Nonlinear Association Between Lithocholic Acid-Related Metabolism and Dysglycemia in Pediatric Obesity

Background: Bile acids regulate glucose metabolism through enterohepatic signaling and gut microbiota-mediated transformations. However, the role of specific bile acid subtypes, particularly lithocholic acid (LCA) and its derivatives, in pediatric obesity remains incompletely understood. Methods: In this cross-sectional study, 149 children with obesity underwent comprehensive metabolic assessment, including a 75-g oral glucose tolerance test (OGTT) and fasting serum bile acid profiling using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Bile acid-derived indices were used for unsupervised clustering to identify metabolic phenotypes. Associations between LCA-related indices and dysglycemia (defined as HbA1c ≥ 5.7% and/or 2-h plasma glucose ≥ 7.8 mmol/L) were evaluated using multivariable regression models. The LCA derivative sum was analyzed separately using tertile categories and continuous linear and quadratic models. Cluster-stratified patterns were further assessed. Results: Three bile acid-derived clusters with distinct metabolic profiles were identified. Despite similar anthropometric characteristics, clusters differed significantly in glycemic status and insulin dynamics. LCA-related bile acid indices showed a non-monotonic redistribution across clusters. Compared with the lowest tertile, adjusted odds ratios for dysglycemia were 1.44 (95% CI: 0.62–3.37) for the intermediate tertile and 0.33 (0.13–0.83) for the highest tertile. The continuous linear model showed an inverse association per SD increase (OR 0.646 [0.441–0.946]). A separate continuous quadratic model suggested an inverted U-shaped exposure–response pattern, describing variation across the continuous exposure range rather than comparisons between tertile categories. Interaction analyses did not demonstrate a statistically significant modification of the association for the primary outcome, although analyses of continuous glycemic traits suggested potential heterogeneity across clusters. Conclusions: Bile acid-based clustering identifies distinct metabolic phenotypes in pediatric obesity. LCA-related bile acid metabolism shows nonlinear associations with dysglycemia and may exhibit heterogeneity across metabolic phenotypes. These findings highlight the importance of considering bile acid subtype specificity and metabolic context in understanding bile acid–glucose interactions.