Beyond Passive Congestion: The Inflammatory Gut-Liver Axis in Fontan Circulation.

Fontan circulation has traditionally been viewed as passive venous congestion caused by absence of a subpulmonary ventricle. Emerging multi-omic data suggest a broader inflammatory gut-liver-heart syndrome. This viewpoint integrates findings from metabolomics, lipidomics, microbiome-derived metabolites, cytokine-chemokine profiling, and tryptophan-kynurenine pathway analysis to propose that hepatic congestion is biologically active. Bile acid dysregulation, short-chain fatty acid perturbation, mitochondrial stress, interferon-γ/IP-10 signaling, SDF-1α elevation, and kynurenine pathway activation may interact in a feed-forward loop contributing to frailty, impaired exercise capacity, Fontan-associated liver disease, and multiorgan dysfunction. Longitudinal and interventional studies are needed to define reversibility.