The Commensal Microflora Suppresses Liver Fibrosis

共生微生物群抑制肝纤维化

基本信息

批准号：
8975084
负责人：
Bernd G. Schnabl
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-10-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8975084
关键词：
Affect Alcohol abuse Animal Experiments Antioxidants Apoptosis Bacteria Binding Biology California Cell Death Cessation of life Chronic Chronic Disease Cirrhosis Core Facility Data Enteral Epithelial Etiology Experimental Models Extracellular Matrix Fibrosis Genetic Models Germ-Free Gnotobiotic Health Health Sciences Heat shock proteins Hepatic Hepatic Fibrogenesis Hepatic Stellate Cell Hepatocyte Homeostasis Immune system Indoles Intestines Knockout Mice Knowledge Laboratories Laboratory Animal Production and Facilities Lead Liver Liver Cirrhosis Liver Fibrosis Mediating Medical Modeling Molecular Molecular Biology Morbidity - disease rate Mus Obesity Oxidative Stress Patients Pattern Permeability Phenotype Physician Executives Plasma Play Preventive Preventive Intervention Property Propionic Acids Proteins Public Health Regulation Reporting Research Role Severity of illness Signal Transduction South Carolina Testing Therapeutic Therapeutic Intervention Toll-like receptors Toxin United States Universities Veterans Viral hepatitis acute liver injury cell type chronic liver disease design drinking water end stage disease fibrogenesis germ free condition hepatotoxin innovation insight liver inflammation liver injury metabolomics microbial microbiome microbiota mortality mouse model new therapeutic target novel pathogen prevent receptor reconstitution targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Liver fibrosis is the result of chronic liver damage from various etiologies including alcohol abuse, obesity, or viral hepatitis. Chronic liver disease may progress to cirrhosis, an end stage disease and major cause of morbidity and mortality in the United States and in particular among Veterans. Patients with chronic liver disease show intestinal bacterial overgrowth and dysbiosis. They also demonstrate increased intestinal permeability, and disease severity correlates with systemic levels of bacterial products. Although experimental liver fibrosis is dependent on gut derived bacterial products, yet the exact contribution of the commensal microflora to liver fibrosis is unknown. Since the interaction of pathogen associated molecular patterns (PAMPs) with the innate immune system can also confer protection to the host, we subjected germfree mice to experimental models of liver fibrosis. Results from our laboratory demonstrate that germfree mice show exacerbated liver fibrosis as compared with conventional mice. Livers of germfree mice have a decreased expression of the antioxidant heat shock protein (Hsp)-25, more oxidative stress and a higher rate of apoptosis. The focus of this application is to further characterize the relationship between the intestinal microflora and the progression of chronic liver disease. We hypothesize that the commensal microflora is an important suppressor of oxidative stress and hence fibrosis upon chronic liver injury in mice. Our experimental approach is to apply mouse models of toxin-induced and cholestatic liver fibrosis to germfree and conventional mice and to investigate the contribution of the bacterial microflora to chronic liver disease (Aim 1). We will then assess the mechanism by which the microflora ameliorates experimental liver fibrosis. The focus will be on Hsp25 that is lower expressed in hepatocytes of germfree mice as compared with conventional mice and that has antioxidant properties. We will test the new concept that bacterial products or metabolites induce Hsp25 in hepatocytes. We will also focus on hepatic stellate cells to explain the phenotype with increased fibrosis under germ-free conditions (Aim 2). We will then supplement germfree mice with one bacterial metabolite or colonize germ-free mice with indole-3-propionic acid (IPA) synthesizing bacteria, and subject them to experimental liver fibrosis. A preventive and therapeutic approach will be chosen. Bacterial products or metabolites might confer antioxidant properties directly or via the induction of antioxidant molecules to the liver (Aim 3). We believe these studies will provide important insights into the contribution of the commensal microflora to liver fibrosis. This will establish a novel shift in the current paradigm that all translocated bacteria and their products are bad for liver injury and chronic liver disease. Eventually this approach might lead to new therapeutic targets and therapies for patients with chronic liver disease.

描述（由申请人提供）：肝纤维化是多种病因导致的慢性肝损伤的结果，包括酗酒、肥胖或病毒性肝炎。慢性肝病可能发展为肝硬化，这是一种终末期疾病，也是美国尤其是退伍军人发病和死亡的主要原因。慢性肝病患者表现出肠道细菌过度生长和菌群失调。他们还证明肠道通透性增加，疾病严重程度与细菌产物的全身水平相关。尽管实验性肝纤维化依赖于肠道衍生的细菌产物，但共生微生物群对肝纤维化的确切贡献尚不清楚。由于病原体相关分子模式（PAMP）与先天免疫系统的相互作用也可以为宿主提供保护，因此我们对无菌小鼠进行了肝纤维化实验模型。我们实验室的结果表明，与传统小鼠相比，无菌小鼠的肝纤维化加剧。无菌小鼠的肝脏抗氧化热休克蛋白（Hsp）-25的表达降低，氧化应激更多，细胞凋亡率更高。该应用的重点是进一步表征肠道菌群与慢性肝病进展之间的关系。我们假设共生微生物群是氧化应激的重要抑制因子，因此是小鼠慢性肝损伤时纤维化的重要抑制因子。我们的实验方法是将毒素诱导和胆汁淤积性肝纤维化的小鼠模型应用于无菌小鼠和常规小鼠，并研究细菌微生物群落对慢性肝病的影响（目标 1）。然后我们将评估微生物群改善实验性肝纤维化的机制。重点是 Hsp25，与传统小鼠相比，它在无菌小鼠的肝细胞中表达较低，并且具有抗氧化特性。我们将测试细菌产物或代谢物在肝细胞中诱导 Hsp25 的新概念。我们还将重点关注肝星状细胞，以解释无菌条件下纤维化增加的表型（目标 2）。然后，我们将向无菌小鼠补充一种细菌代谢物，或用合成吲哚-3-丙酸（IPA）的细菌定植无菌小鼠，并使它们进行实验性肝纤维化。将选择预防和治疗方法。细菌产物或代谢物可能直接或通过诱导肝脏抗氧化分子赋予抗氧化特性（目标 3）。我们相信这些研究将为共生微生物群对肝纤维化的贡献提供重要的见解。这将为当前的范式带来新的转变，即所有易位的细菌及其产物都对肝损伤和慢性肝病有害。最终，这种方法可能会为慢性肝病患者带来新的治疗靶点和疗法。