The """"""""Translational Research and Evolving Alcoholic-hepatitis Treatment"""""""" (TREAT) consortium was established in response to the RFA-AA-12-007. This consortium comprises of Indiana University (IU), Mayo Clinic (MC) and the Virginia Commonwealth University (VCU). The main objective of TREAT consortium is to perform patient oriented research in close collaboration with basic scientists in alcoholic hepatitis (AH) and expedite the translation of emerging findings. The three overarching aims of TREAT consortium are: (1) to perform a prospective, multicenter observational study leading to a well characterized registry and bio-sample repository together with newer insights into the natural history of AH~ (2) to perform three phase 2a """"""""proof of concept"""""""" trials with three novel agents targeting putative mechanisms of AH, and (3) to better understand the mechanisms involved in the pathophysiology of human AH and predictors of response to therapy utilizing samples collected under specific aims 1 and 2. All centers will contribute for specific aim 1. The TREAT-VCU will focus on the role of gut integrity, endotoxemia, gut microbiota, metabolomics and role of eicosanoids specifically lipoxygenases.
Specific aim 2 proposes a phase 2a """"""""proof of concept"""""""" placebo- controlled, dose-ranging study of Imm 124-E (bovine colostrum enriched with IgG anti-lipopolysaccharide (LPS)) in subjects with severe AH. Subjects with severe AH will receive standard of care and steroids when indicated. The subjects when starting steroids will be randomized to receive the study drug or placebo. The subjects will be monitored to treatment success and failure, safety, tolerability and efficacy of the study drug.
The specific aim 3 of TREAT-VCU is to define the role of systemic activation of lipoxygenases (LOX) as a driver of the severity of AH. We will test the hypothesis that intestinal microbiome-derived metabolites activate circulating macrophages to produce pro-inflammatory LOX that activate pathways that drive the phenotype of severe AH. We will perform detailed characterization of the microbiome-metagenome and the systemic eicosanoid profile and further establish their relationship to the hepatic transcriptome using a """"""""systems biology"""""""" approach in subjects with severe AH, mild AH, heavy drinkers without AH and matched non-alcoholic controls. The proposed studies are expected to demonstrate new insights into the natural history of AH, novel therapies as proof of concept and identify newer targets for intervention and drug development moving closer to the goal of accelerating the translation of newer findings in direct alignment with the priorities of NIAAA.

Public Health Relevance

The """"""""Translational Research and Evolving Alcoholic-hepatitis Treatment"""""""" (TREAT) consortium comprises of Indiana University (IU), Mayo Clinic (MC) and the Virginia Commonwealth University (VCU). The main objective is to perform patient oriented research in close collaboration with basic scientists in alcoholic hepatitis (AH) and translate newer findings into clinical practice expeditiously. This application is directly aligned with the strategic plan of National Institute of Alcohol Abuse and Alcoholism (NIAAA).

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-JJ (07))
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Orosz, Andras
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Virginia Commonwealth University
Internal Medicine/Medicine
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United States
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Li, Wei; Amet, Tohti; Xing, Yanyan et al. (2017) Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study. Hepatology 66:575-590
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