The Candida albicans exotoxin Candidalysin promotes alcohol-associated liver disease,Journal of Hepatology

当前位置： X-MOL 学术 › J. Hepatol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

The Candida albicans exotoxin Candidalysin promotes alcohol-associated liver disease
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-03-01 , DOI: 10.1016/j.jhep.2019.09.029
Huikuan Chu ₁ , Yi Duan ₂ , Sonja Lang ₃ , Lu Jiang ₂ , Yanhan Wang ₂ , Cristina Llorente ₂ , Jinyuan Liu ₄ , Selene Mogavero ₅ , Francisco Bosques-Padilla ₆ , Juan G Abraldes ₇ , Victor Vargas ₈ , Xin M Tu ₄ , Ling Yang ₉ , Xiaohua Hou ₉ , Bernhard Hube ₁₀ , Peter Stärkel ₁₁ , Bernd Schnabl ₂

Affiliation

Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany.
Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada.
Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany; Institute of Microbiology, Friedrich-Schiller-University, Jena, Germany.
St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.

BACKGROUND AND AIMS Alcohol-associated liver disease is a leading indication for liver transplantation and leading cause of mortality. Alterations of the gut microbiota contribute to pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome. However, little is known about the effect of intestinal Candida on alcohol-associated liver disease. Here we evaluated the contributions of Candida albicans and its exotoxin Candidalysin on alcoholic liver disease. METHODS C. albicans and ECE1 were analyzed in fecal samples from controls, patients with alcohol use disorder and alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with Candidalysin. RESULTS The percentages of subjects carrying ECE1 are 0%, 4.76% and 30.77% in non-alcoholic controls, alcohol use disorder patients and alcoholic hepatitis patients, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independent of the β-glucan receptor CLEC7A on bone-marrow derived cells, and Candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. CONCLUSIONS Candidalysin is associated with progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis. LAY SUMMARY Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independent of the β-glucan receptor CLEC7A on bone-marrow derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of Candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.

中文翻译：

白色念珠菌外毒素念珠菌溶血素促进酒精相关性肝病

背景和目的酒精相关性肝病是肝移植的主要适应症和死亡的主要原因。肠道微生物群的改变有助于酒精相关性肝病的发病机制。酒精相关性肝病患者的念珠菌比例增加。在粪便菌群中。然而，关于肠道念珠菌对酒精相关性肝病的影响知之甚少。在这里，我们评估了白色念珠菌及其外毒素念珠菌溶血素对酒精性肝病的贡献。方法对对照组、酒精使用障碍患者和酒精性肝炎患者的粪便样本中的白色念珠菌和 ECE1 进行分析。用不同的和基因操作的白色念珠菌菌株定殖的小鼠接受慢性加暴食乙醇饮食模型。分离原代肝细胞并与念珠菌素一起孵育。结果在非酒精性对照、酒精使用障碍患者和酒精性肝炎患者中，携带ECE1的受试者的百分比分别为0%、4.76%和30.77%。念珠菌素会加剧乙醇引起的肝病，并与小鼠死亡率增加有关。念珠菌素可增强乙醇诱导的肝病，而与骨髓衍生细胞上的 β-葡聚糖受体 CLEC7A 无关，并且念珠菌素不会改变肠道屏障功能。念珠菌素可以在体外以剂量依赖性方式损伤原代肝细胞，并且与酒精性肝炎患者的肝病严重程度和死亡率有关。结论念珠菌素与酒精性肝炎患者临床前模型中乙醇诱导的肝病的进展和较差的临床结果相关。概述念珠菌溶素是一种由共生肠道真菌白色念珠菌分泌的肽毒素。念珠菌溶素可增强酒精相关性肝病，不依赖于小鼠骨髓衍生细胞上的 β-葡聚糖受体 CLEC7A，而不会影响肠道通透性。念珠菌素对原代肝细胞具有细胞毒性，表明念珠菌素对乙醇诱导的肝病有直接作用。念珠菌溶素可能是治疗酒精相关性肝病患者的有效靶点。念珠菌溶素可增强酒精相关性肝病，不依赖于小鼠骨髓衍生细胞上的 β-葡聚糖受体 CLEC7A，而不会影响肠道通透性。念珠菌素对原代肝细胞具有细胞毒性，表明念珠菌素对乙醇诱导的肝病有直接作用。念珠菌溶素可能是治疗酒精相关性肝病患者的有效靶点。念珠菌溶素可增强酒精相关性肝病，不依赖于小鼠骨髓衍生细胞上的 β-葡聚糖受体 CLEC7A，而不会影响肠道通透性。念珠菌素对原代肝细胞具有细胞毒性，表明念珠菌素对乙醇诱导的肝病有直接作用。念珠菌溶素可能是治疗酒精相关性肝病患者的有效靶点。

更新日期：2020-03-01

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11