Pathogenic Role of Loss of Butyrate Producing Bacteria in Immune Dysregulation and Development of Alcoholic Liver Disease (ALD)

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This project (Project 2) will define specific pathogenic features of alcohol-induced gut dysbiosis and investigate its causative role (and underlying mechanisms) in systemic/hepatic immune dysregulation in alcoholic liver disease (ALD). Based on our compelling preliminary data from pre-clinical and clinical studies, we hypothesize that loss of butyrate producing bacteria is a significant pathogenic feature of gut dysbiosis in patients with ALD, which plays a major role in developing a pro-inflammatory T cell-IL-17 milieu leading to pathogenic changes in the gut-liver axis in ALD. This project will utilize a highly innovative animal model of human fecal microbiota transplant (FMT) from alcoholic hepatitis patients into conventional mice that recapitulates key features of human ALD, to identify mechanisms and develop targeted therapeutic interventions. Specifically, the project will test the efficacy of evidence-based nutritional therapeutic strategies that target gut dysbiosis, namely, (i) Tributyrin (Tb), a dietary butyrate pro-drug and known HDAC inhibitor and (ii) Faecalibacterium prausnitzi - a major human butyrate producing probiotic. The proposal leverages existing resources of the NIH funded AlcHepNet clinical consortium (U01AA026980) which include a large available cohort of ALD patients and control subjects, participant recruitment, validated demographic and clinical data, biospecimen and biomarker collection and clinical expertise in liver diseases. This proposed study will provide new insights into the mechanisms underlying ALD and identify new targets for ALD treatment, thereby contributing to the ULARC program and theme of nutrition and alcohol-induced organ injury. The specific aims of the proposal are: AIM 1) Determine the qualitative and quantitative loss of butyrate producing microbial communities as a defining pathogenic feature of alcohol-induced gut dysbiosis leading to immune dysregulation represented by the activation of the proinflammatory T cell-IL-17 axis in patients with ALD, AIM 2) Determine the causative role of alcohol-induced loss of butyrate producing bacteria on the activation of the proinflammatory T cell/IL-17 axis and neutrophil recruitment in hepatic inflammation/injury, and AIM 3) Evaluate the efficacy of nutritional interventions targeting the alcohol-induced loss of enteric butyrate producing bacteria and butyrate production in attenuating the pathogenic changes in the gut-liver axis in ALD.