Alcoholic Liver Disease and the Gut Microbiome

NCT05007470 | Active Not Recruiting DMC

• 1 other identifier: 21-000674
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Significant sex differences exist in regard to alcohol use disorder (AUD) and alcoholic liver disease (ALD). To date, no studies have examined the brain-gut-microbiome (BGM) axis (which is the relationship between the gut, brain, and the bacteria within the gut) and sex-differences in AUD and ALD. Aims: 1) Demonstrate baseline sex differences in the microbiome and metatranscriptome of AUD and ALD and correlate those differences to severity, 2) determine if these baseline sex differences predicts abstinence or ALD related outcomes, and 3) show how altering the microbiome can decrease the severity of AUD and ALD in a sexdependent manner. Hypothesis: Our project is aimed to explore the hypothesis that sex-related differences of the BGM axis in AUD and ALD explains the variation in patient severity and outcome by sex, and that alterations of the BGM axis can decrease the severity of AUD and ALD in a sex-dependent manner. Methods: A pilot randomized placebo (VSL#3 vs placebo) control trial will be performed in patients with AUD and ALD for 6 months. Questionnaire data, clinical labs, serum, and feces for shotgun metagenomics will be collected at baseline, 3-months, and 6-months. Anticipated Results: Patients with severe AUD/ALD will have more microbes and microbial genes associated with inflammation. These differences will predict outcomes at 6-months and that changes of this baseline microbiome with VSL#3 will lead to more positive outcomes than placebo, with men having greater benefit from VSL#3 than women. Implications and Future Studies: The discovery of the mechanisms underlying sex-related differences in AUD/ALD is needed for the development of personalized recommendations for prevention and treatment in men and women

Conditions

Alcohol Use Disorder; Alcoholic Liver Disease; Microbiome

Keywords

Alcohol Use Disorder; Alcoholic Liver Disease; Microbiome; Microbes; Microbial Genes; Inflammation; Metatranscriptome

Outcome Measures

Primary Outcomes (1)

• Sex differences within ALD

  Sex differences in the rate abstinence and the proportion of resolution of ALD as measured by the Maddrey's Discriminant Function score, MELD-Na score, Glasgow Alcoholic Hepatitis Score, and transaminases

  Baseline to 6 months

Secondary Outcomes (4)

• Microbiome changes due to sex differences within ALD

  Baseline to 6 months

• Alcohol consumption changes due to sex differences within ALD

  Baseline to 6 months

• Quality of life changes due to sex differences within ALD

  Baseline to 6 months

• Alcohol Craving changes due to sex differences within ALD

  Baseline to 6 months

Study Arms (2)

Probiotic

EXPERIMENTAL

VSL#3

Drug: VSL #3 112.5 Capsule

Pacebo

PLACEBO COMPARATOR

Other: Placebo

Interventions

VSL #3 112.5 Capsule DRUG

VSL#3 is a commercial probiotic mixture consisting of eight bacterial strains: Four strains of Lactobacillus (Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, and Lactobacillus delbrueckii subspecies bulgaricus), three strains of Bifidobacterium (Bifidobacterium breve, Bifidobacterium longum, and Bifidobacterium infantis), and one strain of Streptococcus (Streptococcus salivarius subspecies thermophilus).

Probiotic

Placebo OTHER

100 mg sugar

Pacebo

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Patient will be recruited from the inpatient ward at RR and SM UCLA hospital. The primary team will identify patients who have alcohol use disorder. The study coordinator will then chart review the patient and determine eligibility based on the inclusion and exclusion criteria.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients admitted to Santa Monica UCLA hospital or Ronald Reagan UCLA Hospital with a diagnosis of AUD and ALD will be screened and potentially recruited.
• ALD patients will be identified based on the recent American Association of the Study of Liver Disease (AASLD) guidelines: onset of jaundice within 8 weeks, 2) ongoing consumption of ethanol of \>40 for women or \>60 in men for 6 months or \<60 days of abstinence before onset of jaundice, AST\>50, AST:ALT\>1.5 and both \<400 IU/L, total bilirubin \>3, or liver biopsy showing histologic features of ALD.
• AUD will be defined based on the current DSM-V definition

