Background/Purpose: Although gut microbiome dysbiosis has been implicated in symptomatic hand OA (SHOA), the potential contribution of bile acids (BAs), key metabolites in host-microbiota interactions, to SHOA pathogenesis remains unexplored. This study examined the association between plasma BA metabolism and SHOA using data from multiple cohorts, aiming to elucidate potential pathogenic mechanisms underlying SHOA and investigate potential therapeutic targets.

Methods: Participants in the discovery cohort were drawn from the Xiangya Osteoarthritis (XO) Study, a community-based observational study. SHOA was defined as the presence of both self-reported hand symptoms and radiographic hand OA in at least one hand. Individuals without SHOA in either hand served as controls. 71 SHOA and 1,288 control participants were identified in the discovery cohort. The associations between plasma BAs and SHOA were examined using logistic regression model. We replicated the analysis to validate the association between key BAs and SHOA using a case-control design that include 71 SHOA and 71 age-, sex-, and body mass index-matched control participants, who were identified in an independent validation cohort. Multi-omics analyses were conducted to explore links between SHOA-related microbes and key BAs, while mediation analysis assessed the role of BAs in the gut microbiome-SHOA relationship. Finally, to explore the potential underlying mechanisms of the associations, we conducted gene-based meta-analyses to assess the associations between key BA receptors and SHOA using data from the XO Study and Genetics of OA Consortium.

Results: In the discovery cohort, the plasma BA profiles were primarily dominated by glycochenodeoxycholic acid (GCDCA), chenodeoxycholic acid (CDCA), cholic acid (CA), glycocholic acid (GCA), and deoxycholic acid (DCA) (Figure 1A). Elevated levels of deoxycholic acid (DCA) species (odds ratio [OR]=1.75, 95% confidence interval [CI]: 1.03–2.96), DCA (OR=2.14, 95% CI: 1.24–3.70), isolithocholic acid (OR=3.60, 95% CI: 1.43–9.04), and hyodeoxycholic acid (OR=2.20, 95% CI: 1.17–4.15) were positively associated with SHOA (Figure 1B-D) and its severity (Figure 1E). Similar associations between BAs and SHOA were found in the independent validation cohort (Figure 2). Multi-omics analyses revealed significant correlations between DCA species, DCA, and the DCA species/total BAs ratio with SHOA-related microbial species (Figure 3A).1 Mediation analysis showed that DCA mediated the relationships of four SHOA-related microbial species, with the mediation effects ranged from 7.0% to 24.1% (Figure 3B-E). Gene-based meta-analyses identified a significant association between the gene encoding the Farnesoid X receptor (FXR), a key BA receptor, and SHOA.

Conclusion: Dysregulated BA metabolism, particularly elevated DCA levels, is associated with SHOA and key SHOA-related microbiomes. DCA mediates the link between gut microbiota dysbiosis and SHOA, while FXR could be a treatment target for SHOA.REFERENCES1. Wei J, et al. EBioMedicine 2023;98:104892.

Figure 1. Associations of plasma bile acids with symptomatic hand OA in the discovery cohort. (A) Top 15 most abundant plasma bile acid categories identified in participants with SHOA and controls. (B) Associations of bile acid species, (C) bile acid species ratios, (D) and individual plasma bile acids with SHOA, adjusting for age, sex, body mass index, smoking status, alcohol consumption, and dietary intake of meat/eggs, dairy, and vegetables. (E) Associations between key plasma bile acids and the severity of SHOA. SHOA, symptomatic hand OA; GCDCA, glycochenodeoxycholic acid; CDCA, chenodeoxycholic acid; CA, cholic acid; GCA, glycocholic acid; DCA, deoxycholic acid; GUDCA, glycoursodeoxycholic acid; GDCA, glycodeoxycholic acid; UDCA, ursodeoxycholic acid; TCDCA, taurochenodeoxycholic acid; TCA, taurocholic acid; HCA, hyocholic acid; GHCA, glycohyocholic acid; TDCA, taurodeoxycholic acid; 7-KLCA, 7-Ketolithocholic acid; DCAs, deoxycholic acid species; LCAs, lithocholic acid species; HCAs, hyocholic acid species; UDCAs, ursodeoxycholic acid species; CDCAs, chenodeoxycholic acid species; CAs, cholic acid species; BA, bile acids; KL grade, Kellgren-Lawrence grade; No of joint, number of affected joints.

Figure 2. Associations of plasma bile acids with symptomatic hand OA in the Validation cohort. (A) Top 15 most abundant plasma bile acid categories identified in participants with SHOA and controls. (B) Bile acid species validated in the validation cohort. (C) Bile acid species ratios validated in the validation cohort. (D) Individual plasma bile acid validated in the validation cohort. (E) Associations between key plasma bile acids and the severity of SHOA. SHOA, symptomatic hand OA; GCDCA, glycochenodeoxycholic acid; CDCA, chenodeoxycholic acid; GCA, glycocholic acid; CA, cholic acid; DCA, deoxycholic acid; GDCA, glycodeoxycholic acid; GUDCA, glycoursodeoxycholic acid; TCDCA, taurochenodeoxycholic acid; UDCA, ursodeoxycholic acid; TCA, taurocholic acid; TDCA, taurodeoxycholic acid; HCA, hyocholic acid; GHDCA, glycohyodeoxycholic acid; 7-KLCA, 7-ketolithocholic acid; DCAs, deoxycholic acid species; KL grade, Kellgren-Lawrence grade; No of joint, number of affected joints.

Figure 3. Correlations between gut microbial species to plasma bile acids in symptomatic hand OA. (A) Correlations between SHOA-related plasma bile acids and SHOA-related microbiome species. The correlations were calculated by partial Spearman’s rank correlation test. (B) Mediation effect of DCA on the association between Bilophila wadsworthia and SHOA. (C) Mediation effect of DCA on the association between Bacteroides A mediterraneensis and SHOA. (D) Mediation effect of DCA on the association between Haemophilus D parainfluenzae L and SHOA. (E) Mediation effect of DCA on the association between Haemophilus D parainfluenzae N and SHOA.The proportions of the indirect effect (mediation effect) are labeled at the center of the ring charts. SHOA, symptomatic hand OA; DCA, deoxycholic acid.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bile-acids-metabolism-in-symptomatic-hand-osteoarthritis-data-from-the-xiangya-osteoarthritis-study-and-genetics-of-oa-consortium/