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，1800万美国人虐待 酒精，酒精性肝病(ALD)影响着1000多万人。ALD包括以下频谱 疾病和病理变化，从脂肪变性到酒精性肝炎(AH)和肝硬变。啊就是那个 ALD是ALD最严重的形式，在疾病发展的任何时候都可能发生。强的松龙， 标准疗法治疗重症急性肝炎，对许多患者无效。在类固醇耐药患者中，6个月 死亡率可达45%。急性肝炎的死亡率主要是由终末期肝病的严重程度驱动的，但风险 表现为全身炎症的患者的多器官衰竭(MOF)也增加了AH的死亡率 反应(SIRS)，即使在没有感染、循环内毒素升高或 急性肾损伤(AKI)。了解酗酒驾驶的病理生理机制 这些肝外并发症将导致生物标志物的识别，以识别高危AH患者 针对特定的并发症，以及新的合理设计的治疗靶点，以减少并发症。在.期间 ASH U01财团的第一个资金周期，我们对临床前AH小鼠模型的研究，以及 对AH患者的翻译研究，确定了影响交叉点的酒精行为的关键靶点 肠道微生物新陈代谢与补体激活之间的关系 参与炎症和伤口愈合的系统。在这里，我们建议确定这些 靶点有助于急性呼吸窘迫的严重程度，以及急性呼吸窘迫综合征的并发症，包括全身炎症反应综合征和急性心肌梗死，这有助于 死亡率上升。这些研究将集中在开发可预测高血压病的生物标志物。 AH的致病进展，以及提供机制洞察力，从而改进治疗设计 专门针对疾病进程和解决伤害的干预措施。我们建议的翻译 研究是酒精性肝炎临床和翻译网络的一部分，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但独立的目标，以开发1)生物标记物签名 肠道微生物代谢物TMA和TMAO可预测急性肝炎和急性胰腺炎的严重程度和临床结果 2)补体激活分子模式(CAMP)特征，区分 炎症反应增强预测肝病严重程度、SIRS/AKI发生率和 死亡与创面愈合和修复反应增强与急性呼吸窘迫综合征的存活率提高相关。这个 TMA生物标记物和cAMP生物标记物特征的开发将对临床产生重大影响 使临床医生能够预测急性肝炎的临床病程，并为以下患者的未来治疗决策提供信息 阿。

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.