Microbial metabolites and Innate Immunity in AH: Biomarkers of injury and repair

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ABSTRACT Alcohol abuse is a leading cause of morbidity and mortality worldwide. In the US, 18 million Americans abuse alcohol, with alcoholic liver disease (ALD) affecting over 10 million people. ALD comprises a spectrum of disorders and pathologic changes, ranging from steatosis to alcoholic hepatitis (AH) and cirrhosis. AH is the most severe form of ALD and can develop at any time in the progression of disease. Prednisolone, the standard therapy for severe AH, is not effective in many patients. In steroid-resistant patients, the 6-month mortality rate can reach 45%. Mortality in AH is primarily driven by severity of end-stage liver disease, but risk of death in AH is also increased by multi-organ failure (MOF) in patients presenting with systemic inflammatory response (SIRS), which occurs even in the absence of infections, elevated circulating lipopolysaccharide or acute kidney injury (AKI). Understanding the pathophysiological mechanisms by which alcohol abuse drives these extra-hepatic complications will lead to the identification of biomarkers to identify AH patients at high risk for specific complications, as well new rationally-designed therapeutic targets to reduce complications. During the first funding cycle of the ASH U01 consortia, our studies in pre-clinical murine models of AH, as well as translational studies in patients with AH, identified key targets of alcohol action that impact the intersection between microbial metabolism in the gut and activation of complement, a critical arm of the innate immune system that is involved in both inflammation and wound healing. Here we propose to determine whether these targets contribute to severity of AH, as well as complications in AH, including SIRS and AKI, that contribute to increased mortality. These studies will focus on the development of biomarkers that are predictive of the pathogenic progression of AH, as well as provide mechanistic insight leading to improved design of therapeutic interventions specifically targeting disease processes and resolution of injury. Our proposed Translational Studies are part of the Alcoholic Hepatitis Clinical and Translational Network, making use of clinical samples and patient data from both the Late Phase Clinical Trial and Observational Study, as coordinated by the Data Coordinating Centers. We will pursue two related, but independent, aims to develop 1) A biomarker signature for the gut microbe metabolites TMA and TMAO that predicts severity and clinical outcomes in AH and 2) a complement activation molecular pattern (CAMPs) signature that differentiates between patients with enhanced inflammatory responses predictive of increased severity of liver disease, incidence of SIRS/AKI and death vs enhanced wound healing and reparative responses associated with improved survival from AH. The development of TMA-biomarker and CAMP-biomarker signatures will have significant clinical impact by enabling clinicians to predict the clinical course of AH and inform future treatment decisions for patients with AH.