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

Liver Fibrosis

Advanced liver fibrosis, Fecal bile salt, UDCA, Statin

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.

BACKGROUND AND PURPOSE Patients with advanced liver fibrosis remain at risk of liver-related complications even after successful control of chronic hepatitis B or hepatitis C. Alterations in the gut microbiota and bile acid metabolism may contribute to persistent inflammation and fibrosis progression through the gut-liver axis. Ursodeoxycholic acid (UDCA) modifies the bile acid pool and may influence bile acid metabolism and signaling. Simvastatin may have anti-inflammatory, endothelial, and antifibrotic effects. This exploratory pilot study evaluated gut microbiota, fecal bile acid profiles, inflammatory markers, and fibrosis-related biomarkers in adults with chronic viral hepatitis after viral control. The study had two main objectives: first, to compare baseline biological characteristics between participants with and without advanced liver fibrosis; and second, to explore within-participant changes after six months of treatment with UDCA, simvastatin, or their combination. STUDY DESIGN This was a prospective, single-center, randomized, open-label exploratory pilot study. Participants with presumed advanced liver fibrosis were assigned by block randomization, with a planned 1:1:1:1 allocation, to one of four groups: Observation without study medication; UDCA 10 mg/kg/day for six months; Simvastatin 40 mg/day for six months; or Simvastatin 40 mg/day plus UDCA 10 mg/kg/day for six months. A separate non-randomized cohort of participants without advanced fibrosis was enrolled for baseline comparison. Eligible participants had chronic hepatitis B with viral suppression during antiviral therapy or chronic hepatitis C with sustained virologic response after antiviral treatment. During study enrollment, advanced liver fibrosis was operationally defined as a FibroScan liver stiffness measurement of at least 9.5 kPa. The non-advanced fibrosis comparison cohort was defined by a liver stiffness measurement of less than 6.0 kPa. ACTUAL ENROLLMENT AND FOLLOW-UP The study was originally planned to enroll 120 participants in the four randomized groups and an additional 30 participants in the non-randomized comparison cohort. Recruitment began in January 2024. The study and recruitment period was subsequently extended through December 2025 with formal Institutional Review Board approval. Despite the approved extension, recruitment remained substantially slower than anticipated, and the available study funding was exhausted before the planned sample size could be reached. Recruitment was therefore discontinued, and the study was terminated early. The final actual enrollment was 19 participants. Thirteen participants with presumed advanced fibrosis were randomized. One participant assigned to the UDCA group was subsequently excluded from the final analyses because the advanced-fibrosis eligibility criteria were not confirmed during post-randomization review. This participant remained included in the actual enrollment count. The final analysis set therefore included 18 eligible participants: 12 participants with advanced fibrosis, with three participants in each randomized group, and six participants with non-advanced fibrosis in the non-randomized comparison cohort. Baseline blood and stool samples were collected from all enrolled participants. Samples from the participant whose eligibility was not confirmed were excluded from the final analyses. Six-month follow-up samples were collected from the nine participants in the three active-treatment groups. The observation group and the non-advanced fibrosis comparison group contributed baseline data only. STUDY ASSESSMENTS Study assessments included clinical characteristics, stool microbiota profiles, targeted fecal bile acid measurements, inflammatory markers, and fibrosis-related biomarkers. Microbiota assessments included measures of microbial diversity and taxonomic composition. Fecal bile acid assessments included selected primary, secondary, and conjugated bile acids. Changes from baseline to six months were evaluated in participants receiving active treatment. Because of the small number of participants and the absence of longitudinal sampling in the observation and non-advanced fibrosis comparison groups, all treatment-related assessments were considered exploratory and hypothesis-generating. The study was not adequately powered to establish clinical efficacy, histological fibrosis regression, or superiority of one treatment regimen over another. PROTOCOL NONCOMPLIANCE AND REGULATORY HANDLING The operational liver-stiffness criterion applied during enrollment differed from the more restrictive fibrosis-related eligibility criteria specified in the original protocol and initial ClinicalTrials.gov record. Consequently, some participants included in the operationally defined advanced-fibrosis cohort did not meet the original fibrosis-related eligibility definition. This protocol noncompliance was formally reported to the Institutional Review Board and was acknowledged on June 8, 2026 (IRB protocol no. 202201398A3; noncompliance report no. 202201398A3C2001). The Institutional Review Board subsequently accepted the study closure report on July 23, 2026. The results of this prematurely terminated pilot study should therefore be interpreted as exploratory biological observations rather than confirmatory evidence of treatment efficacy.

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