Studies on gut microbiome-joint connections in arthritis

关节炎肠道微生物组与关节连接的研究

• 批准号: 10378478
• 负责人: STEVEN R. GILL
• 金额: $ 62.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378478
• 关键词: Actinobacteria class; Address; Arthritis; B-Lymphocytes; Bifidobacterium; Blood; Blood Circulation; Cells; Colon; Communication; Communities; Data; Degenerative polyarthritis; Development; Dietary Supplementation; Disease; Epithelial; Family member; Fiber; Health; High Fat Diet; Human; Immune; Inflammation; Inflammatory; Intestines; Joints; Knee; Knee joint; Link; Mechanics; Medial meniscus structure; Messenger RNA; Metabolic; Metabolism; Methods; Modeling; Movement; Mus; Obese Mice; Obesity; Operative Surgical Procedures; Oral; Organoids; Pathogenicity; Peptococcaceae; Plant Roots; Probiotics; Process; Role; Serum; Structure; Supplementation; Synovial Membrane; Taxonomy; Testing; Thinness; Time; Tissue Harvesting; Tissues; Transgenic Mice; Transplantation; Up-Regulation; Work; base; comorbidity; cytokine; design; diet-induced obesity; dysbiosis; experimental study; gut dysbiosis; gut microbiome; joint destruction; macrophage; metabolome; metagenome; metatranscriptome; microbial; microbiota; mouse model; multiple omics; multiplex assay; nano-string; novel therapeutic intervention; palliative; prebiotics; systemic inflammatory response; transcriptomics

ABSTRACT Although mechanical overloading of joints has been implicated in the comorbid association between obesity and osteoarthritis (OA) [1, 2], we and others have established a pathogenic role for obesity-associated inflammation [3-6]. Our work to further study inflammation in this context has led to new data implicating dysbiosis of the gut microbiome as a root cause of inflammation in the colon, circulation, and synovium that culminates in accelerated OA degeneration in joints [7]. Changes include colonic, serum, and synovial upregulation of inflammatory cytokines, which parallel the expansion of Peptococcaceae and Peptostreptococcaceae family members in the obese gut. Correction of this dysbiosis via dietary supplementation with the indigestible prebiotic fiber oligofructose ablates these proinflammatory communities while restoring an Actinobacteria taxa that is lost in obesity, Bifidobacterium pseudolongum (B. pseudolongum). This correction leads to reduced inflammation in niches spanning from the colon to the joint, reduced numbers of macrophages and B cells in the synovium, and protection against the development of OA in the knee [7]. Moreover, we have discovered that oral delivery of a B. pseudolongum probiotic is joint protective and the B. pseudolongum metabolome itself contains molecules that directly inhibit inflammation. Based on these findings, we propose that 1) the OA of obesity is caused by a gut microbiome dysbiosis that triggers an inflammatory cascade starting in the intestine and radiating to the joint, and 2) obesity-related OA can be mitigated either by correcting the obese gut dysbiosis using methods to expand B. pseudolongum or by commandeering its metabolites to reduce inflammation in the colonic epithelium where the obesity-related inflammatory signature initiates. To investigate these concepts, we propose to address the following two Specific Aims. Aim 1 is to establish that gut microbiome dysbiosis is causal in the OA of obesity, with the hypothesis that the obese dysbiotic gut microbiome is the initiator of a systemic inflammatory cascade that initiates in the colon, radiates to joints, and accelerates OA. Aim 2 is to study how B. pseudolongum protects against joint degeneration in obesity, with experiments designed to test the hypothesis that B. pseudolongum mitigates inflammation and is joint protective in the context of obesity and its metabolome contains inflammation-suppressing agents. Completion of these aims will establish that the OA of obesity is an inflammatory process driven by gut microbiome dysbiosis. Expansion of B. pseudolongum or delivery of its metabolites could represent novel therapeutic approaches to address a disease of global scope that is currently only treated palliatively.

抽象的 尽管关节的机械超载与肥胖之间的合并症有关 和骨关节炎（OA）[1，2]，我们和其他人已经确立了与肥胖相关的致病作用 炎症[3-6]。我们在这种情况下进一步研究炎症的工作导致了新的数据牵涉 肠道微生物组的营养不良是结肠，循环和滑膜炎症的根本原因 最终在关节中加速的OA变性[7]。变化包括结肠，血清和滑膜 炎性细胞因子的上调，这与peptococacaceae和 肥胖肠道中的肽链球菌科。通过饮食纠正这种营养不良 补充不可消化的益生元纤维寡果果植物消融这些促炎社区 恢复肥胖症中丢失的静脉细菌分类群，但双歧杆菌伪杆菌（B. 假龙）。这种校正导致从结肠到关节的壁ni的炎症减少， 巨噬细胞数量减少了滑膜中的巨噬细胞和B细胞，并保护OA的发展 在膝盖中[7]。此外，我们已经发现口服伪造b.益生菌是关节 保护性和假胞芽孢杆菌代谢组本身包含直接抑制炎症的分子。 基于这些发现，我们建议1）肥胖的OA是由肠道微生物组营养不良引起的， 触发从肠道开始并辐射到关节的炎症级联反应，以及2）与肥胖相关的OA 可以通过使用扩大假胞芽孢杆菌或通过 指挥其代谢物以减少与肥胖相关的结肠上皮中的炎症 炎症签名启动。为了调查这些概念，我们建议解决以下两个 具体目标。目的1是确定肠道微生物组营养不良是肥胖OA的原因， 假设肥胖的肠道肠道微生物组是系统性炎症级联的发起者 在结肠中启动，辐射到关节，并加速OA。 AIM 2是研究B. pseudolongum如何保护 反对肥胖的关节变性，实验旨在检验假设假设的假设 缓解炎症，并在肥胖症的背景下具有关节保护性 炎症剂。这些目标的完成将确定肥胖的OA是一个 肠道微生物组营养不良驱动的炎症过程。伪内的扩张或交付 代谢物可以代表新的治疗方法来解决全球范围疾病 目前仅接受姑息治疗。