Association of Fontan Circulation With Gut Microbiome Derived Straight and Branched Short Chain Fatty Acids

BACKGROUND: Fontan circulation is associated with progressive multisystem dysfunction, yet its biochemical mechanisms are poorly understood. Gut microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs) and bile acids, shape cardiovascular health. We previously reported elevated secondary bile acids in Fontan patients, but their SCFA profile remains uncharacterized. MATERIALS AND METHODS: Fontan patients and matched healthy subjects were evaluated by body composition, frailty, cardiopulmonary exercise testing, hemodynamics, and plasma SCFA quantification. RESULTS: Twenty Fontan patients (25.5 years [IQR: 22.8-30.3]; 35% women) and 20 healthy controls (30.0 years [25.8-34.3]; 30% women) were enrolled. Compared to controls, Fontan patients exhibited elevated plasma levels of several SCFAs: propionic acid (1.84 [1.45-2.68] vs. 1.19 [1.07-1.49] μM; p = 0.002), butyric acid (1.27 [0.90-1.71] vs. 0.75 [0.52-0.94] μM; p = 0.002), valeric acid (0.25 [0.15-0.36] vs. 0.13 [0.11-0.16] μM; p < 0.001), and caproic acid (0.44 [0.35-0.67] vs. 0.25 [0.21-0.39] μM; p < 0.001). Acetic acid levels did not differ significantly between groups. Additionally, branched-chain SCFAs were elevated in Fontan patients: isobutyric acid (0.44 [0.32-0.68] vs. 0.26 [0.23-0.30] μM; p < 0.001) and 2-methylbutyric acid (0.38 [0.27-0.58] vs. 0.19 [0.15-0.25] μM; p < 0.001). Notably, caproic, isobutyric, and 2-methylbutyric acids showed strong correlations with key clinical and hemodynamic parameters. Furthermore, isobutyric and 2-methylbutyric acids were significantly correlated with dehydrolithocholic acid levels (R = 0.67 and 0.54, respectively) and other bile acid components. CONCLUSION: Fontan patients have elevated plasma straight and branched SCFAs linked to adverse clinical and hemodynamic profiles; further evaluation is warranted.