小柯机器人

靶向肠道细菌的噬菌体可减轻酒精性肝
2019-11-14 14:43

美国加州大学圣地亚哥分校Bernd Schnabl团队的研究发现,靶向肠道细菌的噬菌体可减轻酒精性肝疾病。该项研究成果2019年11月13日在线发表于《自然》。

研究人员确定了溶细胞素(一种由粪肠球菌分泌的二亚基外毒素)是引起肝细胞死亡和肝损伤的原因。

与非酒精性个体或酒精使用障碍患者相比,酒精性肝炎患者的粪便肠球菌数量有所增加。溶细胞素阳性(溶细胞性)粪肠球菌的存在与酒精性肝炎患者的肝病严重程度和死亡率相关。研究人员使用被酒精性肝炎患者粪便细菌定植的人源化小鼠,研究了靶向溶细胞性粪肠球菌的噬菌体的治疗效果。研究人员发现这些噬菌体在人源化小鼠中减少了肝脏中的溶细胞素并消除了乙醇诱导的肝病。这些发现将酒精性肝炎患者的粪便溶解性大肠杆菌与更严重的临床结局和死亡率增加联系起来。因此,噬菌体可以专门针对溶细胞的屎肠球菌,这提供了一种精确编辑肠道菌群的方法。目前仍需要进行更大范围研究的临床试验,以验证这些发现与人类的相关性,并测试这种治疗方法对酒精性肝炎患者是否有效。

据介绍,饮酒障碍引起的慢性肝病明显加重了疾病和死亡率的全球负担。酒精性肝炎是一种严重且威胁生命的酒精相关性肝病。肠道菌群可促进乙醇诱发的小鼠肝脏疾病,但对导致这一过程的微生物因子知之甚少。

附:英文原文

Title: Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

Author: Yi Duan, Cristina Llorente, Sonja Lang, Katharina Brandl, Huikuan Chu, Lu Jiang, Richard C. White, Thomas H. Clarke, Kevin Nguyen, Manolito Torralba, Yan Shao, Jinyuan Liu, Adriana Hernandez-Morales, Lauren Lessor, Imran R. Rahman, Yukiko Miyamoto, Melissa Ly, Bei Gao, Weizhong Sun, Roman Kiesel, Felix Hutmacher, Suhan Lee, Meritxell Ventura-Cots, Francisco Bosques-Padilla, Elizabeth C. Verna, Juan G. Abraldes, Robert S. Brown, Victor Vargas, Jose Altamirano, Juan Caballera, Debbie L. Shawcross, Samuel B. Ho, Alexandre Louvet, Michael R. Lucey, Philippe Mathurin, Guadalupe Garcia-Tsao, Ramon Bataller, Xin M. Tu, Lars Eckmann, Wilfred A. van der Donk, Ry Young, Trevor D. Lawley, Peter Strkel, David Pride, Derrick E. Fouts, Bernd Schnabl

Issue&Volume: 2019-11-13

Abstract: Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality13. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysina two-subunit exotoxin that is secreted by Enterococcus faecalis5,6as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis. In patients with alcoholic hepatitis, cytolysin-positive Enterococcus faecalis strains are correlated with liver disease severity and increased mortality, and in mouse models these strains can be specifically targeted by bacteriophages.

DOI: 10.1038/s41586-019-1742-x

Source:https://www.nature.com/articles/s41586-019-1742-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0