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: 10436313
• 负责人: Xin Li
• 金额: $ 47.63万
• 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/10436313
• 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.

抽象的 炎症是一种以衰老为特征的慢性低度炎症，可能是衰老的结果 不平衡的微生物群及其代谢物与宿主免疫之间的功能失调关系 炎症在衰老和与年龄相关的疾病中发挥着越来越重要的作用。 研究表明，柠檬酸循环中的中间代谢产物琥珀酸的升高与 人类和小鼠的衰老通过增加相对丰度来改变肠道微生物组 琥珀酸升高还会激活 SUCNR1 以增强骨髓生成和炎症。 从机制上讲，我们发现琥珀酸会增加血清和骨髓中的 IL-1β 和 TNFα，并且 诱导白细胞介素 1 受体相关激酶 1 (IRAK1) 表达增加 30 倍，并且增加 50% 我们的初步数据提供了新的骨髓中粒细胞巨噬细胞祖细胞的增加。 机械证据表明肠道微生物、代谢物和骨髓生成之间的相互作用有助于 我们现在试图通过测试以下总体假设来推进该项目： 目标 1：针对肠道微生物组和细胞外琥珀酸受体激活来减轻炎症。 我们将确定琥珀酸升高对年轻和老年 WT 肠道菌群失调和宿主反应的影响 C57/B6 和 IRAK1 KO 小鼠以及这些改变如何调节 IL-1β-IRAK1 信号传导以促进 然后我们将使用抗生素治疗和粪便微生物移植来治疗。 确定对微生物组进行重新编程是否会改变炎症过程。在目标 2 中，我们将使用 WT。 和骨髓谱系特异性SUNCR1 KO小鼠确定骨髓谱系细胞是否是关键 琥珀酸刺激的骨髓生成和炎症的介质最后我们将确定琥珀酸是否-。 通过在 WT 中进行骨髓移植，刺激的炎症和骨髓生成依赖于 IRAK1 和IRAK1 KO从年轻到年老的小鼠，并监测骨髓和淋巴细胞的重建。 拟议的关于与衰老相关的琥珀酸升高对肠道菌群失调和 SUCNR1 激活的影响的研究将 使我们能够了解炎症内在机制的致病变化并提供新的 达到缓解炎症的目的。 影响：该项目直接针对 NIA 的 RFA-AG-20-030“微生物组和衰老：影响” 健康与疾病”，并提供有关肠道微生物组与年龄相关的变化以及如何 宿主免疫系统和微生物群之间的串扰与局部和全身免疫相关 回应。