Intra-Hepatic Microbiota in Alcoholic Hepatitis (HepMAH)

Alcoholic hepatitis (AH) is a serious complication of alcoholic liver disease (ALD). The histological presentation of AH is characterized by neutrophilic lobular inflammation, macrovesicular steatosis, hepatocyte ballooning and necrosis and the presence of Mallory bodies. In cases of severe HA, defined by a modified Maddrey score of 32 or above, mortality at 1 month is estimated at between 10 and 50%. The only treatment to reduce early mortality is corticosteroid therapy. However, only 60% of patients respond to corticosteroids, and no benefit has been demonstrated on late mortality. Identifying new therapeutic targets is therefore a major challenge in this disease.

Numerous pre-clinical studies and human data suggest the involvement of the intestinal microbiota in the pathogenesis of AH. Translocation of viable bacteria and microbial products from the digestive tract to the liver contributes to local and systemic inflammation, hepatocyte death and fibrogenesis. However, the intrahepatic microbial environment has never been characterized in HA.

The study hypothesis is that the intrahepatic microbiota is modulated by bacterial translocation and is associated with clinical outcomes.

The aim of this study is to determine the composition of the intrahepatic (obtained from transjugular liver biopsy), blood and fecal microbiota in patients with suspected severe AH from a monocentric prospective cohort in the Hepatology Department at Croix-Rousse Hospital (Lyon). Fifty consecutive patients with clinical suspicion of AH and indication for transjugular liver biopsy will be included. About thirty-five patients are expected in the confirmed AH group, and 15 in the group "alcoholic liver disease with no AH", based on data from the literature. The composition of the various microbiota will be determined by sequencing the 16S rRNA gene, and the results will be correlated with clinical data (corticosteroid sensitivity, overall survival, transplant-free survival, MELD score in particular) and histological data.

This exploratory study will enable to analyze the intra-hepatic microbiota, and to study its link with intra-hepatic inflammation and the clinical course of patients with AH. The data generated by HepMAH will thus help identify potential new therapeutic targets linked to the gut microbiota, and provide a scientific basis for the development of therapeutic interventions targeting the microbiota in HA.

Study Overview

• Status: Not yet recruiting
• Conditions: Cirrhosis; Alcoholic Liver Disease; Alcoholic Hepatitis
• Intervention / Treatment: Procedure: Biological sampling

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Yasmina CHOUIK, M.D., Ph.D.; Phone Number: +33426109204; Email: yasmina.chouik@chu-lyon.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

A prospective observational multicentric cohort will be conducted at Croix Rousse Hospital (Lyon, France), in the Hepatology and Intensive Care Units.

Fifty consecutive patients hospitalized in either of these units for clinical suspicion of alcoholic hepatitis and indication for transjugular liver biopsy will be included.

Description

Inclusion Criteria:

• Patients suffering from alcoholic liver disease and clinical suspicion of alcoholic hepatitis (subacute jaundice, heavy alcohol consumption active or weaned for ≤ 3 months, modified Maddrey score ≥32) and indication for diagnostic transjugular liver biopsy;
• Non-objection obtained from the patient or trusted person in case of impaired judgment or consciousness before performing liver biopsy;
• Aged ≥ 18 years at the time of study entry;

Exclusion Criteria:

• Patients who have been treated with antibiotics or probiotics within the last 15 days prior to liver biopsy, with the exception of antibiotics used for prophylaxis of ascites infection or hepatic encephalopathy
• Contraindication to transjugular liver biopsy (hepatocellular carcinoma on predicted puncture site)
• Pregnant, parturient or breast-feeding women
• Persons deprived of their liberty by judicial or administrative decision
• Adults under legal protection (guardianship, curators)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Alcoholic hepatitis; Patients with histologically proven AH (after transjugular liver biopsy procedure and histological assessment).	Procedure: Biological sampling; A fragment of the diagnostic transjugular liver biopsy (D0); Plasma samples at D0, and at 1 and 6 months after liver biopsy if possible; Fecal samples at D0, and at 1 and 6 months after liver biopsy if possible
No alcoholic hepatitis; Patients with initially suspected AH (excessive alcohol consumption and modified Maddrey score > 32) but no AH at the histological evaluation of liver biopsy. It corresponds to patients with decompensated alcoholic liver disease but no AH.	Procedure: Biological sampling; A fragment of the diagnostic transjugular liver biopsy (D0); Plasma samples at D0, and at 1 and 6 months after liver biopsy if possible; Fecal samples at D0, and at 1 and 6 months after liver biopsy if possible

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiota composition	Intrahepatic, blood and fecal microbiota composition will be assessed by 16S rRNA sequencing (MiSeq Illumina). Microbiota analysis will be performed on the fragment of transjugular liver biopsy collected for the purpose of the study, and on plasma and fecal samples after bacterial DNA extraction. Bioinformatics analysis will be carried out using Qiime2, LeFSE (Conda) and the Maaslin2 package (v3.16; R software). Microbiota profiles determined at the genus taxonomic level will be compared between the two groups (proven AH and no AH).	At Day 0, 1 month and 6 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Study Chair: Yasmina CHOUIK, M.D., Ph.D., Hospices Civils de Lyon, Croix Rousse Hospital, Hepatology department

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: March 6, 2024
• First Submitted That Met QC Criteria: March 6, 2024
• First Posted (Actual): March 13, 2024

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: cirrhosis; microbiota; alcoholic liver disease; 16S rRNA; bacterial translocation; alcoholic hepatis; intra-hepatic microbiota
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Pathologic Processes; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Alcohol-Induced Disorders; Liver Diseases; Fibrosis; Hepatitis; Hepatitis A; Hepatitis, Alcoholic; Liver Diseases, Alcoholic
• Other Study ID Numbers: 69HCL23_1137; ID-RCB (Other Identifier: ANSM)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No