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Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

机译：靶向噬菌体的肠道细菌可减轻酒精性肝病

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摘要

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality(1-3). Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice(4), but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis(5,6)-as 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.
机译：饮酒障碍导致的慢性肝病显着加重了疾病和​​死亡率的总体负担（1-3）。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（4），但对造成这一过程的微生物因子知之甚少。在这里，我们确定溶胞素-粪肠球菌（5,6）分泌的两个亚基外毒素是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。我们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。我们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。我们的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。我们表明，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。需要进行较大规模的临床试验，以验证我们的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。

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  • 来源
    《Nature》 |2019年第7783期|505-511|共7页
  • 作者

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

  • 作者单位

    Univ Calif San Diego Dept Med La Jolla CA 92093 USA|VA San Diego Healthcare Syst Dept Med San Diego CA 92161 USA;

    Univ Calif San Diego Dept Med La Jolla CA 92093 USA;

    Univ Calif San Diego Skaggs Sch Pharm & Pharmaceut Sci La Jolla CA 92093 USA;

    J Craig Venter Inst Rockville MD USA;

    J Craig Venter Inst La Jolla CA USA;

    Wellcome Sanger Inst Host Microbiota Interact Lab Hinxton England;

    Univ Calif San Diego Dept Family Med & Publ Hlth Div Biostat & Bioinformat La Jolla CA 92093 USA;

    Texas A&M Univ Dept Biochem & Biophys College Stn TX 77843 USA;

    Texas A&M AgriLife Res Ctr Phage Technol College Stn TX USA|Texas A&M Univ College Stn TX USA;

    Univ Illinois Dept Biochem Urbana IL USA;

    Univ Calif San Diego Dept Pathol La Jolla CA 92093 USA;

    Univ Pittsburgh Med Ctr Div Gastroenterol Hepatol & Nutr Dept Med Pittsburgh Liver Res Ctr Pittsburgh PA USA;

    Univ Autonoma Nuevo Leon Hosp Univ Dept Gastroenterol Monterrey Mexico;

    Columbia Univ Coll Phys & Surg Dept Med Div Digest & Liver Dis 630 W 168th St New York NY 10032 USA;

    Univ Alberta Dept Med Edmonton AB Canada;

    Weill Cornell Med Coll Div Gastroenterol & Hepatol New York NY USA;

    Univ Autonoma Barcelona Hosp Univ Vall dHebron Liver Unit Barcelona Spain|Ctr Invest Red Enfermedades Hepat & Digest CIBERE Barcelona Spain;

    Univ Autonoma Barcelona Hosp Univ Vall dHebron Liver Unit Barcelona Spain;

    Ctr Invest Red Enfermedades Hepat & Digest CIBERE Barcelona Spain|Hosp Clin Barcelona Liver Unit Barcelona Spain;

    Kings Coll London Sch Infect Dis & Microbial Sci Dept Inflammat Biol Liver Sci London England;

    Hop Huriez Serv Malad Lappareil Digestif Lille France|Hop Huriez Unite INSERM Lille France;

    Univ Wisconsin Dept Med Div Gastroenterol & Hepatol Sch Med & Publ Hlth Madison WI USA;

    Yale Univ Sch Med Sect Digest Dis New Haven CT USA|VA Connecticut Healthcare Syst Sect Digest Dis West Haven CT USA;

    Univ Illinois Dept Biochem Urbana IL USA|Univ Illinois Dept Chem Urbana IL USA|Univ Illinois Howard Hughes Med Inst Urbana IL USA;

    Texas A&M Univ Dept Biochem & Biophys College Stn TX 77843 USA|Texas A&M AgriLife Res Ctr Phage Technol College Stn TX USA|Texas A&M Univ College Stn TX USA;

    Catholic Univ Louvain St Luc Univ Hosp Brussels Belgium;

    Univ Calif San Diego Dept Med La Jolla CA 92093 USA|Univ Calif San Diego Dept Pathol La Jolla CA 92093 USA|Univ Calif San Diego Ctr Innovat Phage Applicat & Therapeut La Jolla CA 92093 USA;

    Univ Calif San Diego Dept Med La Jolla CA 92093 USA|VA San Diego Healthcare Syst Dept Med San Diego CA 92161 USA|Univ Calif San Diego Ctr Innovat Phage Applicat & Therapeut La Jolla CA 92093 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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