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

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.

Inclusion criteria

• Adults aged 18 to 75 years
• Diagnosed with advanced fibrosis; the cohort was operationally defined by a FibroScan liver stiffness measurement of ≥9.5 kPa.
• Achieved sustained virological response (SVR) at least 6 months after hepatitis C treatment, or
• Non-replicating hepatitis B infection (undetectable viral load) for at least 6 months
• Able and willing to provide informed consent

Exclusion criteria

• Current or prior use of statins
• Liver decompensation (jaundice, ascites, hepatic coma, or esophagogastric varices)
• Diagnosed hepatocellular carcinoma or other liver cancers
• Alcoholic liver disease or moderate-to-severe fatty liver
• Diagnosed diabetes mellitus
• Chronic kidney disease
• Use of antibiotics within the past 3 months
• Use of gastric ulcer medications such as proton pump inhibitors (PPIs)
• Pregnancy or breastfeeding
• Any condition deemed by the investigator to interfere with study participation or outcomes