Remedial Mechanisms of Simvastatin and Ursodeoxycholic Acid in Liver Cirrhosis: Crosstalk Between Bile Secretion, Gut Microbiome, and Host Immune Response

This exploratory, randomized, open-label pilot study evaluated gut microbiota, fecal bile acid profiles, inflammatory markers, and fibrosis-related biomarkers in adults with chronic hepatitis B or hepatitis C after viral control. The study included a randomized cohort with advanced liver fibrosis and a non-randomized comparison cohort without advanced fibrosis. Viral control was defined as hepatitis B virus suppression during antiviral therapy or sustained virologic response after hepatitis C treatment.

The main questions addressed by the study were:

Do participants with advanced liver fibrosis differ from those without advanced fibrosis in their baseline gut microbiota, fecal bile acid profiles, inflammatory markers, or fibrosis-related biomarkers? What within-participant changes in these measures are observed after six months of treatment with ursodeoxycholic acid (UDCA), simvastatin, or combined UDCA plus simvastatin? What descriptive patterns of change are observed across the three active-treatment groups?

Advanced liver fibrosis was operationally defined during enrollment as a FibroScan liver stiffness measurement of ≥9.5 kPa. Thirteen participants with presumed advanced liver fibrosis were randomized to observation without study medication, UDCA alone, simvastatin alone, or combined simvastatin plus UDCA. One randomized participant was subsequently excluded from the analysis after eligibility review because the advanced-fibrosis criteria were not confirmed, leaving 12 eligible randomized participants, with three participants in each study group. An additional six participants with non-advanced fibrosis, defined by a FibroScan liver stiffness measurement of <6.0 kPa, were enrolled as a non-randomized baseline comparison group.

Baseline blood and stool samples were collected from all 19 enrolled participants. The final baseline analysis set included 18 eligible participants: 12 participants with advanced fibrosis and six participants without advanced fibrosis. Follow-up blood and stool samples were collected after six months from the nine participants in the three active-treatment groups. The observation group and the non-advanced fibrosis comparison group contributed baseline data only and did not undergo post-treatment sampling.

Recruitment was substantially slower than anticipated and was discontinued after the available study funding was exhausted. The study was therefore terminated before reaching its originally planned enrollment target. The final actual enrollment was 19 participants, of whom 18 were included in the final analysis set. Because only three participants were available in each randomized study group, all treatment-related analyses were considered exploratory and hypothesis-generating. The study was not designed or adequately powered to establish clinical efficacy, histological fibrosis regression, or superiority of combination therapy.