白色念珠菌外毒素白念珠菌溶素促进酒精相关性肝病。
The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease.
机构信息
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.
出版信息
J Hepatol. 2020 Mar;72(3):391-400. doi: 10.1016/j.jhep.2019.09.029. Epub 2019 Oct 10.
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 β-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 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.
背景与目的
酒精相关性肝病是肝移植的主要适应证，也是主要的死亡原因。肠道微生物群的改变导致了酒精相关性肝病的发病机制。酒精相关性肝病患者的粪便真菌组中念珠菌属的比例增加，但肠道念珠菌对该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血素在酒精相关性肝病中的作用。
方法
分析了对照者、酒精使用障碍患者和酒精性肝炎患者粪便样本中的白色念珠菌和细胞伸长程度 1（ECE1）。用不同和遗传修饰的白色念珠菌菌株定植的小鼠接受慢性加 binge 乙醇饮食模型。分离原代肝细胞并与念珠菌溶血素孵育。
结果
非酒精性对照者、酒精使用障碍患者和酒精性肝炎患者中携带 ECE1 的个体比例分别为 0%、4.76%和 30.77%。念珠菌溶血素加重乙醇诱导的肝损伤，并与小鼠死亡率增加相关。念珠菌溶血素增强乙醇诱导的肝损伤不依赖于骨髓细胞上的β-葡聚糖受体 C 型凝集素家族 7 成员 A（CLEC7A），并且念珠菌溶血素不改变肠道屏障功能。在体外，念珠菌溶血素以剂量依赖的方式损伤原代肝细胞，并与酒精性肝炎患者的肝疾病严重程度和死亡率相关。
结论
念珠菌溶血素与临床前模型中乙醇诱导的肝疾病的进展以及酒精性肝炎患者的临床结局恶化相关。
要点总结
念珠菌溶血素是一种由肠道共生真菌白色念珠菌分泌的肽毒素。在不影响肠道通透性的情况下，念珠菌溶血素在小鼠的骨髓细胞上通过 β-葡聚糖受体 CLEC7A 以外的途径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，表明其在乙醇诱导的肝疾病中具有直接作用。念珠菌溶血素可能是治疗酒精相关性肝病的有效靶点。
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