Can circulating bile acids predict knee OA progression?

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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.