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 酗酒是全世界发病和死亡的主要原因。在美国，有 1800 万美国人虐待 酒精，酒精性肝病 (ALD) 影响着超过 1000 万人。 ALD 包括一系列 疾病和病理变化，从脂肪变性到酒精性肝炎（AH）和肝硬化。啊是 最严重的 ALD 形式，可在疾病进展的任何时间发生。泼尼松龙， 严重 AH 的标准治疗对许多患者无效。对于类固醇抵抗患者，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 全身炎症患者的多器官衰竭 (MOF) 也会增加 AH 的死亡人数 反应（SIRS），即使在没有感染、循环脂多糖升高或没有感染的情况下也会发生 急性肾损伤（AKI）。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鉴定，以识别高危 AH 患者 针对特定并发症，以及合理设计新的治疗靶点以减少并发症。期间 ASH U01 联盟的第一个资助周期，我们对 AH 临床前小鼠模型的研究，以及 针对 AH 患者的转化研究，确定了影响交叉点的酒精作用的关键目标 肠道微生物代谢与补体激活之间的关系，补体是先天免疫的重要组成部分 参与炎症和伤口愈合的系统。在这里我们建议确定这些是否 目标会导致 AH 的严重程度以及 AH 的并发症，包括 SIRS 和 AKI，从而导致 死亡率增加。这些研究将重点关注预测疾病的生物标志物的开发 AH 的致病进展，并提供机制见解，从而改进治疗设计 专门针对疾病过程和损伤解决的干预措施。我们建议的翻译 研究是酒精性肝炎临床和转化网络的一部分，利用临床样本 以及来自后期临床试验和观察研究的患者数据，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果 2) 补体激活分子模式 (CAMP) 特征可区分患者 炎症反应增强预示着肝病严重程度、SIRS/AKI 发生率的增加以及 死亡与增强的伤口愈合和修复反应与 AH 生存率的提高相关。这 TMA 生物标志物和 CAMP 生物标志物特征的开发将产生重大的临床影响 使临床医生能够预测 AH 的临床病程，并为 AH 患者的未来治疗决策提供信息 啊。