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: 10829141
• 负责人: STEVEN R. GILL
• 金额: $ 10.86万
• 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/10829141
• 关键词: Ablation; Acceleration; Actinobacteria class; Address; Arthritis; B-Lymphocytes; Bifidobacterium; Circulation; Colon; Communities; Data; Deceleration; Degenerative polyarthritis; Development; Dietary Supplementation; Disease; Epithelium; Experimental Designs; Family member; Fiber; Grant; Inflammation; Inflammatory; Intestines; Joints; Knee; Macrophage; Mechanics; Methods; Obesity; Oral; Parents; Pathogenicity; Peptococcaceae; Probiotics; Process; Role; Serum; Synovial Membrane; System; Testing; Up-Regulation; Work; comorbidity; cytokine; dysbiosis; gut dysbiosis; gut microbiome; joint destruction; joint loading; metabolome; novel therapeutic intervention; palliative; prebiotics

ABSTRACT [Parent R01 Grant - Attached for System-to-System (S2S) Requirements] 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.

摘要[家长R01授权-随附系统对系统（S2S）要求]

项目成果

Probiotic induced synthesis of microbiota polyamine as a nutraceutical for metabolic syndrome and obesity-related type 2 diabetes.

益生菌诱导的菌群多胺作为代谢综合征和与肥胖相关的2型糖尿病的合成。

• DOI: 10.3389/fendo.2022.1094258
• 发表时间: 2022
• 期刊: FRONTIERS IN ENDOCRINOLOGY
• 影响因子: 5.2
• 作者: Bui, Tina I. I.;Britt, Emily A. A.;Muthukrishnan, Gowrishankar;Gill, Steven R. R.
• 通讯作者: Gill, Steven R. R.