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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要肝脏现在被认为是具有独特特性的免疫器官，其免疫反应是紧密的。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然而，某些危险因素会导致肝脏免疫失调，从而导致肝损伤。高脂肪和高糖饮食（HFS）是典型的西式饮食（WD）。被确定为导致非酒精性脂肪性肝病（NAFLD）发展的主要危险因素，从简单的脂肪变性到晚期的非酒精性脂肪性肝炎（NASH）。随着全球范围内的变化，NAFLD 正迅速成为肝病的主要原因，影响了 25% 的人越来越多的证据表明，HFS 和肠道微生物群的相互作用会产生可能诱发肝功能异常的膳食和微生物成分以及结果代谢物的范围免疫激活，表明饮食/肠道/肝脏/免疫轴在 NASH 中发挥着关键作用。此外，人们对具体的微生物和机制知之甚少。为了解决这些主要的知识空白，研究人员研究了调节肝内免疫的代谢物。通过用低胆碱 HFS (CL-HFS)（0.05% 胆碱）喂养野生型小鼠，开发了 NASH 模型该模型的组成与典型的 WD 非常相似，其特点是肠道菌群失调，代谢紊乱、肝脏免疫反应异常、肝脏驻留巨噬细胞 (MΦ) 和肝脏星状细胞 (HSC) 激活，反映了人类 NASH 患者的典型病理特征。研究人员证明，选择性抑制肠道微生物群可以预防和治疗结合体外和体内宏基因组和代谢组分析抑制 CL-HFS 诱导的 NASH。体内实验鉴定出 Blautiaproducta (B.producta) 及其产物 2-油酰甘油 (2-OG) 是一种未识别的细菌和代谢物导致 CL-HFS 诱导的异常肝脏免疫反应。具有特殊临床意义的是，在人类体内发现了肠道 Blautia 的富集和肝脏 2-OG 的高水平 NASH 患者的机制研究表明 2-OG 通过 G 蛋白偶联受体 119 启动 MΦs。这些令人兴奋的结果支持了以下假设：CL-HFS，B.producta，和2-OG通过GPR119信号通路激活MΦs，引起肝脏发病和HSC 该假设将在以下目标中得到检验：目标 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 和肝脏之间的相互作用；目标 2：确定 GPR119 作为 MΦ 介导 CL-HFS 诱导的肝脏发病机制的分子基础，B. 产品和 2-OG 本研究将剖析推动该研究的潜在细胞和分子机制。了解饮食-肠-肝轴在肝脏免疫中的作用，这将促进肝脏免疫的发展饮食和微生物干预措施可有效抑制这一全球健康威胁。