The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease
The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease
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DOI：
10.1016/j.jhep.2019.09.029
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发表时间：
2020-03-01
影响因子：
25.7
通讯作者：
Schnabl, Bernd
中科院分区：
文献类型：
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作者：
Chu, Huikuan;Duan, Yi;Schnabl, Bernd
背景与目的：酒精相关性肝病是肝移植的主要指征，也是死亡的主要原因。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。在粪便真菌群落中，但对肠道念珠菌对疾病的影响知之甚少。在此，我们评估了白色念珠菌及其外毒素念珠菌溶素在酒精相关性肝病中的作用。在来自对照、酒精使用障碍患者和酒精性肝炎患者的粪便样品中分析白色念珠菌和细胞伸长程度1（ECE 1）。用不同的和基因操纵的C.对白色念珠菌菌株进行慢性加酗酒乙醇饮食模型。结果：非酒精性对照组、酒精使用障碍组和酒精性肝炎组的ECE 1阳性率分别为0%、4.76%和30.77%。甘草甜素加重乙醇诱导的肝脏疾病，并与小鼠死亡率增加有关。白念珠菌溶血素增强乙醇诱导的肝脏疾病，与骨髓源性细胞上β-葡聚糖受体C型凝集素结构域家族7成员A（CLEC 7A）无关，而白念珠菌溶血素不改变肠道屏障功能。在体外，依地酸能以剂量依赖的方式损伤原代肝细胞，并与酒精性hepatitis.Conclusions：依地酸与酒精性hepatitis.Lay summary：依地酸是一种由肠道真菌白色念珠菌分泌的肽毒素。在不影响肠通透性的情况下，拟南芥素独立于小鼠骨髓源性细胞上的β-葡聚糖受体CLEC 7A增强酒精相关性肝病念珠菌溶血素对原代肝细胞具有细胞毒性，表明念珠菌溶血素对乙醇诱导的肝病具有直接作用。甘草甜素可能是治疗酒精相关性肝病的有效靶点。由Elsevier B. V.代表欧洲肝脏研究协会发表。
Background & Aims: Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease.Methods: C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with 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 individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the beta-glucan receptor C-type lectin domain family 7 member A (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 the 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 independently of the beta-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. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.