Alcoholic Liver Disease and the Gut Microbiome
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
Inclusion Criteria: 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
Exclusion Criteria: 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, 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.