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

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.

Fontan patients and matched healthy subjects were evaluated by body composition, frailty, cardiopulmonary exercise testing, hemodynamics, and plasma SCFA quantification.

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.

Fontan patients have elevated plasma straight and branched SCFAs linked to adverse clinical and hemodynamic profiles; further evaluation is warranted.