French National MICMAF Cohort (MICMAF)

Study of the Evolution of the Intestinal Microbiome (Taxonomic and Functional Composition) During Alcoholic Liver Disease

Excessive alcohol consumption is a major public health problem, particularly in France. It is the leading cause of cirrhosis and hepatocellular carcinoma. Among subjects with heavy alcohol consumption, the majority of patients develop fatty liver overload (steatosis), but only 10 to 35% develop acute alcoholic hepatitis (AAH) and 8 to 20% progress to cirrhosis. Steatosis is the earliest lesion, rapidly reversible after abstinence from alcohol. On the other hand, the occurrence of AAH leads to a strong progression of fibrosis. The investigators have shown on serial liver biopsies that a subgroup of heavy drinkers develop episodes of AAH and progress to cirrhosis. Therefore, factors other than the amount of alcohol consumed alone influence the development and progression of alcoholic liver disease (ALD). Among these factors, it is now accepted that the gut microbiome plays an important role in the pathogenesis of ALD. Increased intestinal permeability and activation of the innate immune system by lipolysaccharide (LPS) of digestive origin is a key factor in the initiation of AAH. The alteration of the intestinal barrier induced by alcohol abuse seems to involve dysbiosis. Furthermore, the investigatorshave shown that the sensitivity of the liver to alcohol toxicity is transmissible from humans to mice via the gut microbiome. Despite these advances, the causal relationship between mycobiome disruption and ALD in humans requires confirmation in prospective studies.

The intestinal microbiome represents all the microorganisms found in the digestive tract: bacteria (bacterial microbiome), viruses (virome), fungi (mycobiome).

Recent data point to the role of disturbances of the mycobiome and the virome in human pathology. The intestinal virome consists of two major types of viruses: eukaryotic RNA and DNA viruses that infect host cells and prokaryotic or bacteriophage viruses that infect the bacterial microbiome. Recent evidence suggests that the virome participates in immune system homeostasis. Infection of axenic mice with murine norovirus restores the functionality of intestinal lymphocytes. However, the involvement of the intestinal virome in ALD has never been studied.

Cessation of alcohol consumption has a beneficial effect in all stages of ALD . It reduces the risk of complications of cirrhosis and, for early stages of liver damage, prevents progression to advanced stages (severe AAH and cirrhosis). Unfortunately, most patients with alcohol addiction do not achieve long-term abstinence or significant reduction in their consumption despite psychological and medical support. Depression and anxiety are also associated with gut dysbiosis in humans. The causal role, at least partial, of this dysbiosis in addictive phenomena, whether alcohol or other addictions such as cocaine, has been shown. Thus, the modification of MI influences the addictive behavior of cocaine-dependent mice (. All these data show the major role of the microbiota-central nervous system (CNS) axis in mental disorders such as alcohol addiction and its consequences (craving, depression, anxiety). This interaction is mediated by several mechanisms such as the production of active metabolites by the intestinal microbiome and the translocation of bacteria or bacterial derivatives.

Primary Objective:

To characterize temporal changes in the gut microbiome (bacterial, viral, and fungal) within sequential specimens (stool, saliva, serum) prior to the occurrence of acute alcoholic hepatitis episodes

Secondary Objectives:

• Demonstrate that specific fecal, serum, or saliva microbiome profiles (bacterial, viral, and fungal) can predict the progression of alcoholic liver disease to severe alcoholic hepatitis, fibrosis, and cirrhosis.
• Characterize changes in the composition of the gut microbiome (bacterial, viral and fungal) associated with the progression of alcoholic liver disease to severe alcoholic hepatitis and cirrhosis.
• Characterize the changes in the microbiome during alcohol withdrawal.
• Identify microbiome profiles associated with alcohol dependence and anxiety-depressive events related to alcohol addiction.
• To identify bacterial species with a protective effect in alcoholic liver disease.
• To identify beneficial bacterial species against alcohol dependence.
• To study the microbiome-host interaction in alcoholic liver disease and alcohol addiction.
• To identify microbiome profiles with prognostic value in severe alcoholic hepatitis and alcoholic cirrhosis.

Number of centers: 7 Number of subjects expected 1000 Population concerned: The study will include a population of patients with excessive alcohol consumption seen in consultation or hospitalized for alcohol addiction problems and/or exploration of alcohol-related liver damage Inclusion period: January 2020 - January 2030 Patient observation period: 5 to 20 years Study duration: 30 years

Study Overview

• Status: Recruiting
• Conditions: Alcoholic Liver Disease
• Intervention / Treatment: Genetic: Sequential sampling (stool, saliva, serum) .

