Uncovering metabolite-inflammatory protein interactions in gout pathogenesis: A 2-sample bidirectional Mendelian randomization study

Gout is a widespread inflammatory arthritis whose current treatments focus mainly on symptom relief and urate lowering. Recent work suggests that circulating metabolites and inflammatory proteins interact in complex ways to influence disease risk, with fibroblast growth factor 19 (FGF19) standing out as a potential regulatory node linking metabolism and inflammation. We performed bidirectional 2-sample Mendelian randomization using genome-wide association study summary statistics for 1440 serum metabolites and 91 inflammatory proteins, with gout outcomes drawn from FinnGen R12. Mediation analyses were then applied to examine whether FGF19 acts as an intermediary in selected metabolite-gout pathways. Genetically predicted levels of vanillactate and histidine betaine were associated with higher gout risk, whereas sphingomyelin species and taurolithocholate 3-sulfate showed protective effects. Among inflammatory proteins, FGF19, adenosine deaminase and FGF5 appeared protective, while cluster of differentiation 244 increased risk. Bidirectional analyses revealed reciprocal relationships, including a negative causal effect of propionylcarnitine on FGF19. Mediation testing further showed that FGF19 explained 7.88% of the total effect of lipid-related metabolites on gout via glycodeoxycholate 3-sulfate and 9.58% via cis-3,4-methyleneheptanoylglycine. These findings indicate that FGF19 may exert protective effects against gout partly by modulating bile acid and fatty acid metabolism. The results offer genetic evidence for metabolic-immune crosstalk in gout pathogenesis and highlight FGF19-related pathways as possible targets for more precise therapeutic strategies.