Is the gut important in multiple joint osteoarthritis? A multimodal investigation in humans and pet dogs

肠道在多关节骨关节炎中重要吗？

• 批准号: 10419121
• 负责人: Duncan Lascelles
• 金额: $ 70.7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419121
• 关键词: Address; Affect; American; Animal Model; Area; Biological Markers; Black race; Blood specimen; Body Burden; Canis familiaris; Clinical; County; Data; Data Set; Degenerative polyarthritis; Development; Disease; Enrollment; Epithelial Cells; Exposure to; Foundations; Frequencies; Future; Health; Hispanic Populations; Human; Individual; Inflammation; Inflammation Mediators; Injury; Intestinal permeability; Investigation; Iohexol; Joint by Site; Joints; Knee; Leaky Gut; Lipopolysaccharides; Longitudinal Studies; Longitudinal cohort; Measures; Modeling; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Pain; Participant; Patients; Persons; Placebos; Plasma; Public Health; Randomized; Research; Risk; Risk Factors; Rodent Model; Role; Serum; Severities; Severity of illness; Symptoms; Testing; Woman; Work; aged; biomarker identification; burden of illness; cohort; comorbidity; complex chronic conditions; disability; disease prognosis; effective therapy; fecal microbiota; fecal transplantation; fructooligosaccharide; functional status; gut microbiome; improved; inflammatory marker; innovation; intestinal epithelium; lipopolysaccharide-binding protein; men; microbial; microbiome; microbiota; mouse model; multimodality; novel; novel marker; novel therapeutics; prebiotics; predictive marker; progression marker; radiological imaging; risk stratification; sugar; systemic inflammatory response; therapeutic development; therapeutic target

Project Summary The central hypothesis of this work is that increased intestinal permeability (IP), either directly, or via related comorbidities, promotes the development and worsening of multi-joint osteoarthritis (MJOA). Multiple joint osteoarthritis (MJOA; referring to OA in more than one joint site within an individual) is common but understudied. MJOA is progressive, and as whole-body burden of OA increases, associated pain and disability increases, and treatments are less successful. Despite the significant societal impact of MJOA, most OA research remains focused on individual joints. There is an urgent need to understand the factors that promote progression and worsening of MJOA. To address our hypothesis, our group has access to a large, longitudinal cohort of human patients, and, uniquely, access to the naturally occurring MJOA model in pet dogs. There are no rodent models of MJOA, but dogs with naturally occurring MJOA have similar disease manifestations with more rapid progression compared with humans, making pet dogs an ideal model in which to explore underlying mechanisms of MJOA and potential therapies. We have shown that inflammatory mediators are related to overall burden of OA; these and other risk factors may at least partly derive from the gut microbiome via increased intestinal permeability (IP; “leaky gut”). We have evidence that lipopolysaccharide (LPS) and LPS-binding protein (LBP, reflecting increased IP and increased exposure to microbial products), promote OA. Additionally, serum LPS in humans (and serum LBP in dogs) is positively associated with the number of joints affected by MJOA. To further elucidate the role of IP as a mechanism in MJOA, the proposed work will leverage human and dog studies: The JoCoOA, a longitudinal cohort of over 4000 Black and White men and women aged 45 and older; The Johnston County Health Study (JoCoHS), an actively enrolling cohort (2019-, n~2000) including younger (35-70 years) and Hispanic individuals; and a large cohort of readily accessible naturally occurring MJOA in pet dogs. Data from all three cohorts will be used to address the following three aims. In Aim 1, we will determine cross-sectional associations between altered IP, systemic inflammation, and radiographic and symptomatic MJOA in humans and pet dogs. Aim 2 will allow identification of biomarkers predictive of development and worsening of MJOA and determine longitudinal associations with markers of systemic inflammation and IP among JoCoOA participants and dogs. In Aim 3, we will test the effects of a prebiotic on IP, the microbiome and MJOA symptoms by randomizing 70 dogs with MJOA (from Aim 1) to receive either a fructooligosaccharide supplement or placebo for 3 months followed by re-characterization of biomarkers of inflammation and IP. These studies will both verify the association between increased IP and MJOA and robustly define biomarkers predictive of development and worsening MJOA, laying the groundwork for mechanistic studies to understand how increased IP promotes MJOA and to identify therapeutic targets, as well as provide means to identify at-risk individuals for preemptive management.

项目概要 这项工作的中心假设是，直接或通过肠道通透性（IP）增加 相关合并症，促进多关节骨关节炎（MJOA）的发展和恶化。 多关节骨关节炎（MJOA；指一个人体内多个关节部位的 OA）很常见 但尚未充分研究 MJOA 是进行性的，并且随着 OA 的全身负担增加，相关的疼痛和 尽管 MJOA 具有重大的社会影响，但大多数患者的残疾情况有所增加，且治疗效果较差。 骨关节炎研究仍然集中于单个关节，迫切需要了解影响骨关节炎的因素。 促进 MJOA 的进展和恶化 为了解决我们的假设，我们的团队可以获得大量的、 人类患者的纵向队列，以及独特的宠物自然发生的 MJOA 模型 狗没有 MJOA 的啮齿类动物模型，但患有天然 MJOA 的狗也有类似的疾病。 与人类相比，其表现进展更快，使宠物狗成为理想的模型 探索 MJOA 的潜在机制和潜在的治疗方法。 中介因素与 OA 的总体负担有关；这些和其他风险因素可能至少部分源自 我们有证据表明，肠道微生物组通过增加肠道通透性（IP；“漏肠”）来实现。 脂多糖 (LPS) 和 LPS 结合蛋白 (LBP)，反映 IP 增加和接触量增加 微生物产品），促进 OA 此外，人类血清 LPS（以及狗血清 LBP）具有积极作用。 与受 MJOA 影响的关节数量相关 进一步阐明 IP 作为机制的作用。 MJOA，拟议的工作将利用人类和狗的研究：JoCoOA，一个超过 4000 名 45 岁及以上的黑人和白人男性和女性；约翰斯顿县健康研究 (JoCoHS) 积极招募队列（2019-，n~2000），包括年轻人（35-70 岁）和西班牙裔个人以及大量人群； 宠物狗中容易获得的自然发生的 MJOA 队列将用于来自所有三个队列的数据。 解决以下三个目标 在目标 1 中，我们将确定更改的 IP 之间的横截面关联， 目标 2 允许人类和宠物狗出现全身性炎症、放射学和症状性 MJOA。 识别预测 MJOA 发展和恶化的生物标志物并确定纵向 在目标 3 中，JoCoOA 参与者和狗的全身炎症和 IP 标志物的关联。 我们将通过随机抽取 70 只狗来测试益生元对 IP、微生物组和 MJOA 症状的影响 MJOA（来自目标 1）接受低聚果糖补充剂或安慰剂 3 个月，然后 炎症和 IP 生物标志物的重新表征将验证这种关联。 增加 IP 和 MJOA 之间的关系，并强有力地定义预测发展和恶化的生物标志物 MJOA，为机制研究奠定基础，以了解增加的 IP 如何促进 MJOA 并 确定治疗目标，并提供识别高危个体以进行先发制人管理的方法。