The Role of the Intestinal Mycobiome in Alcoholic Liver Disease

肠道菌群在酒精性肝病中的作用

• 批准号: 10296622
• 负责人: Bernd G. Schnabl
• 金额: $ 54.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10296622
• 关键词: Adoptive Transfer; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcoholism; Alcohols; Animal Model; Antifungal Agents; Antigens; Bacteria; Belgium; Binding; Blood Circulation; CD4 Positive T Lymphocytes; California; Candida; Candida albicans; Cells; Chronic; Data; Developed Countries; Disease; Ethanol; Etiology; Experimental Animal Model; Functional disorder; Germany; Goals; Health; Hepatic; Human; Immune response; Immunity; Infrastructure; Institutes; Interdisciplinary Study; Interleukin-17; Intervention; Intestinal permeability; Intestines; Kupffer Cells; Laboratories; Lead; Ligation; Liver; Liver diseases; Malassezia; Mediating; Medical; Methods; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Nature; Patients; Persons; Pharmacology; Portal vein structure; Principal Investigator; 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; base; cohort; design; dysbiosis; feeding; fungal microbiota; fungus; gut microbiome; gut-liver axis; innovation; insight; liver inflammation; liver injury; macrophage; microbial; microbiome research; microbiome sequencing; microbiota; migration; mortality; mouse dectin-2; mouse model; mycobiome; new therapeutic target; novel; prevent; preventive intervention; receptor

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.

项目摘要 酒精相关的健康问题是工业化国家的主要医疗负担。患者 酒精相关的肝病显示肠道细菌营养不良，肠道通透性增加。 尽管在理解宿主与肠之间的相互作用方面取得了很大进展 细菌，肠道真菌微生物组（也称为Mycobiome）在酒精相关的肝脏中的作用 疾病不是很好的理解。我们实验室的结果表明比例增加 酒精使用障碍患者的白色念珠菌（白色念珠菌）和马拉西亚限制性（M. dristricta）。 小鼠慢性乙醇给药或患者慢性酒精滥用的结果表明 白色念珠菌特异性T细胞反应发生在肠中。 CD4+ T细胞重新传输到肝脏，在那里它们 通过易位的白色念珠菌抗原重新激活，产生白介素17（IL17），并有助于进展 乙醇诱导的脂肪性肝炎。此外，M. dristricta的产品从肠道内流动到 全身循环和肝脏。 M. Dristricta通过与Dectin-2结扎诱导肝脏炎症 （CLEC4N）库普弗细胞上的受体并增强了乙醇诱导的小鼠肝病。可测试的中央 该提出的合作和多学科研究应用程序的假设暗示了干扰 在肠道真菌菌根中，作为自适应和先天性调制的重要病因学因素 肝脏的免疫力。通过拟议的研究，我们将表征宿主的肠道菌组合和 人类队列中的免疫反应。我们将在小鼠模型中机械地检验我们的假设 乙醇诱导的肝病。为了实现这一目标，我们将使用药理学干预措施， 补充真菌和转基因小鼠。我们预测两个病原因素有助于 酒精相关肝病中肠道轴功能障碍：白色念珠菌过度生长驱动Th17细胞 膨胀导致肝脏炎症和损伤（AIM 1）。 M.限制与Dectin-2的结合诱导 肝炎并加剧与酒精相关的肝病（AIM 2）。我们相信这些研究 将为酒精介导的肠道菌物的变化提供重要的见解，从而导致 免疫反应导致与酒精相关的肝病。最终，这种方法可能会导致 针对酒精相关肝病患者的新治疗靶标。