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

• Study Contact: Name: Cosmin Voican, Dr; Phone Number: +33 01 45 37 47 75; Email: cosmin.voican@aphp.fr
• Study Contact Backup: Name: Brahim Mohamed Elarbi; Phone Number: +33 01 40 05 43 60; Email: brahim.mohamed-elarbi@aphp.fr

Study Locations

• France
  • Ile De France
    • Clamart, Ile De France, France, 92140
      • Recruiting
      • Cosmin Voican
      • Contact: Brahim Mohamed Elarbi; Phone Number: +33 01 40 05 43 60; Email: brahim.mohamed-elarbi@aphp.fr
      • Contact: Cosmin Voican, Dr; Phone Number: +33 0145374775; Email: cosmin.voican@aphp.fr

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The study will include a population of patients with excessive alcohol consumption seen in consultation or hospitalized for alcohol addiction problems and/or exploration of alcohol-related liver damage.

Description

Inclusion Criteria:

• Age between 18 and 75 years
• Average alcohol consumption of more than 20 g per day in women and 30 g per day in men during the previous year;
• Patients seen in consultation or hospitalized for assessment of alcoholic liver disease and management of alcohol addiction;
• Having given their consent to participate in this study;
• Affiliated to a social security system (beneficiary or beneficiary's right).

Exclusion Criteria:

• Antibiotic, probiotic or prebiotic treatment within the previous 3 months ;
• Digestive hemorrhage, acute pancreatitis, acute or chronic diarrhea (except diarrhea related to excessive alcohol consumption) or chronic inflammatory bowel disease;
• Another cause of liver damage;
• A serious associated pathology (respiratory failure, heart failure, severe psychiatric disorders, active cancer).
• Patient under guardianship or curatorship

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohorte; The study will include a population of patients with excessive alcohol consumption seen in consultation or hospitalized for alcohol addiction problems and/or exploration of alcohol-related liver damage	Genetic: Sequential sampling (stool, saliva, serum) .; Sequential sampling (stool, saliva, serum) prior to the occurrence of AAH episodes in heavy drinking patients to identify protective or deleterious profiles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Temporal changes in the gut microbiome	Differences in gut microbiome composition between inclusion and different follow-up visits	every 6 months until 240 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in gut microbiome composition as a function of the rate of progression of liver fibrosis	Differences in the composition of the gut microbiome, analyzed using the metagenomic technique, the rate of progression of liver fibrosis, as measured by median elasticity (kPa/year)	every 6 months until 240 months
Differences in gut microbiome composition at inclusion between patients with and without the development of severe acute alcoholic hepatitis or cirrhosis between inclusion and different follow-up visits.	Differences in the composition of the gut microbiome, analyzed using the metagenomic technique	every 6 months until 240 months
Differences in gut microbiome composition at baseline between failed and weaned patients and between baseline and follow-up visits.	Differences in the composition of the gut microbiome, analyzed using the metagenomic technique,	every 6 months until 240 months
Differences in gut microbiome composition as a function of craving intensity, depression and anxiety.	Differences in the composition of the gut microbiome, analyzed using the metagenomic technique	every 6 months until 240 months
The correlation between gut microbiome, host genotype and FAD severity.	Differences in the composition of the gut microbiome, analyzed using the metagenomic technique	every 6 months until 240 months
Effect of bacteria identified as beneficial, on mouse models of alcoholic liver disease, depression and anxiety.	Differences in the composition of the gut microbiome, analyzed using the metagenomic technique	every 6 months until 240 months
The association between the gut microbiome and the prognosis of patients with acute alcoholic hepatitis or cirrhosis.	Differences in the composition of the gut microbiome, analyzed using the metagenomic technique	every 6 months until 240 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Cosmin Voican, Dr, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2022
• Primary Completion (Estimated): February 1, 2043
• Study Completion (Estimated): February 1, 2053

Study Registration Dates

• First Submitted: February 20, 2023
• First Submitted That Met QC Criteria: May 30, 2023
• First Posted (Actual): June 9, 2023

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Depression; Liver Disease; Addiction; Alcoholic; Intestinal microbiome
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol-Induced Disorders; Liver Diseases; Liver Diseases, Alcoholic
• Other Study ID Numbers: 200312; 2019-A01331-56 (Other Identifier: French Agency for the Safety of Health Products)

Drug and device information, study documents

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