核细胞生成的开发 疾病设置。这些细菌和感兴趣的代谢物，包括我们的数据支持的 SCFA， 还可以用作生物标志物来预测过度巨核细胞生成的风险。