Mechanisms of gut microbiota/metabolite interface-mediated hepatic inflammation

肠道微生物群/代谢物界面介导的肝脏炎症机制

• 批准号: 10678944
• 负责人: Guangfu Li
• 金额: $ 39.45万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678944
• 关键词: Address; Advanced Development; Affect; Agonist; Antibiotics; Bacteria; Choline; Choline Deficiency; Data; Development; Diet; Drug Metabolic Detoxication; Ensure; Fatty acid glycerol esters; G-Protein-Coupled Receptors; Hepatic; Hepatic Stellate Cell; High Fat Diet; Human; Imipenem; Immune; Immune Tolerance; Immune response; Immunity; Immunologics; In Vitro; Infiltration; Inflammation; Inflammatory; Knowledge; Kupffer Cells; Lipase; Lipids; Liver; Liver Cirrhosis; Liver diseases; Macrophage; Malignant neoplasm of liver; Mediating; Mediation; Mediator; Metabolic; Metagenomics; Microbe; Modeling; Molecular; Mus; Neomycin; Nutrient; Organ; Outcome; Pathogenesis; Pathologic; Patients; Phenotype; Population; Portal vein structure; Positioning Attribute; Preventive; Production; Proliferating; Property; Reaction; Research Personnel; Risk Factors; Role; Shapes; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; Therapeutic Intervention; Vancomycin; Wild Type Mouse; clinically relevant; commensal bacteria; cytokine; dietary; dysbiosis; experimental study; feeding; global health; gut dysbiosis; gut microbiota; gut-liver axis; immune activation; in vivo; intrahepatic; intravenous administration; liver development; liver inflammation; metabolomics; microbial; monocyte; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; response; simple steatosis; sugar; treatment response; western diet

Project Summary/Abstract The liver is now recognized as an immunological organ with unique properties. Its immune response is tightly controlled to ensure immune tolerance to microbial, dietary, and metabolic products flowing from gut to liver through the portal vein. However, certain risk factors induce hepatic immune dysregulation, resulting in the development of liver disease. A high-fat and high-sugar diet (HFS), a typical Western-type diet (WD), is identified as a major risk factor contributing to the development of nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH). Given dietary changes worldwide, NAFLD is rapidly becoming the leading cause of liver disease affecting 25% of the population worldwide. Mounting evidence indicates that the HFS and gut microbiota interaction generates a spectrum of dietary and microbial components and outcome metabolites that can induce inappropriate hepatic immune activation, suggesting a key role of the Diet/Gut/Liver/Immune axis in NASH . However, the underlying mechanisms are poorly understood. Furthermore, very little is known about the specific microbes and metabolites that regulate intrahepatic immunity. To address these major knowledge gaps, the investigators have developed a NASH model by feeding wild-type mice with a choline-low HFS (CL-HFS) (0.05% choline) which closely approximates a typical WD in composition. This model is characterized by gut dysbiosis, metabolic disarray, abnormal hepatic immune response, and liver-resident macrophage (MΦ) and hepatic stellate cell (HSC) activation, reflecting typical pathologic properties in human NASH patients. Using the model, the investigators demonstrate that selective suppression of gut microbiota preventively and therapeutically inhibits CL-HFS-induced NASH. Metagenomic and metabolomic analyses in combination with in vitro and in vivo experiments identified Blautia producta (B. producta) and its product 2-oleoyglycerol (2-OG) as an unrecognized bacterium and metabolite contributing to CL-HFS-induced abnormal hepatic immune response. Of particular clinical relevance, enrichment of gut Blautia and high levels of hepatic 2-OG are found in human NASH patients. Mechanistic studies suggest that 2-OG primes MΦs via G protein-coupled receptor 119 signaling, subsequently activating HSCs. These exciting results support the hypothesis: CL-HFS, B. producta, and 2-OG, by activating MΦs through GPR119 signaling pathways, cause hepatic pathogenesis and HSC activation. This hypothesis will be tested in the following Aims: Aim 1: Determine MΦ as a cellular basis of CL- HFS-induced NASH pathogenesis mediating crosstalk between gut microbiota, HFS, and liver; Aim 2: Determine GPR119 as a molecular basis of MΦ mediating hepatic pathogenesis induced by CL-HFS, B. product, and 2-OG. This study will dissect the underlying cellular and molecular mechanisms to advance the understanding of the role of the Diet-Gut-Liver axis in hepatic immunity, which will advance the development of dietary and microbial interventions that therapeutically suppress this global health threat.

项目总结/摘要 肝脏现在被认为是具有独特性质的免疫器官。它的免疫反应 控制以确保对从肠道流向肝脏的微生物、饮食和代谢产物的免疫耐受性 通过门静脉然而，某些危险因素诱导肝脏免疫失调，导致肝脏免疫功能低下。 肝病的发展。高脂高糖饮食（HFS）是一种典型的西式饮食（WD）， 被认为是导致非酒精性脂肪性肝病（NAFLD）发展的主要风险因素， 范围从简单的脂肪变性到非酒精性脂肪性肝炎（NASH）的晚期形式。给定膳食 随着世界范围内的变化，NAFLD正在迅速成为影响25%的美国人的肝脏疾病的主要原因。 全球人口。越来越多的证据表明，HFS和肠道微生物群的相互作用产生了一种新的机制。 可能引起不适当肝损害的饮食和微生物成分以及结果代谢物的谱 免疫激活，表明饮食/肠道/肝脏/免疫轴在NASH中的关键作用。但是，底层 机制知之甚少。此外，人们对特定的微生物知之甚少， 调节肝内免疫的代谢物。为了解决这些主要的知识差距，研究人员 通过用低胆碱HFS（CL-HFS）（0.05%胆碱）喂养野生型小鼠， 其在组成上非常接近典型的WD。该模型的特征在于肠道生态失调， 代谢紊乱、肝脏免疫应答异常、肝脏巨噬细胞（MΦ）和肝脏 星状细胞（HSC）活化，反映了人类NASH患者的典型病理性质。使用该模型， 研究人员证明，选择性抑制肠道微生物群的预防和治疗， 抑制CL-HFS诱导的NASH。宏基因组学和代谢组学分析结合体外和体内 体内实验鉴定了Blautia producta（B. producta）及其产物2-油酰甘油（2-OG）作为 导致CL-HFS诱导的异常肝脏免疫应答的未识别细菌和代谢物。 特别具有临床意义的是，在人类中发现了肠道布劳特氏菌的富集和高水平的肝脏2-OG NASH患者。机制研究表明2-OG通过G蛋白偶联受体119启动MΦs 信号传导，随后激活HSC。这些令人兴奋的结果支持了CL-HFS，B的假说。产品a， 2-OG通过GPR 119信号通路激活MΦs，引起肝损伤和HSC activation.该假设将在以下目的中进行检验：目的1：确定MΦ作为CL的细胞基础。 HFS诱导的NASH发病机制介导肠道微生物群、HFS和肝脏之间的串扰;目的2： 确定GPR 119是MΦ介导CL-HFS，B肝损伤的分子基础。 产品和2-OG。这项研究将剖析潜在的细胞和分子机制，以促进 了解饮食-肠道-肝脏轴在肝脏免疫中的作用，这将促进 饮食和微生物干预，治疗抑制这一全球健康威胁。