Can circulating bile acids predict knee OA progression?

循环胆汁酸可以预测膝关节 OA 的进展吗？

• 批准号: 10575385
• 负责人: Monica Guma
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575385
• 关键词: Acceleration; Acids; Address; Affect; Arthritis; Bile Acids; Biological Markers; Cartilage; Cells; Chenodeoxycholic Acid; Cholesterol; Cholic Acids; Chronic; Clinical; Data; Degenerative polyarthritis; Deoxycholic Acid; Development; Diagnostic tests; Elderly; Elements; Fatty acid glycerol esters; Foundations; Goals; High Prevalence; Human; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intestinal permeability; Investigation; Joints; Knee; Knee Osteoarthritis; Knee joint; Link; Lipids; Lipopolysaccharides; Lithocholic Acid; Magnetic Resonance Imaging; Mass Spectrum Analysis; Mediating; Mediator; Metabolic; Morbidity - disease rate; Natural Immunity; Non obese; Obesity; Outcome; Pain; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; Populations at Risk; Reporting; Risk Factors; Role; Sampling; Serum; Severities; Signaling Molecule; Stratification; Synovial joint; Synovitis; Tissues; Western Ontario and McMaster Universities Arthritis Index; bile acid metabolism; cartilage degradation; cell type; cohort; effusion; experimental study; gut microbiota; high risk; host microbiota; indexing; interest; joint inflammation; knee pain; knowledge base; lipid mediator; lipopolysaccharide-binding protein; microbiome; novel; nutrient absorption; pain score; personalized intervention; personalized medicine; predictive marker; public health relevance; radiological imaging; receptor; sample archive; web site

Can Circulating Bile Acids Predict Knee OA Progression? Osteoarthritis (OA) is the most common form of arthritis. Biomarkers that could predict the individuals with similar risk factors that would progress is an unmet need. Increasing evidence indicates that OA progression is mediated by low-grade systemic (obesity) and local (inflamed synovium) inflammation. Recently, a positive correlation between serum lipopolysaccharide (LPS), a key proinflammatory product of the microbiome, obesity, joint inflammation, and OA severity was reported and suggests an influence of microbiome and gut permeability in the pathogenesis of OA. However, the extent to which low-grade inflammation-based mediators can predict OA progression remains unclear. Once known only for their role in nutrients absorption, primary bile acids (BAs) such as chenodeoxycholic and cholic acid, and secondary BAs, such as deoxycholic and lithocholic acid, are signaling molecules generated from cholesterol breakdown by the interaction of the host and intestinal microbiota that modulate intestinal permeability. These bioactive metabolites act on several receptors that are highly expressed in cells of innate immunity. They regulate diverse metabolic and inflammatory pathways in multiple cell types and tissues. Importantly, human obesity is associated with altered BA metabolism and increased intestinal permeability. Our preliminary studies in knee OA (KOA) subjects show that circulating BAs are significantly associated with radiographic KOA and outcome scores. The most significant association was for cholic acid, that was significantly associated with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (r=0.44, p=0.01). Interestingly, BAs also associated with synovitis (glycoursodeoxycholic acid, r=0.39, p=0.04), and with LPS binding protein (LBP), a biomarker of KOA progression (cholic acid, r=0.41, p=0.03). Of interest, these associations differed between obese and non-obese subjects. These observations suggest distinct BAs may be key mediators of OA development and progression. Therefore, we hypothesize that (1) BA profiles will be associated with MRI phenotypes of KOA, especially with synovitis/effusion; 2) altered BA profiles are associated with KOA progression. To address this goal, we will conduct our investigation in the carefully phenotyped FNIH/OAI Biomarkers Project cohort, with semiquantitative and quantitative MRI scores and clinical and radiographic outcomes at 48 months available in the OAI website, to relate circulating BAs with synovitis and KOA progression. The proposed experiments are high risk and we will determine if 1) specific circulating BA are related to synovitis and KOA 2) define elements of lipid pathogenesis that link KOA outcomes among all persons at risk. However, these studies might provide a foundation to determine phenotypes of KOA and investigations into novel personalized interventions to reduce KOA-related morbidity.

循环胆汁酸可以预测膝盖OA进展吗？ 骨关节炎（OA）是关节炎的最常见形式。可以预测具有相似个人的生物标志物 进展的风险因素是未满足的需求。越来越多的证据表明OA进展是介导的 通过低度系统性（肥胖）和局部（发炎的滑膜）炎症。最近，正相关 在血清脂多糖（LPS）之间，这是微生物组，肥胖，关节的关键促炎产物 报告了炎症和OA的严重程度，并提示微生物组和肠道渗透性影响 OA的发病机理。但是，低度炎症的介体可以预测OA的程度 进展尚不清楚。 曾经仅以其在营养吸收中的作用而闻名，原发性胆汁酸（BAS），例如chenoxycholic和 胆酸和次生碱，例如脱氧胆碱和岩性酸，是产生的信号分子 从宿主和肠道微生物群的相互作用来调节肠道的胆固醇分解。 渗透性。这些生物活性代谢物作用于几种在先天细胞中高度表达的受体 免疫。它们调节多种细胞类型和组织中的多种代谢和炎症途径。 重要的是，人类肥胖与BA代谢改变和肠道通透性的增加有关。 我们在膝盖OA（KOA）受试者中的初步研究表明，循环BAS与 影像学KOA和结果得分。最重要的关联是胆酸，这是显着的 与西安大略省和麦克马斯特大学骨关节炎指数（WOMAC）有关（r = 0.44，p = 0.01）。 有趣的是，BAS也与滑膜炎有关（糖脱氧乙酸，r = 0.39，p = 0.04），并且与LPS 结合蛋白（LBP），一种KOA进展的生物标志物（胆酸，r = 0.41，p = 0.03）。感兴趣的，这些 肥胖和非肥胖受试者之间的关联不同。这些观察结果表明不同的BAS可能是 OA发展和进步的主要介体。 因此，我们假设（1）BA剖面将与KOA的MRI表型有关，尤其是在 滑膜炎/积液； 2）BA轮廓改变与KOA进程有关。为了解决这个目标，我们将 在经过精心表型的FNIH/OAI生物标志物项目队列中进行调查，与 在48个月时，可在 OAI网站，将循环的BAS与滑膜炎和KOA进展相关联。提出的实验是 高风险，我们将确定1）特定的循环BA是否与滑膜炎有关，KOA 2）定义元素 在所有有风险的人之间将KOA结局联系起来的脂质发病机理。但是，这些研究可能会提供 确定KOA表型和对新型个性化干预措施的调查以减少的基础 与KOA相关的发病率。