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，表征衰老的慢性低度炎症可能是 不平衡的微生物群和它们的代谢物与宿主的免疫力之间的功能失调的关系 系统。炎症在衰老和与年龄有关的疾病的速度中起着越来越重要的作用。我们 已经表明，在柠檬酸周期中的中间代谢物的琥珀酸盐升高与 人和小鼠的衰老都通过增加相对丰度而改变了肠道微生物组 Pathobionts。琥珀酸盐升高还激活了SucNR1以增强骨髓性和炎症。 从机械上讲，我们表明血清和骨髓中的IL-1β和TNFα增加，以及 诱导白介素-1受体相关激酶1（IRAK1）表达30倍，50％ 骨髓中粒细胞巨噬细胞祖细胞的增加。我们的初步数据提供了新的 肠道微生物，改变的代谢产物和髓鞘之间的相互作用的机械证明有助于 发炎。现在，我们试图通过测试以下规范假设来推进该项目 靶向肠道微生物组和细胞外琥珀酸酯受体激活减轻炎症。在目标1中 我们将确定琥珀酸盐升高对肠道营养不良和宿主反应的影响 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 发炎。然后，我们将使用gnotobiotic，抗生素治疗和粪便菌群移植到 确定重编程微生物组是否改变了炎症的过程。在AIM 2中，我们将使用wt 和髓样谱系特异性Suncr1 KO小鼠确定髓样谱系是否为关键 琥珀酸酯刺激的脊髓性和炎症的介体。最后，我们将确定是否琥珀 通过在WT中进行骨髓移植，刺激的注射和髓氧化是IRAK1的依赖性 从小到老鼠的Irak1 KO，并监测髓样和淋巴样细胞的重建。 拟议的关于衰老相关琥珀酸酯在肠道营养不良和SUCNR1激活上的研究将 使我们能够理解炎症的内在机制的病因变化并提供新颖 减轻炎症的目标。 影响：该项目直接解决了NIA的RFA-AG-20-030有关“微生物组和老化：影响力” 关于健康和疾病”，并提供有关年龄相关的肠道微生物组变化的信息，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 回答。