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

Area of Science:

• Hepatology
• Gastroenterology
• Immunology

Background:

• The gut-liver axis plays a crucial role in liver disease pathogenesis.
• The tryptophan pathway's involvement in hepatitis C virus (HCV) infection and liver disease progression is not well understood.
• Investigating tryptophan metabolites offers insights into gut-liver interactions during HCV.

Purpose of the Study:

• To investigate tryptophan metabolites in portal and peripheral serum during and after HCV infection.
• To explore the relationship between tryptophan metabolites and inflammatory and clinical markers in HCV patients.
• To understand the role of the tryptophan pathway in the gut-liver axis during HCV infection.

Main Methods:

• Evaluated HCV-infected patients during infection and after sustained virologic response (SVR) to sofosbuvir/velpatasvir.
• Collected liver biopsies, portal and peripheral blood, and stool samples at both time points.
• Performed statistical analyses to assess metabolite abundance, cytokine levels, clinical parameters, and microbiome composition.

Main Results:

• Peripheral tryptophan and kynurenine were elevated, while indolelactate and xanthurenate were reduced during HCV infection.
• Portal kynurenine/tryptophan ratio and kynurenine increased, with decreased indoleacetate and xanthurenate.
• Tryptophan metabolites correlated with liver disease activity, bilirubin, spleen enlargement, pro-inflammatory cytokines (CXCL9, CXCL10, TNFα, IL6, IL-12p40), and specific gut microbes.

Conclusions:

• Elevated portal kynurenine suggests upregulated gut-mediated pro-inflammatory pathways in HCV infection.
• The tryptophan pathway significantly contributes to inflammatory responses in HCV via the gut-liver axis.
• Further research with larger cohorts and functional analyses is needed to elucidate causal mechanisms and therapeutic potential.