Succinate triggers gut dysbiosis and activates SUCNR1 to enhance inflammaging

琥珀酸引发肠道菌群失调并激活 SUCNR1 以增强炎症

• 批准号: 10237290
• 负责人: Xin Li
• 金额: $ 49.59万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10237290
• 关键词: Ablation; Address; Adult; Aging; Antibiotic Therapy; Antibiotics; Bacteria; Bone Marrow; Bone Marrow Transplantation; Cell Lineage; Cells; Chronic; Data; Disease; Functional disorder; Germ-Free; Gnotobiotic; Growth; Health; Hematopoietic stem cells; Human; IRAK1 gene; Immune; Immune response; Immune system; Immunity; Immunosuppression; Inflammaging; Inflammation; Inflammatory; Interleukin-1 beta; Intestines; Knockout Mice; Lymphoid Cell; Measures; Mediator of activation protein; Metabolism; Modeling; Monitor; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis; Organ; Pathogenicity; Play; Population; Process; Receptor Activation; Research; Role; Sampling; Serum; Signal Transduction; Succinates; Surface; T cell differentiation; T-Lymphocyte; TNF gene; Testing; Tissues; age related; aging population; bone; cohort; cytokine; experimental study; extracellular; fecal transplantation; granulocyte; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; immune activation; improved; inflammatory marker; macrophage; metagenomic sequencing; microbial; microbiome; microbiome alteration; microbiome composition; microbiota; novel; pathobiont; pathogenic bacteria; progenitor; receptor; reconstitution

Abstract Inflammaging, the chronic low-grade inflammation that characterizes aging is a likely consequence of a dysfunctional relationship between the imbalanced microbiota and their metabolites with the host's immune system. Inflammaging plays an increasingly important role in the rate of aging and age-related diseases. We have shown that the elevation of succinate, an intermediate metabolite in citric cycle, was associated with aging in both human and mouse which altered the gut microbiome by increasing the relative abundance of pathobionts. Succinate elevation also activates the SUCNR1 to augment myelopoiesis and inflammation. Mechanistically we showed that succinate increased IL-1β and TNFα in the serum and bone marrow, and induced a 30-fold increase of Interleukin-1 receptor-associated kinase 1 (IRAK1) expression and a 50% increase of granulocyte macrophage progenitors in bone marrow. Our preliminary data provided new mechanistic proof that the interplay among gut microbes, altered metabolites and myelopoiesis contributes to inflammaging. We now seek to advance this project by testing the following over-arching hypothesis that targeting the gut microbiome and extracellular succinate receptor activation alleviate inflammaging. In Aim 1 we will determine the impact of succinate elevation on gut dysbiosis and host response in young and old WT C57/B6 and IRAK1 KO mice and how these alterations regulate IL-1β-IRAK1 signaling to promote inflammaging. Then we will use gnotobiotic, antibiotic treatment and Fecal Microbiota Transplantation to determine whether reprogramming the microbiome alters the course of inflammaging. In Aim 2 we will use WT and myeloid lineage-specific SUNCR1 KO mice determine whether the myeloid lineage cells are the key mediators of succinate-stimulated myelopoiesis and inflammation. Finally we will determine whether succinate- stimulated inflammation and myelopoiesis is IRAK1-dependent by conducting bone marrow transplant in WT and IRAK1 KO from young to old mice and monitor the reconstitution of myeloid and lymphoid cells. The proposed study on aging-related succinate elevation on gut dysbiosis and SUCNR1 activation will enable us to understand the causative changes in the intrinsic mechanisms of inflammaging and provide novel target to alleviate inflammaging. Impact: This project directly addresses the NIA's RFA-AG-20-030 on “Microbiome and Aging: Impact on Health and Disease” and provides information on age-related changes in the gut microbiome and how a cross-talk between the host immune system and microbiota correlates to the local and systemic immune responses.

摘要 炎症，一种以衰老为特征的慢性低度炎症，可能是 微生物区系失衡及其代谢产物与宿主免疫功能失调的关系 系统。炎症在老龄化和与年龄相关的疾病的发生率中扮演着越来越重要的角色。我们 已经表明，柠檬酸循环中的中间代谢物琥珀酸的升高与 人和小鼠的衰老通过增加肠道微生物群的相对丰度来改变肠道微生物群 可怜虫。琥珀酸升高也激活了SUCNR1，以促进骨髓生成和炎症。 从机制上讲，琥珀酸可增加血清和骨髓中IL-1β和肿瘤坏死因子α，并 诱导白细胞介素1受体相关激酶1(IRAK1)表达增加30倍，并增加50% 骨髓粒细胞-巨噬细胞祖细胞增多。我们的初步数据提供了新的 肠道微生物、代谢产物改变和骨髓生成之间相互作用的机制证据 着火了。我们现在试图通过测试下面的总体假设来推进这个项目 针对肠道微生物群和细胞外琥珀酸受体激活，减轻炎症。在目标1中 我们将确定琥珀酸升高对青年和老年WT肠道生态失调和宿主反应的影响 C57/B6和IRAK1KO小鼠及其调控IL-1β-IRAK1信号转导途径的研究 着火了。然后我们将使用诺生菌、抗生素治疗和粪便微生物区系移植来 确定重新编程微生物组是否会改变炎症过程。在目标2中，我们将使用WT 而髓系特异的SUNCR1 KO小鼠决定了髓系细胞是否是关键 琥珀酸刺激的骨髓生成和炎症的介体。最后我们将确定琥珀酸是否- 西医骨髓移植刺激的炎症和骨髓生成依赖于IRAK1 和IRAK1 KO，并监测髓系细胞和淋巴系细胞的重建。 与衰老相关的琥珀酸升高对肠道生物失调和SUCNR1激活的拟议研究将 使我们能够了解炎症的内在机制的致病变化，并为我们提供新的 目标是减轻炎症。 影响：该项目直接针对NIA的RFA-AG-20-030中的“微生物组与衰老：影响” 关于健康和疾病》，并提供有关肠道微生物群随年龄变化的信息以及如何 宿主免疫系统和微生物区系之间的相互作用与局部和系统免疫相关。 回应。