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

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.