The Commensal Microflora Suppresses Liver Fibrosis

共生微生物群抑制肝纤维化

• 批准号: 8814609
• 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
• 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/8814609
• 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; mortality; mouse model; new therapeutic target; novel; pathogen; prevent; receptor; reconstitution; targeted treatment

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)： 肝纤维化是各种原因造成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变，在美国，特别是在退伍军人中，这是一种终末期疾病，也是发病率和死亡率的主要原因。慢性肝病患者表现为肠道细菌过度生长和生物失调。他们还表现出肠道通透性的增加，疾病的严重程度与全身细菌产品的水平有关。虽然实验性肝纤维化依赖于肠道来源的细菌产物，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(PAMPs)与先天免疫系统的相互作用也可以为宿主提供保护，我们将无菌小鼠置于肝纤维化的实验模型中。我们实验室的结果表明，与常规小鼠相比，无菌小鼠表现出加重的肝纤维化。无菌小鼠的肝脏中抗氧化性热休克蛋白(HSP)-25的表达减少，氧化应激更严重，细胞凋亡率更高。这项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，在小鼠的慢性肝损伤中，共生菌群是氧化应激和纤维化的重要抑制因子。我们的实验方法是将毒素诱导的小鼠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，并研究细菌菌群在慢性肝病中的作用(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。重点将放在HSP25上，它在无菌小鼠的肝细胞中的表达低于常规小鼠，并且具有抗氧化特性。我们将测试细菌产品或代谢产物在肝细胞中诱导HSP25这一新概念。我们还将重点研究肝星状细胞，以解释在无菌条件下肝纤维化增加的表型(目标2)。然后，我们将给无菌小鼠补充一种细菌代谢物，或用合成吲哚-3-丙酸(IPA)的细菌定居无菌小鼠，并使它们遭受实验性肝纤维化。将选择预防和治疗方法。细菌产品或代谢产物可能直接或通过诱导抗氧化剂分子对肝脏产生抗氧化性(目标3)。我们相信，这些研究将为共生微生物群在肝纤维化中的作用提供重要的见解。这将为目前的模式建立一个新的转变，即所有易位的细菌及其产品都对肝脏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目标和疗法。