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

摘要 酗酒是全世界发病率和死亡率的主要原因。在美国，1800万美国人滥用 酒精性肝病（ALD）影响着超过1000万人。ALD包括以下光谱 疾病和病理变化，从脂肪变性到酒精性肝炎（AH）和肝硬化。AH是 ALD是最严重的形式，可以在疾病进展的任何时间发展。泼尼松龙 严重AH的标准治疗在许多患者中无效。在类固醇耐药患者中，6个月 死亡率可达45%。AH的死亡率主要由终末期肝病的严重程度决定，但风险 在全身炎症性疾病患者中，多器官功能衰竭（MOF）也增加了AH的死亡率。 炎症反应（SIRS），即使在没有感染、循环脂多糖升高或 急性肾损伤（阿基）。了解酒精滥用的病理生理机制 这些肝外并发症将导致生物标志物的识别，以识别高风险的AH患者 针对特定并发症，以及合理设计的新治疗靶点，以减少并发症。期间 ASH U 01联盟的第一个资助周期，我们在AH临床前小鼠模型中的研究，以及 在AH患者中的转化研究，确定了影响交叉点的酒精作用的关键靶点， 肠道微生物代谢和补体激活之间的关系，补体是先天免疫的关键武器， 炎症和伤口愈合都涉及的系统。在这里，我们建议确定这些 靶点有助于AH的严重程度，以及AH中的并发症，包括SIRS和阿基， 增加死亡率。这些研究将集中在生物标志物的发展，是预测 AH的致病性进展，以及提供机制的见解，导致改进的治疗设计， 专门针对疾病过程和损伤解决的干预措施。我们的翻译建议 研究是酒精性肝炎临床和转化网络的一部分，利用临床样本 以及来自晚期临床试验和观察性研究的患者数据，由数据协调 协调中心。我们将追求两个相关的，但独立的，旨在开发1）生物标志物签名 肠道微生物代谢物TMA和TMAO可预测AH的严重程度和临床结局， 2)补体激活分子模式（CAMPs）特征，其区分患有以下疾病的患者： 炎症反应增强可预测肝病严重程度、SIRS/阿基发生率和 死亡与增强伤口愈合和修复反应与AH生存率提高相关。的 TMA-生物标志物和cAMP-生物标志物特征的开发将具有显著的临床影响， 使临床医生能够预测AH的临床过程，并为患者提供未来的治疗决策， 啊

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.