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Phages Fight Alcoholic Hepatitis

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Phages Fight Alcoholic Hepatitis RESEARCH HIGHLIGHTS LIVER DISEASE Phages fight alcoholic hepatitis Alcoholic hepatitis is a life- Gram-positive bacteria and also from the intestine to the liver, threatening disease, for which eukaryotic cells. The presence resulting in increased levels of current corticosteroid therapy is phage gavage of cytolysin-positive (cytolytic) liver cytolysin. In isolated mouse only mildly effective. Now, writing one day E. faecalis correlated with the severity hepatocytes, cytolysin induced in Nature, Schnabl and colleagues of liver disease and with mortality cell death. demonstrate that bacteriophages prior to an in patients with alcoholic hepatitis: Next, the authors focused their may be harnessed to attenuate ethanol binge 89% of cytolysin-positive patients studies on a strain of mouse (Atp4aSl/Sl ethanol-induced liver disease in decreased liver with alcoholic hepatitis died within mice), which exhibits an overgrowth mice, through modulation of the cytolysin levels 180 days of hospital admission, of intestinal entero cocci, associated gut microbiome. compared with only 3.8% of with increased susceptibility to Previous studies in mice have and abolished cytolysin-negative patients. alcoholic hepatitis. Four phages shown that alcohol-related liver ethanol-induced Next, to determine whether capable of lysing a cytolytic E. faecalis disease can be transmitted via liver injury and cytolysin contributes to liver damage, strain found in the Atp4aSl/Sl mice faecal microbiota. However, little is steatosis the authors gavaged mice with were isolated from sewage water. known about the microorganisms either a cytolytic or non-cytolytic Gavaging Atp4aSl/Sl mice with these and microbial factors that mediate E. faecalis strain and placed them phages resulted in less severe liver this process. on a chronic-binge ethanol diet. injury, steatosis and inflammation To understand this, Schnabl and Those mice receiving cytolytic after chronic ethanol feeding, colleagues first analysed differences E. faecalis exhibited increased compared with mice gavaged in the faecal microbiota composition levels of cytolysin in the liver and with control phages or vehicle. of patients with alcoholic hepatitis developed more severe ethanol- Importantly, the phages significantly or alcohol use disorder compared induced liver injury, increased reduced levels of cytolysin in the with controls. 16S rRNA sequencing hepatic steatosis and increased liver liver as well as faecal amounts of of faecal microbiota revealed a inflammation compared with mice Enterococcus, without affecting the substantial increase in the proportion receiving a non-cytolytic strain. overall composition of the faecal of Enterococcus species in patients Consistent with these findings, microbiome based on 16S rRNA with alcoholic hepatitis, compared with gnotobiotic mice transplanted sequencing analysis. those with alcohol use disorder with faeces from cytolysin-positive Finally, the authors assessed or non-alcoholic control subjects. patients experienced more severe the therapeutic potential of Additional quantitative PCR analysis ethanol-induced liver injury, steatosis, bacteriophages in the treatment indicated an approximate 2,700-fold inflammation and fibrosis, than mice of ethanol-induced liver disease. increase in Enterococcus faecalis in given faeces from cytolysin-negative Cytolytic E. faecalis strains were alcoholic hepatitis faecal samples patients. cultured from faecal samples from compared with controls. Mechanistic studies indicated patients with alcoholic hepatitis E. faecalis secretes a bacterial that ethanol-induced changes in and then lytic phages against these exotoxin, named cytolysin, that the gut barrier likely enable bacterial strains were again isolated exhibits lytic activity against translocation of cytolytic E. faecalis from sewage water. In gnotobiotic mice colonized with faeces from cytolysin-positive patients, phage gavage 1 day before an ethanol binge decreased liver cytolysin levels and abolished ethanol-induced liver injury and steatosis. These findings provide hope of a novel effective therapy for the treatment of alcoholic hepatitis. The authors are currently expanding their biobank of phages against cytolytic isolates from patients with alcoholic hepatitis and have plans for a future phase I safety trial. Sarah Crunkhorn ORIGINAL articLE Duan, Y. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature https://doi.org/10.1038/ s41586-019-1742-x (2019) Credit: Design Cells/iStock/Getty Images Plus Images Cells/iStock/Getty Design Credit: 20 | JANUARY 2020 | VOLUME 19 www.nature.com/nrd.
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