Portal Vein Tryptophan Pathway Analysis Reveals Gut‐Mediated Inflammatory Pathway Predominance in HCV Infection

BACKGROUND AND AIMS: The tryptophan pathway is an integral component of the gut-liver axis; however, the role in hepatitis C virus infection (HCV) and liver disease progression remains poorly understood. This study investigated tryptophan metabolites in portal and peripheral serum during and after HCV, and their relationship to inflammatory and clinical markers. METHODS: HCV infected patients were evaluated during infection (HCVi, n = 24) and 6 months after sofosbuvir/velpatasvir mediated sustained virologic response (SVR, n = 19) (NCT02400216). Liver biopsies, portal and peripheral blood collection, and stool sampling were performed at both time points. Statistical analyses assessed metabolite abundance during infection and recovery, and their associations with cytokines, clinical parameters, and the microbiome. RESULTS: During infection, peripheral tryptophan and kynurenine were elevated while indolelactate and xanthurenate were reduced (p < 0.05). In the portal blood, kynurenine/tryptophan ratio and kynurenine were increased, whereas indoleacetate and xanthurenate were decreased (p < 0.05). Tryptophan metabolites positively correlated with hepatic activity index, gamma-glutamyl transferase, total bilirubin, spleen volume/height ratio, and pro-inflammatory cytokines including CXCL9, CXCL10, TNFα, IL6, and IL-12p40. Negatively, correlations were observed with gut microbes Dorea longicatena and Qiania dongpingenesis. CONCLUSIONS: Elevated kynurenine in portal blood suggests upregulation of gut-mediated pro-inflammatory pathways during HCV infection. Integration of multi-omics data from the gut-liver axis highlights the contribution of the tryptophan pathway to inflammatory responses in HCV. However, small sample size, absence of quantitative values for all pathway metabolites, and reliance on correlative rather than causative associations limit mechanistic interpretation. Future studies with larger cohorts and functional analyses are needed to clarify causal mechanisms and evaluate therapeutic potential of targeting the tryptophan pathway. TRIAL REGISTRATION: NCT02400216.