Microbiome and intestinal innate immune response in alcoholic liver disease

酒精性肝病中的微生物组和肠道先天免疫反应

• 批准号: 9174353
• 负责人: Bernd G. Schnabl
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-25 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174353
• 关键词: Ablation; Affect; Agonist; Alcohol abuse; Alcohol dependence; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcoholic liver damage; Alcoholism; Alcohols; Animal Model; Bacteria; Bacterial Translocation; Bile Acid Biosynthesis Pathway; Bile Acids; Chronic; Cirrhosis; Country; Data; Defect; Developed Countries; Development; Diffusion; Disease; Distal part of ileum; Endotoxins; Enterohepatic Circulation; Epithelial Cells; Ethanol; Fatty Liver; Funding; Gastric Acid; Gastric Acid Secretion Inhibition; Genetic; Genomic DNA; Hepatic; Hepatocyte; Homeostasis; Host Defense; Hydrolase; Immune response; Intervention; Intestines; Laboratories; Lead; Lectin; Link; Lipopolysaccharides; Liver; Liver Cirrhosis; Liver diseases; Mediating; Medical; Metabolism; Metagenomics; Morbidity - disease rate; Mouse Strains; Mucous Membrane; Mus; Natural regeneration; Nature; Patients; Permeability; Preventive Intervention; Proteins; Proton Pump Inhibitors; Publications; Research; Role; Small Intestines; Steatohepatitis; System; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; United States; antimicrobial; base; chronic alcohol ingestion; defined contribution; design; feeding; gut microbiome; gut microbiota; human data; innovation; insight; islet; jejunum; metabolomics; metagenome; metagenomic sequencing; microbial; microbiome; microbiota; mortality; mouse model; novel; overexpression; prevent; problem drinker

Project Summary Alcohol abuse and alcohol-related diseases are a major medical burden in industrialized countries. Chronic alcoholism is associated with changes in the intestinal microbiome, increases in intestinal permeability, and elevated systemic levels of bacterial products. We have demonstrated quantitative (overgrowth) and qualitative dysbiotic changes in the intestinal microbiota in mouse models of chronic alcohol administration. A strong association exists between gut-derived bacterial products and progression of alcoholic liver diseases in several animal models, yet factors facilitating the onset of intestinal dysbiosis are unknown. Furthermore, how dysbiosis contributes to alcoholic liver disease beyond increasing intestinal permeability is also not known. Results from our laboratory suggest that suppression of gastric acid secretion and inhibition of the intestinal antimicrobial proteins regenerating-islet derived (Reg)-3b and Reg3g contribute to dysbiosis and liver disease following chronic ethanol feeding in mice. Furthermore, dysbiosis leads to deconjugation of intestinal bile acids in the proximal small intestine. Deconjugated bile acids are rapidly absorbed by nonionic diffusion in the jejunum, and a smaller amount of conjugated bile acids reaches the terminal ileum, which disrupts the enterohepatic circulation and results in increased hepatic bile acid synthesis. A larger bile acid pool contributes to more hepatocyte damage and alcoholic liver disease. The focus of this application is to characterize factors contributing to changes in the microbiota and to investigate how dysbiosis affects liver disease after chronic alcohol administration. We hypothesize that gastric acid suppression and alcohol-mediated inhibition of the antimicrobial Reg3 lectins modulate the intestinal microbiota. Dysbiosis in turn disrupts enterohepatic circulation of bile acids and increases the total bile acid pool, which enhances alcohol-induced liver damage. Our experimental approach is to use mouse models of chronic alcohol feeding to investigate the role of gastric acid in inducing intestinal dysbiosis and liver disease (Aim 1). We will also assess the functional contribution of the antimicrobial proteins Reg3b and Reg3g to changes in the microbiota composition, bacterial translocation and alcoholic liver disease (Aim 2). We will then determine the consequences of dysbiotic microbiome changes by focusing on bile acid metabolism (Aim 3). We believe these studies will provide novel insights into the contribution of the microbiota and its metabolites to alcoholic liver disease. New strategies will evolve to prevent or ameliorate alcoholic liver disease in patients.

项目摘要 酒精滥用和与酒精有关的疾病是工业化国家的主要医疗负担。慢性的 酒精中毒与肠道微生物组的变化有关，肠道通透性增加和 细菌产物的全身水平升高。我们已经证明了定量（过度生长）和定性 在慢性酒精给药的小鼠模型中，肠道菌群的不植物变化。强壮 肠道衍生的细菌产物与几种酒精性肝病的进展之间存在关联 动物模型，但促进肠道营养不良发作的因素尚不清楚。此外，如何 营养不良导致酒精性肝病超出肠道渗透性的增加，这也不为人所知。 我们实验室的结果表明，抑制胃酸分泌和抑制肠道 衍生的抗菌蛋白再生胚胎（REG）-3B和REG3G有助于营养不良和肝病 慢性乙醇在小鼠中进食。此外，营养不良会导致肠胆汁酸解偶 在近端小肠中。非离子扩散迅速地吸收了散布的胆汁酸 空肠，少量共轭胆汁酸到达末端回肠，这破坏了 肠肝循环并导致肝胆酸合成增加。较大的胆汁酸池有助于 更多的肝细胞损伤和酒精性肝病。该应用的重点是表征因素 导致微生物群的变化，并研究慢性病后营养不良如何影响肝病 酒精管理。我们假设胃酸抑制和酒精介导的抑制 抗菌reg3凝集素调节肠菌群。营养不良反过来破坏肠肝 胆汁酸的循环并增加了总胆汁酸池，从而增强了酒精诱导的肝脏损伤。 我们的实验方法是使用慢性酒精喂养的小鼠模型来研究胃的作用 酸诱导肠道营养不良和肝病（AIM 1）。我们还将评估 抗菌蛋白Reg3b和Reg3g对微生物群的变化，细菌易位 和酒精性肝病（AIM 2）。然后，我们将确定不植物微生物组变化的后果 通过专注于胆汁酸代谢（AIM 3）。我们认为这些研究将为您提供新颖的见解 微生物群及其代谢物对酒精性肝病的贡献。新策略将发展为 预防或改善患者的酒精性肝病。