Regulation of oxidative liver injury by the probiotic Lactobacillus rhamnosus GG

项目总结/摘要 肠道微生物组由肠道中多样化和动态的微生物群落组成 道。利用无菌模式生物，最近的研究已经确定了这些社区的重要性 在宿主体内进行关键的代谢、内分泌和免疫过程。这项研究的大部分 一直专注于微生物组对肠道的影响，肠道是与微生物组最亲密的组织。 contact.然而，最近的研究表明，这些影响更为深远， 在肝脏、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中心， 肝脏是肠道消化功能和身体其他部分之间的关键检查点。因此 肠道微生物群的改变可能会影响肝脏健康和体内平衡。我们使用无菌的， 微生物组充满小鼠，以研究肠道微生物组对肝脏代谢的影响。分析 初步的代谢组学数据表明，肝脏代谢发生了显著变化，最明显的是 抗氧化剂和异生物质解毒途径经典地由转录因子Nrf 2控制。 Nrf 2及其下游通路的激活对一系列氧化性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。为了扩展这些发现 在人工无菌系统之外，我们建议研究微生物组操作对 这些关键的解毒途径的激活和功能。我们的小组先前已经表明， 广泛研究的益生菌鼠李糖乳杆菌GG（LGG）可以介导肠道保护作用 通过激活Nrf 2通路。基于这些观察，我们假设LGG诱导Nrf 2 这是一种保护肝脏免受氧化性肝损伤的机制。本提案的具体目标 是1）确定响应LGG给药的肝脏中Nrf 2活化的程度和2）鉴定 口服LGG给药对氧化性肝损伤发病机制的影响， 对乙酰氨基酚诱导的肝毒性。这项研究的长期目标是了解 益生菌和微生物组通过其促进宿主体内平衡和疾病。

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.