The Role of the Intestinal Mycobiome in Alcoholic 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 酒精相关性肝病显示肠道细菌生态失调和肠道通透性增加。 虽然在理解宿主和肠道之间的相互作用方面有了相当大的进展， 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 疾病还不是很清楚。我们实验室的结果表明， 白色念珠菌（C. albicans）和限制马拉色菌（Malassezia restricta）（M. restricta）在酒精使用障碍患者中。 小鼠长期服用乙醇或患者长期滥用酒精的结果表明， C.白色念珠菌特异性T细胞应答发生在肠中。CD 4 + T细胞再循环到肝脏， 通过易位的C.白念珠菌抗原，产生白细胞介素17（IL 17），并有助于进展 酒精引起的脂肪性肝炎此外，M. restricta从肠腔转移到 体循环和肝脏。M. restricta通过与Dectin-2连接诱导肝脏炎症 Kupffer细胞上的Clec 4 n受体并增强小鼠乙醇诱导的肝病。可测试中心 这一提议的协作和多学科研究应用的假设暗示了干扰 在肠道真菌菌群作为一个重要的致病因素，在适应性和先天性的调制 肝脏的免疫力。通过拟议的研究，我们将表征宿主肠道真菌生物群， 免疫应答的研究。我们将在一个小鼠模型中机械地测试我们的假设。 酒精引起的肝病为了实现这一目标，我们将使用药物干预， 真菌和转基因小鼠的补充。我们预测有两种致病因素导致 酒精相关性肝病中肠-肝轴功能障碍：C.白色念珠菌过度生长驱动Th 17细胞 导致肝脏炎症和损伤的扩张（目的1）。M的结合。对Dectin-2的限制诱导 肝脏炎症并加重酒精相关性肝病（目的2）。我们相信这些研究 将为酒精介导的肠道真菌群变化提供重要的见解， 导致酒精相关性肝病的免疫反应。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。

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.