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

AH 中的微生物代谢物和先天免疫：损伤和修复的生物标志物

• 批准号: 10428502
• 负责人: LAURA E. NAGY
• 金额: $ 25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428502
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Alcohol abuse; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; American; Amines; Area; Biological Markers; Cells; Cessation of life; Clinical; Clinical Trials; Complement; Complement Activation; Data; Data Coordinating Center; Development; Disease; Disease Progression; Extrahepatic; FMO3; Funding; Future; G-Protein-Coupled Receptors; Heavy Drinking; Hepatocyte; Immune; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Innate Immune System; Interruption; Investigation; Lipopolysaccharides; Liver; Liver diseases; Messenger RNA; Metabolism; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Natural Immunity; Natural regeneration; Observational Study; Outcome; Pathogenicity; Pathologic; Pathway interactions; Patients; Pattern; Persons; Phase; Plasma; Process; Proteins; Recovery; Resolution; Role; Sampling; Severities; Severity of illness; Signal Transduction; Steroid Resistance; Therapeutic Intervention; Time; Urine; arm; biomarker development; biomarker identification; biomarker panel; biomarker signature; clinical predictors; design; dysbiosis; effective therapy; end stage liver disease; gut microbes; gut microbiota; hepatocyte injury; high risk; improved; injury and repair; insight; liver inflammation; liver injury; microbial; monocyte; mortality; mortality risk; mouse model; novel therapeutic intervention; peripheral blood; phenotypic data; pre-clinical; predicting response; predictive marker; predictive signature; prednisolone; rational design; receptor; response; systemic inflammatory response; therapeutic target; translational study; treatment response; treatment strategy; trimethylamine; trimethyloxamine; wound healing

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.

抽象的 酗酒是全球发病率和死亡率的主要原因。在美国，有1800万美国人滥用 酒精，酒精性肝病（ALD）影响超过1000万人。 ALD包括 疾病和病理变化，从脂肪变性到酒精性肝炎（AH）和肝硬化。啊 最严重的ALD形式，可以随时在疾病发展中发展。泼尼松龙 严重AH的标准疗法在许多患者中无效。在抗类固醇的患者中，6个月 死亡率可以达到45％。 AH中的死亡率主要由终末期肝病的严重程度驱动，但风险 出现全身性炎症患者的多器官失败（MOF）也增加了AH中的死亡 反应（SIRS），即使在没有感染的情况下也发生，循环脂多糖或 急性肾脏损伤（AKI）。了解酒精滥用驱动的病理生理机制 这些肝外的并发症将导致生物标志物鉴定出高风险的AH患者 对于特定的并发症，以及新的合理设计的治疗靶标，以减少并发症。期间 ASH U01联盟的第一个资金周期，我们在AH的临床前鼠模型中的研究以及 AH患者的转化研究确定了影响交叉点的酒精作用的关键靶标 在肠道中的微生物代谢和补体激活之间，这是先天免疫的关键臂 涉及炎症和伤口愈合的系统。在这里，我们建议确定是否 目标有助于AH的严重性以及AH的并发症，包括SIRS和AKI，有助于 死亡率增加。这些研究将着重于预测的生物标志物的发展 AH的致病进展，并提供机械洞察力，从而改善治疗的设计 干预措施专门针对疾病过程和损伤的解决。我们提出的翻译 研究是酒精性肝炎临床和转化网络的一部分，利用临床样品 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旨在开发1）生物标志物签名 对于肠道微生物代谢物TMA和TMAO，可预测AH和 2）补体激活分子模式（CAMP）签名，该特征区分患者 增强炎症反应可预测肝病严重程度增加，SIRS/AKI的发生率和 死亡与与AH的生存率提高有关的伤口愈合和修复反应增强了。这 TMA-BIOMARKER和CAMP-BIOMARKER特征的开发将受到重大临床影响 使临床医生能够预测AH的临床过程，并为患者的未来治疗决策提供信息 啊。