Disease progression of chronic hepatitis B virus (HBV) infection is driven by the interactions between viral replication and the host immune response against the infection. This study aimed to clarify the relationship between HBV replication and hepatic inflammation during disease progression.

Cholangiocarcinoma (CCA), a highly aggressive biliary tract malignancy, exhibits rising incidence rates and an extremely poor prognosis. Recent studies reveal that gut-liver axis dysregulation drives CCA progression through gut microbiota dysbiosis, bile acid (BA) metabolic disturbances, and immune microenvironment remodeling. Clinical evidence highlights significant alterations in the gut and biliary microbial composition of CCA patients, which correlate with tumor stage, vascular invasion, and survival outcomes. Dysregulated BA metabolism in CCA, characterized by accumulation of primary conjugated BAs, promotes tumor invasiveness via interaction with specific BA receptors and fosters an immunosuppressive microenvironment. Emerging therapeutic strategies include antibiotics for pathogenic microbiota modulation, probiotics for microbial homeostasis restoration, fecal microbiota transplantation, and BA pathway modulators. Future directions necessitate integrating synthetic biology (engineered microbiota), multi-omics, and artificial intelligence to develop precision therapies. Targeting the gut-liver axis offers novel therapeutic perspectives for CCA; however, clinical translation demands deeper mechanistic insights and standardized protocols to address challenges such as microbiota heterogeneity and receptor signaling duality.

Introduction Malnutrition is a common complication of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) typically associated with poor prognosis. Despite nutritional treatment, the outcomes for these patients are limited by the symptoms and complications associated with ACLF. So far, the benefits of nutritional interventions in these populations have not been proven. This study aims to explore a new nutritional intervention method for patients with HBV-ACLF and evaluate its safety and efficacy. Methods and analysis This study is an investigator-initiated, nonblind, randomised controlled clinical trial. We will recruit 60 patients with HBV-ACLF according to the Chinese Group on the Study of Severe Hepatitis B criteria hospitalised in the Infectious Diseases Department of the Third Affiliated Hospital of Sun Yat-Sen University. Eligible patients will be randomly allocated to the nutrition support group (intervention group) and the control group in a 1:1 ratio. Patients in the nutrition support group will receive 10 days of tailor-made nutrition therapy consisting of oral nutritional supplements and supplementary parenteral nutrition. Patients in the control group will receive standard nutrition with dietary advice. All assessments will be conducted at baseline, 30 days and 90 days. The primary outcome measure is the liver transplant-free mortality rate. The secondary indicators include the incidence of clinical adverse outcomes and changes in indicators such as muscle mass, muscle strength, physical function and quality of life (EQ-5D scale). Ethics and dissemination This study has been approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University (approval number: II2023-242-03). The results and conclusions of the clinical trial will be published in academic conferences or journals. Trial registration number NCT06128421.