Regulation of oxidative liver injury by the probiotic Lactobacillus rhamnosus GG

益生菌鼠李糖乳杆菌 GG 对氧化性肝损伤的调节

• 批准号: 9754575
• 负责人: Bejan Jon Saeedi
• 金额: $ 5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754575
• 关键词: Acetaminophen; Acute; Affect; Alcoholic Liver Diseases; Animal Model; Antioxidants; Area; Bacteria; Biological Assay; C57BL/6 Mouse; Cardiovascular system; Cells; Communities; Consumption; Data; Development; Diet; Disease; Distal; Drug Metabolic Detoxication; Endocrine; Enzymes; Functional disorder; Gastrointestinal tract structure; Genes; Genetic Transcription; Germ-Free; Goals; Health; Hepatic; Hepatic Tissue; Hepatotoxicity; Homeostasis; Human; Immunofluorescence Immunologic; Immunologics; Individual; Injury; Intestinal Diseases; Intestines; Knockout Mice; Lactobacillus casei rhamnosus; Link; Liver; Mediating; Metabolic; Modeling; Mus; NQO1 gene; Nature; Neurologic; Nuclear; Oral; Oral Administration; Organ; Oxidative Regulation; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiology; Play; Predisposition; Probiotics; Process; Production; Publishing; Reactive Oxygen Species; Reporting; Research; Rest; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Signal Transduction; Stress; System; TXN gene; Therapeutic; Tissues; Transcript; United States; Western Blotting; Work; Xenobiotics; acetaminophen overdose; base; experimental study; gut microbiome; gut microbiota; human disease; improved; insight; intestinal epithelium; liver injury; liver metabolism; metabolomics; microbiome; microbiome research; microorganism; mitochondrial membrane; mouse model; non-alcoholic; novel therapeutics; physical separation; programs; protective effect; response; transcription factor

Project Summary/Abstract The gut microbiome is composed of a diverse and dynamic community of microorganisms in the intestinal tract. Using germ-free model organisms, recent research has established the importance of these communities in performing key metabolic, endocrine, and immunologic processes in the host. The majority of this research has focused on the microbiome's effects on the intestine, the tissue with which it is in the most intimate contact. Recent studies, however, have revealed that these effects are significantly more far-reaching, with roles in hepatic, cardiovascular, and even neurological health. As the primary metabolic and detoxification hub, the liver is a critical checkpoint between the digestive functions of the gut and the rest of the body. Therefore, it is likely that alterations in the gut microbiota affect liver health and homeostasis. We utilized germ-free and microbiome-replete mice to investigate the effects of the gut microbiome on liver metabolism. Analysis of preliminary metabolomics data suggests significant alterations in hepatic metabolism, most notably in the antioxidant and xenobiotic detoxification pathways classically controlled by the transcription factor Nrf2. Activation of Nrf2 and its downstream pathways are cytoprotective against an array of oxidative liver insults, including drug-induced liver injuries such as acetaminophen-induced hepatotoxicity. To extend these findings beyond the artificial germ-free system, we propose to investigate the effect of microbiome manipulation on the activation and functionality of these critical detoxification pathways. Our group has previously shown that the widely studied probiotic Lactobacillus rhamnosus GG (LGG) can mediate protective effects in the intestine through activation of the Nrf2 pathway. Based on these observations, we hypothesize that LGG induces Nrf2 signaling in the liver and that this is protective against oxidative liver injury. The specific aims of this proposal are 1) to determine the extent of Nrf2 activation in the liver in response to LGG administration and 2) to identify the effect of oral LGG administration on the pathogenesis of oxidative liver injury using a mouse model of acetaminophen-induced hepatotoxicity. The long-term goal of this research is to understand the mechanisms by which probiotics and the microbiome contribute to host homeostasis and disease.

项目摘要/摘要 肠道微生物组由肠道中的微生物的多样化和动态群落组成 道。使用无菌模型生物，最近的研究确定了这些社区的重要性 在宿主中执行关键的代谢，内分泌和免疫过程。这项研究的大多数 已经集中在微生物组对肠的影响，该组织是最亲密的组织 接触。然而，最近的研究表明，这些影响明显更深远 在肝，心血管甚至神经系统健康中的作用。作为主要的代谢和解毒枢纽， 肝脏是肠道消化功能与身体其余部分之间的关​​键检查点。因此，它 肠道菌群的改变可能会影响肝脏健康和稳态。我们使用了无菌和 微生物组复发小鼠研究肠道微生物组对肝代谢的影响。分析 初步代谢组学数据表明，肝代谢发生了重大变化，尤其是在 由转录因子NRF2经典控制的抗氧化剂和异生元解毒途径。 NRF2及其下游途径的激活对一系列氧化肝损伤具有细胞保护作用， 包括药物诱导的肝损伤，例如对乙酰氨基酚诱导的肝毒性。扩展这些发现 除了无人工种系系统之外，我们建议研究微生物组操纵对 这些关键排毒途径的激活和功能。我们的小组以前已经表明 广泛研究的益生菌乳酸乳杆菌GG（LGG）可以介导肠中的保护作用 通过激活NRF2途径。基于这些观察结果，我们假设LGG诱导NRF2 肝脏中的信号传导，这是防止氧化肝损伤的保护作用。该提议的具体目的 1）确定响应LGG给药的NRF2激活程度和2） 口服LGG给药对使用小鼠模型的氧化肝损伤发病机理的影响 对乙酰氨基酚诱导的肝毒性。这项研究的长期目标是了解机制 益生菌和微生物组促成宿主的稳态和疾病。