You may not qualify if:

• To avoid any confounders to the gut microbiome analysis, patients will be excluded if they have been on antibiotics within 3 months or probiotics within 1 month of enrollment
• If patients have a history of inflammatory bowel disease, irritable bowel syndrome, gastrointestinal malignancy, or gastrointestinal surgery.
• If patients are started on antibiotics while in the study, they will be withdrawn from the study to avoid confounders of antibiotic use on microbiome analysis.
• To avoid any cofounders of advanced liver fibrosis on the microbiome analysis, we will also exclude patients with underlying cirrhosis and/or overt hepatic encephalopathy (West Haven criteria \>3).
• Patients with acute pancreatitis or history of chronic pancreatitis will also be excluded. The diagnosis of acute pancreatitis and chronic pancreatitis will be ascertained from their history and physical.
• Cirrhosis will be determined by a review of their medical charts and Fib4 calculation. If their medical charts do not mention any history of cirrhosis and their Fib4 score is less than or equal to 1.35 then they will be deemed as being non-cirrhotic. Subjects will be provided their Fib4 score if it is greater than 1.35 and instructed to follow up with their primary care physician for further evaluation if warranted. Fib4 is based on their clinical blood work and age which will be abstracted from their chart and is validated at ruling out advanced liver fibrosis and cirrhosis.

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (1)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Related Publications (6)

• Kelly JF. E. M. Jellinek's Disease Concept of Alcoholism. Addiction. 2019 Mar;114(3):555-559. doi: 10.1111/add.14400. Epub 2018 Sep 2. No abstract available.

  PMID: 30064157 BACKGROUND

• Grant BF, Chou SP, Saha TD, Pickering RP, Kerridge BT, Ruan WJ, Huang B, Jung J, Zhang H, Fan A, Hasin DS. Prevalence of 12-Month Alcohol Use, High-Risk Drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 2017 Sep 1;74(9):911-923. doi: 10.1001/jamapsychiatry.2017.2161.

  PMID: 28793133 BACKGROUND

• Erol A, Karpyak VM. Sex and gender-related differences in alcohol use and its consequences: Contemporary knowledge and future research considerations. Drug Alcohol Depend. 2015 Nov 1;156:1-13. doi: 10.1016/j.drugalcdep.2015.08.023. Epub 2015 Sep 5.

  PMID: 26371405 BACKGROUND

• Rodriguez-Gonzalez A, Orio L. Microbiota and Alcohol Use Disorder: Are Psychobiotics a Novel Therapeutic Strategy? Curr Pharm Des. 2020;26(20):2426-2437. doi: 10.2174/1381612826666200122153541.

  PMID: 31969090 BACKGROUND

• Bajaj JS, Gavis EA, Fagan A, Wade JB, Thacker LR, Fuchs M, Patel S, Davis B, Meador J, Puri P, Sikaroodi M, Gillevet PM. A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder. Hepatology. 2021 May;73(5):1688-1700. doi: 10.1002/hep.31496. Epub 2021 Mar 16.

  PMID: 32750174 BACKGROUND

• Leclercq S, de Timary P, Delzenne NM, Starkel P. The link between inflammation, bugs, the intestine and the brain in alcohol dependence. Transl Psychiatry. 2017 Feb 28;7(2):e1048. doi: 10.1038/tp.2017.15.

  PMID: 28244981 BACKGROUND

MeSH Terms

Conditions

Alcoholism; Liver Diseases, Alcoholic; Inflammation

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Liver Diseases; Digestive System Diseases; Alcohol-Induced Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomized placebo controlled trial

Study Record Dates

• First Submitted: August 9, 2021
• First Posted: August 16, 2021
• Study Start: January 31, 2022
• Primary Completion: June 30, 2025
• Study Completion: September 1, 2025
• Last Updated: January 6, 2025

Record last verified: 2025-01

Locations

US (1)