The Role of the Intestinal Mycobiome in Alcoholic Liver Disease

肠道菌群在酒精性肝病中的作用

基本信息

批准号：
10652248
负责人：
Bernd G. Schnabl
金额：
$ 49.93万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652248
关键词：
Adoptive Transfer Affect Alcohol abuse Alcoholic Liver Diseases Alcoholism Alcohols Antifungal Agents Antigens Bacteria Belgium Binding CD4 Positive T Lymphocytes California Candida Candida albicans Cells Chronic Circulation Data Developed Countries Disease Ethanol Etiology Experimental Animal Model Functional disorder Genetic Transcription Germany Glucans Goals Growth Health Hepatic Human IL17 gene Immune response Immunity Infrastructure Interdisciplinary Study Intervention Intestinal permeability Intestines Kupffer Cells Laboratories Ligation Liver Liver diseases Macrophage Malassezia Mediating Medical Methods Molecular Morbidity - disease rate Mus Natural Immunity Nature Patients Persons Population Portal vein structure Principal Investigator Publications Research Research Personnel Ribosomal DNA Role Steatohepatitis Supplementation T cell response T-Cell Receptor Testing Therapeutic Intervention Transgenic Mice United States Universities University Hospitals Virulence Factors Virus adaptive immunity alcohol response alcohol use disorder bacteriome cohort design dysbiosis feeding fungal microbiota fungus gut microbiome gut-liver axis innovation insight liver inflammation liver injury microbial microbiome research microbiome sequencing microbiota migration mortality mouse dectin-2 mouse model mycobiome new therapeutic target novel pharmacologic prevent preventive intervention receptor

项目摘要

Project Summary Alcohol associated health problems are a major medical burden in industrialized countries. Patients with alcohol-associated liver disease show intestinal bacterial dysbiosis and increased intestinal permeability. Although there is considerable progress in understanding the interaction between the host and intestinal bacteria, the role of the intestinal fungal microbiome (also called mycobiome) in alcohol-associated liver disease is not very well understood. Results from our laboratories indicate a proportional increase of Candida albicans (C. albicans) and Malassezia restricta (M. restricta) in patients with alcohol use disorder. Results from chronic ethanol administration in mice or chronic alcohol abuse in patients show that C. albicans-specific T cell responses occur in the intestine. CD4+ T cells re-circulate to the liver, where they re-activate by translocated C. albicans antigens, produce interleukin 17 (IL17) and contribute to progression of ethanol-induced steatohepatitis. In addition, products from M. restricta translocate from the gut lumen to the systemic circulation and liver. M. restricta induces liver inflammation via ligation with the Dectin-2 (Clec4n) receptor on Kupffer cells and augments ethanol-induced liver disease in mice. The testable central hypothesis of this proposed collaborative and multidisciplinary research application implicates disturbances in the gut fungal mycobiota as an important etiological factor in the modulation of adaptive and innate immunity in the liver. Through the proposed study, we will characterize the host gut mycobiome and immune response in a human cohort. We will mechanistically test our hypothesis in a mouse model of ethanol-induced liver disease. Towards this goal, we will use pharmacological interventions, supplementation of fungi and genetically modified mice. We predict that two pathogenic factors contribute to dysfunction of the gut-liver axis in alcohol-associated liver disease: C. albicans overgrowth drives Th17 cell expansion contributing to liver inflammation and damage (Aim 1). Binding of M. restricta to Dectin-2 induces hepatic inflammation and exacerbates alcohol-associated liver disease (Aim 2). We believe these studies will provide important insights into alcohol-mediated changes of the intestinal mycobiome that result in an immune response contributing to alcohol-associated liver disease. Eventually this approach might lead to new therapeutic targets for patients with alcohol-associated liver disease.

项目概要与酒精相关的健康问题是工业化国家的主要医疗负担。患者患有酒精相关的肝病表现出肠道细菌失调和肠道通透性增加。尽管在理解宿主和肠道之间的相互作用方面取得了相当大的进展细菌，肠道真菌微生物组（也称为真菌组）在酒精相关肝脏中的作用对这种疾病还不是很了解。我们实验室的结果表明，酒精使用障碍患者的白色念珠菌（C. albicans）和限制马拉色菌（M. limita）。小鼠长期服用乙醇或患者长期酗酒的结果表明白色念珠菌特异性 T 细胞反应发生在肠道中。 CD4+ T 细胞再循环至肝脏，在那里它们通过易位的白色念珠菌抗原重新激活，产生白细胞介素 17 (IL17) 并促进进展乙醇诱发的脂肪性肝炎。此外，M. limita 的产物从肠腔易位至体循环和肝脏。 M. limita 通过与 Dectin-2 连接诱导肝脏炎症库普弗细胞上的 (Clec4n) 受体会加重小鼠乙醇诱导的肝病。可测试的中央这项拟议的协作和多学科研究应用的假设涉及干扰在肠道真菌菌群中作为调节适应性和先天性的重要病因肝脏的免疫力。通过拟议的研究，我们将描述宿主肠道真菌组的特征，并人类群体中的免疫反应。我们将在小鼠模型中机械地检验我们的假设乙醇诱发的肝病。为了实现这一目标，我们将使用药物干预措施，补充真菌和转基因小鼠。我们预测有两个致病因素酒精相关性肝病中肠肝轴功能障碍：白色念珠菌过度生长驱动 Th17 细胞扩张导致肝脏炎症和损伤（目标 1）。 M. limita 与 Dectin-2 的结合诱导肝脏炎症并加剧酒精相关的肝病（目标 2）。我们相信这些研究将为酒精介导的肠道菌群变化提供重要的见解，从而导致免疫反应导致酒精相关性肝病。最终这种方法可能会导致酒精相关性肝病患者的新治疗靶点。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease.

小代谢物，可能发生大变化：以微生物群为中心的非酒精性脂肪肝疾病观点。

DOI：
发表时间：
2019-02
期刊：
影响因子：
24.5
作者：
Chu, Huikuan;Duan, Yi;Yang, Ling;Schnabl, Bernd
通讯作者：
Schnabl, Bernd

Targeting pathobionts for the treatment of alcohol-associated liver disease.

针对病原体治疗酒精相关性肝病。

DOI：
发表时间：
2021-01
期刊：
影响因子：
0
作者：
Lang, Sonja;Demir, Münevver;Schnabl, Bernd
通讯作者：
Schnabl, Bernd

Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice.

在肠道中产生 IL-22 的细菌可诱导 REG3G 表达，从而减少小鼠乙醇诱导的肝病。

DOI：
发表时间：
2019-08
期刊：
影响因子：
24.5
作者：
Hendrikx, Tim;Duan, Yi;Wang, Yanhan;Oh, Jee;Alexander, Laura M;Huang, Wendy;Stärkel, Peter;Ho, Samuel B;Gao, Bei;Fiehn, Oliver;Emond, Patrick;Sokol, Harry;van Pijkeren, Jan;Schnabl, Bernd
通讯作者：
Schnabl, Bernd

Indoles: metabolites produced by intestinal bacteria capable of controlling liver disease manifestation.

吲哚：肠道细菌产生的代谢物，能够控制肝脏疾病的表现。